An R201H activating mutation of the GNAS1 (Gsalpha) gene in a corticotroph pituitary adenoma. (1/9)

In the pituitary gland, activating mutations of the GNAS1 (Gsalpha) gene at Gln227 have been identified in adrenocorticotrophin secreting, growth hormone secreting, and prolactin secreting adenomas. To date, mutations at the codon encoding R201, typically underlying the McCune-Albright syndrome and isolated fibrous dysplasia of bone, have been demonstrated only in growth hormone secreting pituitary adenomas. In this study, a polymerase chain reaction amplified target sequence in exon 8 of the GNAS1 gene was sequenced, identifying the first R201 mutation seen in an isolated basophilic adenoma which generated Cushing's disease in a child. This case adds Cushing's disease to the range of human diseases caused by R201 mutations of the GNAS1 gene.  (+info)

A 2-year dose-response study of lesion sequences during hepatocellular carcinogenesis in the male B6C3F(1) mouse given the drinking water chemical dichloroacetic acid. (2/9)

Dichloroacetic acid (DCA) is carcinogenic to the B6C3F(1) mouse and the F344 rat. Given the carcinogenic potential of DCA in rodent liver and the known concentrations of this compound in drinking water, reliable biologically based models to reduce the uncertainty of risk assessment for human exposure to DCA are needed. Development of such models requires identification and quantification of premalignant hepatic lesions, identification of the doses at which these lesions occur, and determination of the likelihood that these lesions will progress to cancer. In this study we determined the dose response of histopathologic changes occurring in the livers of mice exposed to DCA (0.05-3.5 g/L) for 26-100 weeks. Lesions were classified as foci of cellular alteration smaller than one liver lobule (altered hepatic foci; AHF), foci of cellular alteration larger than one liver lobule (large foci of cellular alteration; LFCA), adenomas (ADs), or carcinomas (CAs). Histopathologic analysis of 598 premalignant lesions revealed that (a)) each lesion class had a predominant phenotype; (b)) AHF, LFCA, and AD demonstrated neoplastic progression with time; and (c)) independent of DCA dose and length of exposure effects, some toxic/adaptive changes in non-involved liver were related to this neoplastic progression. A lesion sequence for carcinogenesis in male B6C3F(1) mouse liver has been proposed that will enable development of a biologically based mathematical model for DCA. Because all classes of premalignant lesions and CAs were found at both lower and higher doses, these data are consistent with the conclusion that nongenotoxic mechanisms, such as negative selection, are relevant to DCA carcinogenesis at lower doses where DCA genotoxicity has not been observed.  (+info)

Analysis of pituitary hormones and chromogranin A mRNAs in null cell adenomas, oncocytomas, and gonadotroph adenomas by in situ hybridization. (3/9)

To study the relationship between null cell adenomas, oncocytomas and gonadotroph adenomas, we analyzed 32 surgically removed formalin-fixed paraffin-embedded pituitary tumors for the expression of pituitary hormone messenger RNAs (mRNAs) by in situ hybridization (ISH). Most tumors were also analyzed for chromogranin A mRNA. To identify the cell type constituting the tumors and to assess hormone content, all tumors were investigated by histology, transmission electron microscopy and immunohistochemistry. Most null cell adenomas (6/11) and gonadotroph adenomas (9/10) expressed the mRNAs for alpha-subunit of glycoprotein hormones whereas only 2/11 oncocytomas expressed alpha-subunit mRNA. FSH beta and/or LH beta mRNA were present in most null cell and gonadotroph adenomas but only in a few oncocytomas. Prolactin (PRL) mRNA was detected in two null cell tumors and in one gonadotroph adenoma, whereas GH and POMC mRNA were present in one null cell adenoma. Chromogranin A mRNA, which codes for the major secretory granule protein, was present in 25/26 tumors including all tumors that were negative for pituitary hormone mRNAs, indicating adequate preservation of specific mRNA transcripts in the paraffin-embedded sections of tumor cells. These results indicate that null cell adenomas and gonadotroph adenomas are closely related neoplasms and that oncocytomas may represent a functionally defective form of null cell adenoma characterized by mitochondrial abundance, which has retained the capacity to synthesize the major secretory granule protein chromogranin A. Although the cytogenesis of null cell adenomas and oncocytomas is not clear, it can be suggested that these two tumor types are derived from a pluripotential precursor cell that is capable of undergoing multidirectional differentiation and synthesizing various hormones, mainly glycoproteins.  (+info)

Transcranial management of pituitary tumours with suprasellar extension. (4/9)

A consecutive series of 101 pituitary tumours treated in the 10 year period 1968-78 has been examined, giant lesions being excluded. There were 48 female cases and 53 male, women predominating in the ratio of three to two in the age group 40-50 years and men showing a slight predominance in the age group 50-60 years. Most cases presented with visual deterioration which in 22 cases had been present for between one and two years, and in a further 22 for an even longer period, between two and 10 years. All patients underwent subfrontal craniotomy with mainly radical excision of the tumour followed by radiotherapy. The operative mortality was 0.99%. A system of grading of visual field defect has been described and used to compare preoperatively visual loss with postoperative visual recovery. Fifty-six per cent of cases returned to normal vision over the first two years, and a further 37% showed appreciable improvement in visual fields or acuity or both. Six per cent of cases showed no improvement in visual fields, and one patient died of postoperative deep vein thrombosis and pulmonary embolism. The degree of visual improvement has been correlated with the extent of visual defect, length of visual complaint, and size of the tumour. The importance of central and peripheral visual field analysis is emphasised yet again.  (+info)

Gonadotroph adenomas of the human pituitary: sex-related fine-structural dichotomy. A histologic, immunocytochemical, and electron-microscopic study of 30 tumors. (5/9)

Thirty pituitary tumors, removed from 14 men and 15 women, were diagnosed as gonadotroph adenomas on the basis of their immunocytochemical and/or ultrastructural features. Serum follicle-stimulating hormone (FSH), but not luteinizing hormone (LH), was elevated in 8 men, whereas none of the women had gonadotropin levels, as measured by radioimmunoassay, inappropriately high for their age. Immunoreactive FSH (sometimes also LH) was present in 13 of 15 tumors in men but only 6 of 13 adenomas in women. By electron microscopy, gonadotroph adenomas in men had uncharacteristic features often similar to those of null-cell adenomas with poorly or moderately developed cytoplasmic organelles. In women, all tumors were well differentiated, with a highly distinctive vesicular dilatation of the Golgi complex ("honeycomb Golgi") as a diagnostic marker present in 14 of 15 adenomas. To the author's knowledge, this is the first example of sex-linked dichotomy within a tumor type expressed as the markedly different ultrastructural appearance of cytoplasmic organelles, especially the Golgi apparatus.  (+info)

Cytoplasmic filaments of Crooke's hyaline change belong to the cytokeratin class. An immunocytochemical and ultrastructural study. (6/9)

Crooke's hyaline change was studied by immunocytochemistry using an anti-adrenocorticotropic hormone (ACTH) antiserum and five different antisera against cytokeratins. Crooke's hyaline appears in basophil cells of the adenohypophysis in patients with hypercortisolism, presumably as a part of the negative feedback on corticotropin secretion. Previous studies have identified the hyaline material as a simple protein, apparently unrelated to ACTH, and electron microscopy has revealed a loss of secretory granules and an accumulation of 6-9-nm filaments in the cytoplasm of affected cells. In this study, the secretory granules in adenohypophysial cells exhibiting Crooke's hyaline change were labeled by anti-ACTH antibodies, while the hyaline material was positive for cytokeratin with each of the five antisera used. The results suggest that high levels of glucocorticoids may stimulate elaboration of cytokeratins in basophils while they suppress the production and release of ACTH.  (+info)

Silent corticotropic adenomas of the human pituitary gland: a histologic, immunocytologic, and ultrastructural study. (7/9)

Among 300 surgically removed pituitary adenomas, 17 tumors containing immunoreactive 1-39 adrenocorticotropin (ACTH) and/or 19-39 ACTH, beta-lipotropin, and alpha-endorphin but unassociated with clinical signs of Cushing's disease have been detected. These neoplasms were divided into basophilic adenomas with strong periodic acid-Schiff (PAS) and lead-hematoxylin positivity and chromophobic tumors with moderate or no PAS and lead-hematoxylin positivity. The former were densely granulated tumors with a fine structure strikingly similar to that of functioning corticotropic cell adenomas. The latter were sparsely granulated with varying ultrastructural patterns. The marked morphologic diversity suggests that these adenomas, despite their similar immunocytologic characteristics, represent more than one entity. Clinically, the most common finding was a rapidly progressing visual defect. An unusually high incidence of infarction (5 cases) and recurrence (5 cases) was noted, underlining the importance of correct morphologic diagnosis and careful follow-up.  (+info)

Immunohistochemical and immunoelectron-microscopic study of pituitary adenomas associated with Cushing's disease. A report of 13 cases. (8/9)

Thirteen pituitary adenomas were removed from patients with Cushing's disease by the transphenoidal route. All cases demonstrated a typical histochemical and ultrastructural pattern. Immunocytochemical study by means of the immunoperoxidase technique and light or electron microscopy demonstrated 1-24/1-39 adrenocorticotropic hormone (ACTH) in all cases, lipotropin/melanotropin (beta-LPH/beta-MSH) in 10 cases, beta-endorphin in 8 cases, and an absence of calcitonin in all cases. In addition, in 2 cases tumor tissue contained a few antiprolactin immunoreactive cells. These ACTH, beta-LPH, and beta-endorphin immunoreactivities may reflect either the peptides themselves or their precursors or intermediate products. The authors also suggest a possible intermediate-lobe-like processing of beta-LPH leading to beta-endorphin production, which may act on PRL cells. In addition, no positive arguments for the existence of a common precursor for calcitonin and ACTH could be provided from this study.  (+info)

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