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Objective. We investigated the correlation between immunohistochemical expression of the pituitary tumor transforming gene (PTTG) and pituitary adenoma subtype. Methods. Pituitary adenomas (n = 89) were stained for PTTG using the streptavidin-biotin-peroxidase complex method and a monoclonal PTTG antibody. Results. PTTG staining was found to be cytoplasmic with a pronounced paranuclear expression pattern. Reactivity was highest in growth hormone (GH) adenomas as compared with other tumors, including prolactin (PRL), follicle-stimulating hormone/luteinizing hormone/a subunit, as well as adrenocorticotrophic hormone-secreting adenomas. PRL adenomas exhibited the lowest expression levels. Among GH adenomas, untreated tumors demonstrated significantly higher PTTG levels than octreotide-treated examples. Although dopamine agonist-treated PRL adenomas tended to show lower expression levels, statistical significance was not reached. Conclusions. Our finding that PTTG was differentially expressed in pituitary adenoma subtypes suggests a cellspecific function for PTTG. Moreover, treatment of GH adenomas with somatostatin analogues lowered PTTG expression. Further investigation into mechanisms mediating cell-specific expression of PTTG is warranted. [ABSTRACT FROM AUTHOR]

The sellar region is the site of a large number of pathological entities arising from the pituitary and adjacent anatomical structures, including brain, blood vessels, nerves and meninges. The surgical pathology of this area requires the accurate identification of neoplastic lesions, including pituitary adenoma and carcinoma, craniopharyngioma, neurological neoplasms, germ cell tumours, haematological malignancies and metastases, as well as non-neoplastic lesions such as cysts, hyperplasias and inflammatory disorders. This review provides a practical approach to the diagnosis of pituitary specimens that are sent to the pathologist at the time of surgery. The initial examination requires routine haematoxylin and eosin staining to establish whether the lesion is a primary adenohypophysial proliferation or one of the many other pathologies that occurs in this area. The most common lesions resected surgically are pituitary adenomas. These are evaluated with several special stains and immunohistochemical markers that are now available to accurately classify these pathologies. The complex subclassification of pituitary adenomas is now recognised to reflect specific clinical features and genetic changes that predict targeted treatments for patients with pituitary disorders. [ABSTRACT FROM AUTHOR]

Thyrotropin (TSH)-secreting adenomas are rare and, as most adenomas are large, invasive and difficult to cure by surgery only, many require additional medical treatment. Many TSH-secreting adenomas cosecrete growth hormone (GH) and/or prolactin (PRL). We evaluated the relationship between pathology and the effect of dopamine agonist bromocriptine and somatostatin analogue octreotide in 20 operated patients with TSH-secreting adenomas. The four men and 16 women ranged in age from 23 to 62 years; three had clinically overt acromegaly; two manifested galactorrhea-amenorrhea. Endocrinologically, elevated serum GH, and/or IGF-1 were observed in six patients and elevated serum PRL was observed in eight. Immunohistochemically, 16 of the 20 adenomas were positive for GH and/or PRL (GH-positive, n=13; PRL-positive, n=9). Pituitary-specific transcription factor Pit-1 was demonstrated in the nuclei of all adenoma cells. Octreotide tests showed suppression of serum TSH (<50%) in ten of 14 patients. Preoperative octreotide treatment effectively reduced serum TSH and tumor size in two patients. Electron micrographs of octreotide-treated TSH-secreting adenomas showed shrinkage of the cytoplasm and diffuse distribution of secretory granules. Our study suggests that cosecretion of GH and/or PRL from TSH-secreting adenoma has no correlation with response of tumor cells to medical treatment. [ABSTRACT FROM AUTHOR]

Ultrastructural and immunocytochemical observations of pituitary folliculo-stellate cells (FSC) in a large series of adenomatous and nontumorous human pituitaries led to the following conclusions: (1) The endocrine cells of both the nontumorous and the adenomatous pituitary are capable of transforming into FSC while changing from endocrine to nonendocrine phenotype. (2) As shown on consecutive sections in prolactin cell adenomas with FSC-rich areas including microcyst formation, S-100 protein and glial fibrillary acidic protein (GFAP) immunoreactivities are strongest in the smallest newly formed follicles. The 2 immunoreactivities do not overlap. The epithelium of older microcysts is immunonegative, implying that expression of the 2 markers is restricted to the early phase of FSC formation. (3) Transformation of endocrine cells into FSC may signify retrodifferentiation into their Rathke's pouch derived precursors as suggested by occasional presence of ciliated and/or mucin producing cells in the lining of microcysts. (4) In lymphocytic hypophysitis a marked activation as well as increase of number and size of FSC are evident in areas of ongoing immune destruction supporting their immune role. (5) Considering the multifaceted nature of FSC, it is suggested that they represent a type of pluripotent adult stem cell. [ABSTRACT FROM AUTHOR]

Summary. p21/WAF1 blocks cell cycle progression through inhibition of cyclin/cyclin-dependent kinases (cdks) complexes and, simultaneously, has been associated with cell cycle exit and the process of differentiation. In this series, the expression of p21/WAF1 was assessed immunohistochemically in 47 cases of pituitary adenomas in relation to endocrine activity and cell proliferation. To evaluate cell proliferation, a monoclonal antibody, MIB-1, against Ki-67 antigen was used in all of the available cases. The study revealed positive p21/WAF1 staining in 24 cases of 26 functioning parenchymas, whereas 14 cases of 21 non-functioning parenchymas stained negative. The MIB-1 index ranged from less than 1% to 5.1% (mean: less than 1.7%) in functioning adenomas, and from less than 1% to 3.6% (mean: less than 1.6%) in non-functioning adenomas. Regardless of endocrine activity, p21/WAF1 positivity did not correlate with the MIB-1 index. Double staining techniques revealed the co-expression of p21/WAF1/GH or p21/WAF1/PRL in functioning adenomas. In 22 cases of p21/WAF1-positive functioning adenomas, p21/WAF1 immunoreactivity was seen in the cytoplasma as well as nuclei. These results indicate that in pituitary adenomas, p21/WAF1 expression is associated with endocrine activity, but not with cell proliferation. Taken together with recent findings demonstrating that cytoplasmic p21/WAF1 acts as an inhibitor of apoptosis, it is possible that pituitary adenomas expressing cytoplasmic p21/WAF1 have resistance against DNA-damaging agents such as ionizing radiation. [ABSTRACT FROM AUTHOR]

Ultrastructurally, the antigenicity of major pituitary hormones in secretory granules was quantitatively investigated in five growth hormone (GH)-secreting adenomas, five prolactin (PRL)-secreting adenomas and eight clinically non-functioning (CN-F) adenomas. Sparsely granulated cells with a few or several small secretory granules (60–100 nm) exhibiting little or only weak antigenicity of various biochemically unrelated hormones were commonly observed in CN-F adenomas and occasionally in GH- and PRL-secreting adenomas. GH- or PRL-secreting adenomas consisted of many densely granulated cells with medium-sized (200–250 nm) or large (over 250 nm) secretory granules and a few or several sparsely granulated cells with small secretory granules. The densely granulated cells showed intense GH or PRL antigenicity and slight to moderate antigenicity for other hormones in large secretory granules and little or only weak antigenicity for various hormones including GH or PRL in small secretory granules. Their secretory granules larger than 160 nm or 140 nm significantly exhibited intense GH or PRL antigenicity (Fisher’s exact test; P < 0.05 and < 0.01, respectively). Two CN-F adenomas showed sparsely and densely granulated cells as well as intermediate cells. The densely granulated cells closely resembled GH-secreting cells. The intermediate cells simultaneously included small and medium-sized or large secretory granules exhibiting little/slight and intense GH-antigenicity, respectively. This study indicates that sparsely granulated cells of different categories showing slight antigenicity for various hormones, antigenically share the same origin, and that their hormonality, single or multiple, may be selectively activated in the developmental course of secretory granules. [ABSTRACT FROM AUTHOR]

The pituitary-specific transcriptional factor Pit-1 is known to play a role in the development and differentiation of pituitary cells. Recent investigations have suggested a role for this transcriptional factor in pituitary adenomas, especially growth hormone (GH)- and prolactin (PRL)-secreting pituitary adenomas. In this study we analyzed the expression of Pit-1 mRNA and its protein in 24 clinically nonfunctioning pituitary adenomas in comparison with normal pituitary glands using in situ hybridization (ISH) and immunohistochemistry (IHC). The interaction between inhibin/activin, a member of the transforming growth factor-β family, and Pit-1 was also studied. Immunohistochemically, Pit-1 protein was detected in 9 of 24 adenomas (37.5%), and 8 of these 9 were also positive for the α subunit of glycoprotein (αSU). The expression of Pit-1 mRNA was detected in 14 of 24 (58.3%) clinically nonfunctioning adenomas, and it was found in all cases which expressed the Pit-1 protein. By the combined ISH and IHC method, Pit-1 mRNA was frequently observed in αSU-immunopositive cells in adenomas. The inhibin/activin α subunit was detected in all 24 adenomas and the βA subunit was detected in 13 of 24 adenomas. The inhibin/activin βA subunit was detected frequently with Pit-1 mRNA. From our observations, the inhibin/activin βA subunit in nonfunctioning adenomas may have related the expression of Pit-1 mRNA in these adenomas. [ABSTRACT FROM AUTHOR]

To compare the pituitary pathology of gigantism to that of acromegaly, 19 surgically resected lesions were studied from 10 males and 9 females, ages 13-49 (mean, 19 yr) with excessive height (≥95th percentile), onset of disease prior to puberty, elevated growth hormone (GH) levels despite glucose suppression, and a pathologically confirmed GH-producing pituitary mass. One patient had MEN-I. The lesions included 18 adenomas and 1 case of pure hyperplasia. The median, mean, and range of serum GH and prolactin (PRL) levels were 64, 235, 5-1000 ng/mL and 47, 146, 29-770 ng/mL, respectively. Of the 8 adenoma specimens accompanied by nontumoral pituitary (i.e., tissue wherein the presence of hyperplasia was assessable), 3 (37%) demonstrated both. Of the 18 tumors, 78% were macroadenomas and 22% were grossly invasive; their immunophenotypes included GH (5%), GH and PRL (19%), and GH-PRL and a glycoprotein hormone, usually TSH and/or α-subunit (76%). Of the 10 adenoma-containing lesions subject to electron microscopy (EM), 2 consisted of GH cells alone; 2 of mammosomatotroph (MS) cells alone; 1 of GH and MS cells; 1 of GH and PRL cells; 2 of GH, PRL, and MS cells; 1 of GH, PRL, and glycoprotein cells; and 1 was a subtype 3 adenoma. Ultrastructurally, GH cells and/or MS cells predominated in these lesions. Immuno-EM of one GH and PRL cell and of one GH-PRL-MS tumor showed GH and PRL to be present not only in single cells but within the same granules. Nine of 12 adenoma-associated lesions subject to combined in situ hybridization (ISH) and immunostaining showed double labeling for PRL (or GH) mRNA and for GH (or PRL), respectively, features indicating MS differentiation. In the 4 lesions exhibiting hyperplasia, either alone (1) or in association with adenoma (3), EM showed MS cells in 3, and immuno-EM as well as combined immunohistochemistry and ISH showed double labeling for GH and PRL in both of the 2 cases studied. In summary, although in terms of their tinctorial characteristics and tumor size, the lesions of giants resemble those of acromegalics, those of the former are less often invasive and glycoprotein hormone containing, and more often contain ultrastructurally distinctive MS cells. The high frequency of adenoma with hyperplasia (37%) and the occurrence of hyperplasia alone (6%) is of particular notice since this finding is rare in patients with acromegaly. Hyperplasia is, however, seen in ectopic GH-releasing hormone production and the McCune-Albright syndrome. We conclude that the presence of MS is not rare in the pituitary lesions of patients with gigantism. Their presence may be a reflection of either hypothalamic dysfunction or of an intrinsic abnormality of pituitary cells. [ABSTRACT FROM AUTHOR]

Ectopic pituitary adenoma with an empty sella is extremely rare. We report an unusual patient with an ectopic growth hormone-secreting pituitary adenoma in the sphenoid sinus with an empty sella. The association is related to a development disorder of the anterior pituitary tissues. Tumor in the sphenoid sinus was completely removed by endoscopic endonasal transsphenoidal approach. During the follow-up, the patient met the criteria for endocrinological cure. [ABSTRACT FROM AUTHOR]