Shigeyuki Tahara

DNA Mismatch Repair Protein (MSH6) Correlated With the Responses of Atypical Pituitary Adenomas and Pituitary Carcinomas to Temozolomide: The National Cooperative Study by the Japan Society for Hypothalamic and Pituitary Tumors

CONTEXT Temozolomide (TMZ) is an alkylating agent and was a first-line chemotherapeutic agent for malignant gliomas. Recently, TMZ has been documented to be effective against atypical pituitary adenomas (APAs) and pituitary carcinomas (PCs). OBJECTIVE The clinical and pathological characteristics of APAs and PCs treated with TMZ in Japan were surveyed and analyzed retrospectively. DESIGN Members of the Japan Society of Hypothalamic and Pituitary Tumors were surveyed regarding the clinical characteristics of APAs and PCs treated with TMZ. Stored tumor samples were gathered from the responders and were assessed by the immunohistochemistry of Ki-67, O(6)-methyl-guanine-DNA methyltransferase, p53, MSH6, and anterior pituitary hormones. Responses to TMZ treatment were defined as complete response (CR), partial response (PR), progressive disease (PD), and stable disease (SD) according to RECIST (Response Evaluation Criteria in Solid Tumors) version 2.0. SUBJECTS Three samples from 3 subjects with APA and 11 samples from 10 subjects with PC were available. RESULTS The 13 subjects had APAs and PCs consisting of 5 prolactin-producing tumors, 5 ACTH-producing tumors, and 3 null cell adenomas. The clinical response to TMZ treatment was as follows: 4 cases of CR and PR (31%), 2 cases of SD (15%), 6 cases of recurrence after CR and PR (46%), and 1 case of PD (8%). However, considerable subjects had recurrent disease after a response to TMZ. The immunohistochemical findings of Ki-67, O(6)-methyl-guanine-DNA methyltransferase, and p53 did not show any significant correlation with the efficacy of TMZ. However, the immunopositivity of MSH6 was positively correlated with TMZ response (P = .015, Fishers exact test). CONCLUSIONS This study showed that preserving MSH6 function was contributory to the effectiveness of TMZ in malignant pituitary neoplasms. It is necessary to survey more cases and evaluate multifactor analyses.

Expression of Ptx1 in the adult rat pituitary glands and pituitary cell lines: hormone-secreting cells and folliculo-stellate cells.

Abstract The pituitary homeobox1 gene (Ptx1) was initially identified as encoding a pituitary-restricted transcription factor for the proopiomelanocortin (POMC) gene. In order to elucidate the expression pattern of the Ptx1 protein, we investigated the localization of the protein in adult rat pituitary gland and in various pituitary cell lines. We produced an antibody specific for Ptx1 protein, and confirmed its specificity by Western blot analysis. Immunohistochemically, many nuclei in the anterior pituitary cells as well as in the intermediate cells were positive for Ptx1 staining with this specific antibody. Immunohistochemical double staining revealed the presence of Ptx1 not only in all types of hormone-secreting cells but also in some folliculo-stellate (FS) cells. Furthermore, the expression of Ptx1 mRNA was confirmed in various pituitary cell lines and in the FS cell line by using the reverse transcriptase-polymerase chain reaction (RT-PCR) method. Our studies indicated that Ptx1 may not only play a role as a basic transcriptional factor for production of various hormones, but may also play some important role(s) in FS cells. Possible synergistic actions with other factors remain to be investigated. The novel finding of Ptx1 in FS cells is of particular interest, and may suggest that FS cells and hormone-secreting cells are derived from a common cellular ancestor.

A case of IgG4-related hypophysitis without pituitary insufficiency.

CONTEXT IgG4-related hypophysitis is a novel clinical disease entity, which is typically complicated by hypopituitarism. OBJECTIVE The objective of the study was to describe a novel case of IgG4-related hypophysitis without pituitary insufficiency and summarize the current relevant literature. PATIENT AND METHODS A 55-year-old Japanese man presented with an enlarged pituitary gland and bitemporal hemianopsia. Endocrine studies revealed normal pituitary function, although his serum IgG4 level was high. The patient underwent a transsphenoidal biopsy of the pituitary gland, and the pathological tissues were consistent with IgG4-related hypophysitis. Oral prednisolone therapy was started, and after 6 months, his serum IgG4 level decreased and visual field improved. CONCLUSION We described the first case of IgG4-related hypophysitis without pituitary insufficiency. However, further case collection is needed to characterize the pathophysiology of IgG4-related hypophysitis.

Expression of Pit-1 mRNA and Activin/Inhibin Subunits in Clinically Nonfunctioning Pituitary Adenomas

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.

Pathological study of thyrotropin-secreting pituitary adenoma: plurihormonality and medical treatment

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.

A case of Cushing's disease caused by pituitary adenoma producing adrenocorticotropic hormone and growth hormone concomitantly: aberrant expression of transcription factors NeuroD1 and Pit-1 as a proposed mechanism.

A 53-year-old Japanese woman was diagnosed with Cushings disease caused by a adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma on the basis of clinical an imaging data. The surgically resected tumor tissue was investigated histopathologically using immunohistochemical analysis of pituitary hormones. Our study revealed that the adenoma expressed not only ACTH but growth hormone (GH) in the tumor cells. Furthermore, immunohistochemical double staining showed that some adenoma cells were positive for both ACTH and GH. In situ hybridization for GH mRNA revealed that the adenoma cells produced GH as opposed to simply storing it. Although many pituitary adenomas produce multiple pituitary hormones, pituitary adenoma producing both ACTH and GH in the same adenoma cells, such as seen in this case, is extremely rare. To elucidate the molecular mechanism involved, we investigated the expression of transcription factors NeuroD1 and Pit-1 and found that both transcription factors were expressed in many tumor cells. This case report describes a very rare case of pituitary adenoma that produced both ACTH and GH. We propose a hitherto undescribed translineage expression of transcription factors as the basic mechanism of this unique functional differentiation.

Contributions of Immunohistochemistry and In Situ Hybridization to the Functional Analysis of Pituitary Adenomas

Immunohistochemistry (IHC) and recently in situ hybridization (ISH) have elucidated various aspects of human pituitary adenomas, i.e., functional differentiation and classification, transcription factors and mechanism of hormone production, regulation of hormone secretion, and processing of prohormones. Recently, the use of tyramide (catalyzed signal amplification; TSA or CSA) and RT-PCR has been effective for detection of trivial amount of proteins (peptides) and mRNA, respectively. Immunomolecular histochemistry is expected to further clarify the function and biology of human pituitary adenomas.e

Petrous apex cholesterol granuloma treated via the endoscopic transsphenoidal approach

SummaryNumerous surgical approaches have been used to treat petrous apex cholesterol granulomas. They are usually treated via the transtemporal- or middle fossa approach; some are managed endoscopically. We present a patient treated by the endoscopic transsphenoidal approach and review the literature.

Ectopic corticotroph adenoma in the cavernous sinus: case report.

OBJECTIVE AND IMPORTANCE Adrenocorticotropin (ACTH)-secreting pituitary adenomas causing Cushings disease are often difficult to identify because of their variable locations and their small size. This report presents histological evidence of an ectopic ACTH-secreting adenoma located entirely within the cavernous sinus. CLINICAL PRESENTATION A 62-year-old woman presented with central obesity, hypertension, and osteoporosis. Endocrinological evaluation suggested the presence of an ACTH-secreting pituitary adenoma; however, imaging studies, including dynamic magnetic resonance imaging, did not reveal any visible lesions in the pituitary gland. Bilateral cavernous sinus sampling demonstrated a large central/peripheral ACTH gradient, with a right/left ACTH gradient. The patient was treated as having pituitary-dependent Cushings disease, until she died suddenly as a result of acute respiratory failure. INTERVENTION In a postmortem histological examination, an ACTH-secreting adenoma was found in the right cavernous sinus, which was completely surrounded by dura mater and had no direct connection with the pituitary gland. CONCLUSION Although they are rare, such adenomas located in the cavernous sinus should be recognized as one of the reasons for inaccurate cavernous sinus sampling and the failure of transsphenoidal surgery for patients with ACTH-dependent Cushings syndrome.

Immunohistochemical analysis of p27 (Kip1) in human pituitary glands and in various types of pituitary adenomas

Abstractp27 (Kip1) plays regulatory roles in the cell cycle by inhibiting the activity of cyclin dependent kinases (CDKs). This immunohistochemical study is aimed at elucidating the expression of p27 in human pituitary and in various types of pituitary adenomas in order to clarify its role in the regulation of proliferation.Sixteen normal pituitary glands and 179 human pituitary adenomas were used for immunohistochemical studies. The tissues were fixed in 10% formalin and embedded in paraffin. Indirect peroxidase method was performed after heat-induced antigen retrieval using a monoclonal antibody against p27 protein. p27 protein was expressed in the nuclei of all 16 normal human pituitary glands. p27 protein was also expressed in 128 of 179 cases of pituitary adenomas (71.5%).A marked decrease of p27 expression was noted in ACTH-secreting adenomas, 8/20 (40.0%), compared with other types of pituitary adenomas—GH-secreting adenomas, 35/46 (76.1%); PRL-secreting adenomas, 22/33 (66.7%); TSH-secreting adenomas, 8/11 (72.7%); and nonfunctioning adenomas, 55/69 (79.7%).These results suggest that p27 may play some role in the regulation of proliferation in all types of pituitary adenomas. The lower levels of p27 in ACTH-secreting adenoma is of particular interest with respect to the intermediate lobe-derived pituitary tumor developed in p27 knockout mice.