Abundant immunohistochemical expression of dopamine D2 receptor and p53 protein in meningiomas: follow-up, relation to gender, age, tumor grade, and recurrence

Meningiomas are common, usually benign tumors, with a high postoperative recurrence rate. However, the genesis and development of these tumors remain controversial. We aimed to investigate the presence and implications of a mutated p53 protein and dopamine D2 receptor in a representative series of meningiomas and to correlate these findings with age, gender, tumor grade, and recurrence. Tumor tissue samples of 157 patients diagnosed with meningioma (37 males and 120 females, mean age 53.6±14.3 years) who underwent surgical resection between 2003 and 2012 at our institution were immunohistochemically evaluated for the presence of p53 protein and dopamine D2 receptor and were followed-up to analyze tumor recurrence or regrowth. Tumors were classified as grades I (n=141, 89.8%), II (n=13, 8.3%), or grade III (n=3, 1.9%). Dopamine D2 receptor and p53 protein expression were positive in 93.6% and 49.7% of the cases, respectively. Neither of the markers showed significant expression differences among different tumor grades or recurrence or regrowth statuses. Our findings highlight the potential role of p53 protein in meningioma development and/or progression. The high positivity of dopamine D2 receptor observed in this study warrants further investigation of the therapeutic potential of dopamine agonists in the evolution of meningiomas.

Abundant immunohistochemical expression of dopamine D2 receptor and p53 protein in meningiomas: follow-up, relation to gender, age, tumor grade, and recurrence.

Meningiomas are common, usually benign tumors, with a high postoperative recurrence rate. However, the genesis and development of these tumors remain controversial. We aimed to investigate the presence and implications of a mutated p53 protein and dopamine D2 receptor in a representative series of meningiomas and to correlate these findings with age, gender, tumor grade, and recurrence. Tumor tissue samples of 157 patients diagnosed with meningioma (37 males and 120 females, mean age 53.6 ± 14.3 years) who underwent surgical resection between 2003 and 2012 at our institution were immunohistochemically evaluated for the presence of p53 protein and dopamine D2 receptor and were followed-up to analyze tumor recurrence or regrowth. Tumors were classified as grades I (n=141, 89.8%), II (n=13, 8.3%), or grade III (n=3, 1.9%). Dopamine D2 receptor and p53 protein expression were positive in 93.6% and 49.7% of the cases, respectively. Neither of the markers showed significant expression differences among different tumor grades or recurrence or regrowth statuses. Our findings highlight the potential role of p53 protein in meningioma development and/or progression. The high positivity of dopamine D2 receptor observed in this study warrants further investigation of the therapeutic potential of dopamine agonists in the evolution of meningiomas.

Male gonadal function, prolactin secretion and lactotroph population in an experimental model of cirrhosis

Liver cirrhosis, a highly prevalent chronic disease, is frequently associated with endocrine dysfunctions, notably in the gonadal axis. We evaluated lactotroph population by immunohistochemistry, gonadotropins and prolactin by immunoradiometric assay and testosterone and estradiol by radioimmunoassay in adult male Wistar rats with cirrhosis induced by carbon tetrachloride. No significant difference in mean ± SEM percentages of lactotrophs was found between cirrhotic animals and controls (N = 12, mean 18.95 ± 1.29 percent). Although there was no significant difference between groups in mean serum levels of prolactin (control: 19.2 ± 4 ng/mL), luteinizing hormone (control: 1.58 ± 0.43 ng/mL), follicle-stimulating hormone (control: 19.11 ± 2.28 ng/mL), estradiol (control: 14.65 ± 3.22 pg/mL), and total testosterone (control: 138.41 ± 20.07 ng/dL), 5 of the cirrhotic animals presented a hormonal profile consistent with hypogonadism, all of them pointing to a central origin of this dysfunction. Four of these animals presented high levels of estradiol and/or prolactin, with a significant correlation between these two hormones in both groups (r = 0.54; P = 0.013). It was possible to detect the presence of central hypogonadism in this model of cirrhotic animals. The hyperestrogenemia and hyperprolactinemia found in some hypogonadal animals suggest a role in the genesis of hypogonadism, and in the present study they were not associated with lactotroph hyperplasia.

Male gonadal function, prolactin secretion and lactotroph population in an experimental model of cirrhosis.

Liver cirrhosis, a highly prevalent chronic disease, is frequently associated with endocrine dysfunctions, notably in the gonadal axis. We evaluated lactotroph population by immunohistochemistry, gonadotropins and prolactin by immunoradiometric assay and testosterone and estradiol by radioimmunoassay in adult male Wistar rats with cirrhosis induced by carbon tetrachloride. No significant difference in mean +/- SEM percentages of lactotrophs was found between cirrhotic animals and controls (N = 12, mean 18.95 +/- 1.29%). Although there was no significant difference between groups in mean serum levels of prolactin (control: 19.2 +/- 4 ng/mL), luteinizing hormone (control: 1.58 +/- 0.43 ng/mL), follicle-stimulating hormone (control: 19.11 +/- 2.28 ng/mL), estradiol (control: 14.65 +/- 3.22 pg/mL), and total testosterone (control: 138.41 +/- 20.07 ng/dL), 5 of the cirrhotic animals presented a hormonal profile consistent with hypogonadism, all of them pointing to a central origin of this dysfunction. Four of these animals presented high levels of estradiol and/or prolactin, with a significant correlation between these two hormones in both groups (r = 0.54; P = 0.013). It was possible to detect the presence of central hypogonadism in this model of cirrhotic animals. The hyperestrogenemia and hyperprolactinemia found in some hypogonadal animals suggest a role in the genesis of hypogonadism, and in the present study they were not associated with lactotroph hyperplasia.

Expression of p53 protein in pituitary adenomas.

Inactivating mutations of TP53, a tumor suppressor gene, are associated with abnormal cell proliferation. Although p53 expression is common in many human malignancies, p53 protein has seldom been evaluated in pituitary tumors. When detected, the percentage of p53-positive cells is low, and, in general, it is exclusive for invasive lesions. The aim of the present study was to use immunohistochemistry to determine the presence of p53 protein in pituitary adenomas from tumor samples of 163 surgeries performed in 148 patients (40% male, 60% female). In 35% of the cases the adenoma was nonfunctional, while in the others it was associated with PRL, GH and/or ACTH endocrine hypersecretion syndrome. Macroadenomas were observed in 83.2% of the cases with available neuroimage evaluation, of which 28% invaded the cavernous, sphenoid and/or ethmoidal sinus, bone, third ventricle or subfrontal lobe. p53 protein was detected in 2/148 patients (1.3%). Immunohistochemistry was positive for PRL and GH in these cases. Due to the high percentage of invasive pituitary adenomas found in our study, the low frequency of p53 detection suggests that it is inadequate as a routine marker for aggressiveness and as a predictive factor of tumor behavior.

Expression of p53 protein in pituitary adenomas

Inactivating mutations of TP53, a tumor suppressor gene, are associated with abnormal cell proliferation. Although p53 expression is common in many human malignancies, p53 protein has seldom been evaluated in pituitary tumors. When detected, the percentage of p53-positive cells is low, and, in general, it is exclusive for invasive lesions. The aim of the present study was to use immunohistochemistry to determine the presence of p53 protein in pituitary adenomas from tumor samples of 163 surgeries performed in 148 patients (40 percent male, 60 percent female). In 35 percent of the cases the adenoma was nonfunctional, while in the others it was associated with PRL, GH and/or ACTH endocrine hypersecretion syndrome. Macroadenomas were observed in 83.2 percent of the cases with available neuroimage evaluation, of which 28 percent invaded the cavernous, sphenoid and/or ethmoidal sinus, bone, third ventricle or subfrontal lobe. p53 protein was detected in 2/148 patients (1.3 percent). Immunohistochemistry was positive for PRL and GH in these cases. Due to the high percentage of invasive pituitary adenomas found in our study, the low frequency of p53 detection suggests that it is inadequate as a routine marker for aggressiveness and as a predictive factor of tumor behavior

[Neuropathology of hard to control epilepsy. Study of 300 consecutive cases]. / Neuropatologia das epilepsias de difícil controle. Estudo de 300 casos consecutivos.

We report histopathological findings in 300 consecutive surgical specimens from epilepsy surgery during 6 years. Our material was mainly from temporal lobe epilepsy (70.33%). In 44% the diagnosis was hippocampal sclerosis. There were tumors in 15% of cases and neuronal migration disorders in 10%. The most common tumors were gangliogliomas (42.22%) and dysembryoplastic neuroepithelial tumors (20%). We review the more frequent diagnosis in epilepsy surgery based on this series and comparing with literature.

Meningiomas and hormonal receptors. Immunohistochemical study in typical and non-typical tumors.

The authors assessed 116 cases of meningiomas classified as typical, atypical and anaplastic and they used an immunohistochemical technique for estrogen and progesterone receptors attempting to determine if there is any difference between typical and non-typical tumors in relation to hormone receptors. The immunohistochemical technique to estrogen receptors was negative in all meningiomas studied. Progesterone receptors were detected in 58.3% of typical, and in 48.2% of non-typical meningiomas. This difference was not statistically significant. However, individually considering the criteria used for selection of non-typical tumours, those that concurrently displayed brain invasion and increased mitotic activity or necrosis, as well as the summation of those three features, were predominantly negative for progesterone receptors (respectively p = 0.038; p = 0.001; and p = 0.044). The authors conclude that estrogen receptors were not present in meningiomas; that progresterone receptors in isolation are not enough to predict a higher tumoral malignancy but can be useful associated with other histological features.

[Changes found in the brain of people over 65 years old and their correlation with Alzheimer disease]. / Alterações encontradas em cérebros de indivíduos acima dos 65 anos e sua correlação com demência de Alzheimer.

Twelve brains of individuals with more than sixty-five years were studied. These samples were submitted to three techniques, with the objective to detect senile plaques which the major component was the beta-amyloid; beta-amyloid immunohistochemistry; Glees technique; and haematoxilin-eosin technique. We detected significant differences between the number of senile plaques found in different techniques. beta-amyloid immunohistochemistry was more efficient. This is very important because we can underdiagnosis Alzheimer's disease when the most adequate technique is not used. The statistical analysis showed no significant differences neither between the number of cortical plaques and the hipocampal plaques, nor between the number of plaques in both hemispheres. A literature review about neuropathological findings and beta-amyloid importance was done.

Effects of bromocriptine on serum prolactin levels, pituitary weight and immunoreactive prolactin cells in estradiol-treated ovariectomized rats: an experimental model of estrogen-dependent hyperprolactinemia.

The present study was designed to assess the effects of bromocriptine, a dopamine agonist, on pituitary wet weight, number of immunoreactive prolactin cells and serum prolactin concentrations in estradiol-treated rats. Ovariectomized Wistar rats were injected subcutaneously with sunflower oil vehicle or estradiol valerate (50 or 300 micrograms/rat(-1) week (-1) for 2, 4, or 10 weeks. Bromocriptine (0.2 or 0.6 mg rat (-1) day (-1)) was injected daily during the last 5 or 12 days of estrogen treatment. Data were compared with those obtained for intact control rats. Administration of both doses of estrogen increased serum prolactin levels. No difference in the number of prolactin cells in rats treated with 50 micrograms estradiol valerate was observed compared to intact adult animals. In contrast, rats treated with 300 micrograms estradiol valerate showed a significant increase in the number of prolactin cells (P < 0.05). Therefore, the increase inn serum prolactin levels observed in rats treated with 50 micrograms estradiol valerate, in the absence of morphological changes in the pituitary cells, suggests a "functional" estrogen-induced hyperprolactinemia. Bromocriptine decreased prolactin levels in all estrogen-treated rats. The administration of this drug to rats previously treated with 300 micrograms estradiol valerate also resulted in a significant decrease in pituitary weight and number of prolactin cells when compared to the group treated with estradiol alone. The general antiprolactinemic and antiproliferative pituitary effects of bromocriptine treatment reported here validate the experimental model of estrogen-induced hyperprolactinemic rats.

Aversive stimulation during the stress-hyporesponsive period does not affect the number of corticotroph cells in neonatal male rats.

Immunohistochemistry was used to evaluate the effects of neonatal handling and aversive stimulation during the first 10 days of life on the number of corticotrophs in the anterior lobe of the pituitary of 11-day-old male Wistar rats. Since adult rats handled during infancy respond with reduced corticosterone secretion in response to stressors and with less behavior inhibition in novel environments, we assumed that neonatal stimulation could affect pituitary morphology during this critical period of cell differentiation. Three groups of animals were studied: intact (no manipulation, N = 5), handled (N = 5) and stimulated (submitted to 3 different aversive stimuli, N = 5). The percentage of ACTH-immunoreactive cells in the anterior lobe of the pituitary (number of ACTH-stained cells divided by total number of cells) was determined by examining three slices per pituitary in which a minimum of 200 cells were counted by two independent researchers. Although animals during the neonatal period are less reactive to stress-like stimulation in terms of ACTH and corticosterone secretion, results showed that the relative number of ACTH-stained cells of neonatal handled (0.25 +/- 0.01) and aversive stimulated (0.29 +/- 0.03) rats was not significantly different from intact (0.30 +/- 0.03) animals. Neonatal stimulation may have a differential effect on the various subpopulations of corticotroph cells in the anterior pituitary.

[Meningiomas. Histopathological aspects and recurrence]. / Meningeomas. Aspectos histopatológicos e recidiva.

The authors assessed 246 cases of meningiomas that were classified as typical, atypical, anaplastic and papillary, according to previously defined criteria. Among the criteria used to define non-typical tumours, brain invasion was predominant in 62.3%. Meningiomas were typical in 75.22%, atypical in 19.1%, anaplastic in 5.68% of the cases. There was recurrence in 3.78% of typical, 42.55% of atypical and 45.45% of anaplastic. The authors conclusion was that the criteria used to define typical and non-typical were adequate to predict a higher chance to tumour recurrences

Effect of estrogen and neuroleptics on prolactin secretion and immunoreactive prolactin cells.

The use of estrogen and dopamine receptor antagonists is associated with elevated prolactin levels and, in rats, chronic estrogen treatment is also associated with lactotroph proliferation. In this study, haloperidol, fluphenazine, sulpiride and metoclopramide, alone or combined with estradiol, were administered to Wistar rats. Pituitary weight, serum prolactin levels and percent of immunoreactive prolactin cells in the anterior pituitary glands were determined at the end of 60 days of treatment. The pituitary weight of rats treated with estrogen alone or in combination with other drugs was significantly higher than the control group. The serum prolactin level was higher than the upper confidence limit in all but three of the 90 treated rats. While in the control group the percent of immunoreactive prolactin cells was 20%, administration of the neuroleptic drugs and metoclopramide increased this percent to approximately 30%, and estrogen alone or in combination with one of the neuroleptic drugs increased it to approximately 40%. The results presented here demonstrate the relationship between prolactin secretion and prolactin cell number when different neuroleptics and related drugs are used.

Effects of tamoxifen on serum prolactin levels, pituitary immunoreactive prolactin cells and uterine growth in estradiol-treated ovariectomized rats.

Pituitary effects of the antiestrogen tamoxifen are not well established, although estrogen is known to have a stimulatory role in prolactin secretion. Effects of tamoxifen on serum prolactin levels, pituitary wet weight and number of prolactin cells were studied. Ovariectomized female Wistar rats were injected, subcutaneously, with estradiol valerate, 50 or 300 micrograms/rat per week for 2 or 10 weeks. Tamoxifen was injected during the last days of estrogen treatment. Data were compared with two other groups, treated with estradiol valerate alone or estradiol valerate plus the dopamine agonist bromocriptine. Serum prolactin levels were increased by estrogen treatment with all doses used. Furthermore, rats treated with 300 micrograms of estradiol valerate, for 2 and 10 weeks, showed a clear increase in pituitary weight and number of prolactin cells (p < 0.05). Bromocriptine decreased prolactin levels, pituitary weight and the number of prolactin cells (p < 0.05). Tamoxifen associated to subacute period of estrogen administration resulted in a significant reduction of serum prolactin levels and pituitary weight (p < 0.05). No effects on prolactin levels or number of prolatin cells were observed with tamoxifen associated to chronic estrogen treatment. Tamoxifen also presented a dose-related inhibitory effect upon estrogen-stimulated rises in uterine weight and DNA content. In conclusion, the results of the present paper showed that tamoxifen reduced estrogen-stimulated prolactin levels in some, but not in other hormonal conditions and that these effects were not mediated by an inhibition of lactotroph cell growth. Further studies are needed to define the exact role of antiestrogens at molecular level in hyperprolactinemic states and their eventual connection with dopamine and its agonists.

Effect of estrogen and neuroleptics on prolactin secretion and immunoreactive prolactin cells

The use of estrogen and dopamine receptor antagonists is associated with elevated prolactin levels and, in rats, chronic estrogen treatment is also associated with lactotroph proliferation. In this study, haloperidol, fluphenazine, sulpiride and metoclopramide, alone or combined with estradiol, were administered to Wistar rats. Pituitary weight, serum prolactin levels and percent of immunoreactive prolactin cells in the anterior pituitary glands were determined at the end of 60 days of treatment. The pituitary weight of rats treated with estrogen alone or in combination with other drugs was significantly higher than the control group. The serum prolactin level was higher than the upper confidence limit in all but three of the 90 treated rats. While in the control group the percent of immunoreactive prolactin cells was 20 per cent, administration of the neuroleptic drugs and metoclopramide increased this percent to approximately 30 per cent, and estrogen alone or in combination with one of the neuroleptic drugs increased it to approximately 40 per cent. The results presented here demonstrate the elationship between prolactin secretion and prolactin cell number when different neuroleptics and related drugs are used.

Effects of norethisterone acetate and tamoxifen on serum prolactin levels, uterine growth and on the presence of uterine immunoreactive prolactin in estradiol-treated ovariectomized rats.

The aim of the present work was to study the effects of the antiestrogen tamoxifen (TAM), of progestin norethisterone acetate (NA) and of their combination on serum prolactin levels, uterine growth and the presence of uterine immunoreactive prolactin in estradiol-treated rats. Ovariectomized female Wistar rats were injected sc with estradiol valerate (VE, 50 micrograms/rat per week) or oil vehicle. During the second week, estradiol-treated rats also received NA (0.12 or 1.0 mg/rat, sc, daily) or TAM (0.06 mg/rat) alone or in combination with NA (0.12 mg). Serum prolactin levels were suppressed to the same extent in the TAM- and 1.0 mg NA-treated groups compared with rats given estrogen alone (2.3 +/- 0.3 and 5.6 +/- 1.5 ng/ml for TAM and NA groups vs 39.7 +/- 3.6 ng/ml for VE groups, P < 0.05). Except for the lowest dose of NA, uterine wet weight and DNA content were significantly reduced in all groups compared to estradiol alone (236.8 +/- 18.0 and 295.6 +/- 27.8 mg vs 309.4 +/- 32.2 mg for uterine weight in TAM and NA groups vs VE, respectively, P < 0.05; and 1.14 +/- 0.05 and 0.93 +/- 0.04 mg/uterus vs 1.33 +/- 0.06 mg/uterus for uterine DNA in TAM and NA groups vs VE groups). The combination of NA and TAM resulted in a higher degree of suppression of uterine growth than when each drug was used alone, indicating an additive antiproliferative effect of NA and TAM. Although no prolactin immunostaining was detected in the uterus of rats treated with estradiol, uterine immunoreactive prolactin was identified in those treated with NA, TAM or both.(ABSTRACT TRUNCATED AT 250 WORDS)

[Holoprosencephaly: study of 6 cases]. / Holoprosencefalia. Estudo de seis casos.

The aim of this study is to classify and analyse macroscopic aspects of the brain and facies in holoprosencephaly. The six cases reported were examined at the Department of Pathology of FFFCMPA. Data observed in this study are compared to those registered in the literature.

[Neonatal encephalitis caused by herpes simplex: immunohistochemical diagnosis of a case]. / Encefalite neo-natal pelo vírus do herpes simplex: diagnóstico imuno-histoquímico de um caso.

The authors report the case of a female newborn infant, who had seizures and vesicles at the nose and inferior lip since the fifth day of life. CSF changes suggested an encephalitis. Signs of neurologic and respiratory deterioration were followed by death. Partial cranial autopsy showed a necrohemorrhagic temporal encephalitis without intranuclear inclusions. Immunohistochemical examination by the avidin-biotin-peroxidase technique with polyclonal antibodies against Herpes simplex type 1 and type 2 was positive to type 2 Herpes simplex virus.

[Macroprolactinoma at 6 years of age: diagnostic difficulties]. / Macroprolactinoma aos 6 anos de idade. Dificuldades diagnósticas.

Prolactinoma is rare in childhood and adolescence. The earliest known diagnosis was reported in a patient at 8 years of age. We report the case of a sellar tumor found in a 6 years old girl. After a long symptomatic period she was brought for treatment. At this time she had partial papillar atrophy, hyperprolactinemia, and diminished reserve of growth hormone and cortisol. Due to rapid visual deterioration, she was submitted to a frontotemporal craniotomy for suspected craniopharyngioma. The tumor tissue immunohistochemistry was positive for prolactin. It is concluded that prolactinoma must be considered in differential diagnosis of sellar tumors in childhood since it benefits from a less aggressive therapy.