Granulated Growth Hormone Cell Adenoma Research Articles

GPR64 promotes cAMP pathway in tumor aggressiveness in sparsely granulated growth hormone cell adenomas

There is an increasing agreement that acromegaly caused by growth hormone (GH) cell adenoma has two distinct subtypes: densely granulated (DG) and sparsely granulated (SG). We hypothesized that differential molecular signatures may explain their behavior. Total transcriptome sequencing was performed on ten DG and seven SG adenomas. The differentially expressed RNAs were identified by bioinformatic analyses, and a candidate RNA was verified by quantitative real-time PCR. Immunohistochemical staining was also performed to detect the protein expression of the candidate. Clinical parameters were correlated with protein expression. Subsequently, cell proliferation, colony formation, and cell cycle progression were analyzed after knockdown of the candidate in pituitary GH3 cells. Activation of the cAMP pathway was assessed by ELISA and Western blot. We confirmed that there were obvious differentially expressed genes between the subtypes. Through gene profiling, we discovered that an orphan adhesion G protein-coupled receptor, GPR64, was overexpressed in more aggressive SG adenomas. Noticeably, GPR64 knockdown significantly inhibited the proliferation of GH3 tumor cells and decreased colony formation. The knockdown also induced cell cycle arrest in GH3 tumor cells. Further studies revealed that GPR64 knockdown decreased cAMP levels and the ratios of p-CREB/CREB, indicating that it suppressed the cAMP/CREB pathway. Our results indicated that GPR64 may promote aggressiveness in SG-type GH cell adenomas and that it is a key factor regulating the cAMP pathway to promote aggressiveness of GH cell adenomas.

Pituitary Adenoma in Carney Complex: An Immunohistochemical, Ultrastructural, and Immunoelectron Microscopic Study

First described in 1985, Carney complex is a rare, heritable disorder featuring abnormal skin pigmentation, cardiac and cutaneous myxoma, melanotic schwannoma of psammomatous type, and endocrine abnormalities, including pituitary adenomas. Patients with the latter present with elevated growth hormone (GH) levels and acromegaly or gigantism. Prolactin (PRL) elevation may also be seen. The authors have investigated 2 resected pituitary adenomas from patients with Carney complex. One, a 19-year-old female acromegalic with elevated GH, IgF-1, and PRL levels, had a mammosomatotroph adenoma immunoreactive for GH and PRL. Ultrastructurally, GH and PRL were present in the same secretory granules. The second patient, a 27-year-old acromegalic, had a sparsely granulated GH cell adenoma that by immuno-electron microscopy revealed GH immunoreactivity only. The lack of morphologic similarity between the 2 adenomas indicates that pituitary tumors in patients with Carney complex may not exhibit the same phenotype.

Pituitary adenoma with neuronal choristoma (PANCH): composite lesion or lineage infidelity?

Fifteen cases of the rare association of pituitary adenoma and neuronal choristoma (PANCH) were investigated by histology, immunohistochemistry, and electron microscopy. Acromegaly was apparent clinically in 11 patients and was equivocal in 1, and 3 lesions appeared to be nonfunctioning. Histology revealed various proportions of chromophobic PA and nervous tissue consisting of neuronlike cells and neuropil. Immunohistochemistry documented growth hormone (GH) in every PA, including those unassociated with clinical acromegaly. In contrast, the NCH component showed no consistent immunohistochemical profile. Most frequent reactivities were for the pituitary hormone alpha subunit, thyroid-stimulating hormone, and GH, whereas only a few cases displayed scattered positivity for GH-releasing hormone. Low-molecular weight keratin tested positive in PAs and in a few cells and processes of an NCH. A few fibrous bodies were immunoreactive for neurofilament protein. Electron microscopy revealed sparsely granulated GH cell adenoma, neurons, and neuropil. Cells intermediate between PA and neurons were numerous in 1 lesion. The present morphologic findings as well as lack of GH cell hyperplasia and the consistent association of NCH with but one type of PA do not support the causative role of NCH in the initiation of PA, as proposed previously. It appears that NCH is the result of neuronal differentiation within sparsely granulated GH cell adenomas.

Analysis of the Gs α gene in growth hormone-secreting pituitary adenomas by the polymerase chain reaction-direct sequencing method using paraffin-embedded tissues

We investigated the prevalence of Gs alpha gene mutations in growth hormone (GH) secreting pituitary adenomas from Japanese patients with acromegaly. Forty-five GH-secreting adenomas were examined for the presence of point mutations in codons 201 or 227 of the Gs alpha gene using the polymerase chain reaction-direct sequencing method and deoxyribonucleic acid extracted from paraffin-embedded tumor specimens. Mutation of codon 227 of the Gs alpha gene was not observed in any of the tumors, but a mis-sense mutation of codon 201 was identified in two tumors (4.4%). One lesion was a densely granulated GH cell adenoma in a patient with adenomatous goiter and breast cancer. The other was a mixed GH cell-prolactin cell adenoma in a patient with multiple endocrine neoplasia type 1 associated with parathyroid hyperplasia and a pancreatic islet cell tumor. The Gs alpha gene detected in parathyroid tissue and pancreatic tumor tissue was of the wild type in this second patient, and the mutation was specific to the pituitary tumor. These results suggest that point mutations of codons 201 or 227 of the Gs alpha gene may not be important mediators of oncogenesis for GH-secreting pituitary adenomas in Japan.

A case of sparsely granulated growth hormone cell adenoma associated with lymphocytic hypophysitis

Lymphocytic hypophysitis is in itself rare and usually occurs in the postpartum period or the last trimester of pregnancy. It has not been described in combination with a pituitary tumor. A twenty-two year old woman, who had never been pregnant, presented with a history of nine months amenorrhea and spontaneous galactorrhea. She was not taking any medication and had never used oral contraceptives. Physical examination was unremarkable except that whitish fluid could be expressed from both breasts. Her visual fields were normal. Her serum PRL levels was high at 105.7 micrograms/l and increased to 138.4 micrograms/l at 60 minutes in a triple bolus test. GH values were normal and there was no evidence of overproduction of other pituitary hormones. CT scan showed an intrasellar mass with suprasellar extension. A tumor was selectively removed transsphenoidally. Morphologic examination revealed a clinically silent sparsely granulated growth hormone cell adenoma with lymphocytic infiltration of the adjacent pituitary tissue. Postoperatively her menstrual periods resumed and she conceived despite a slightly elevated PRL level. Three months after an uneventful pregnancy and full term delivery her PRL level was 69.9 micrograms/l and increased to 102.2 micrograms/l at 60 min. Basal GH and cortisol levels were normal. She remains well without replacement fourteen months after delivery. This case is of interest because it is the first reported simultaneous occurrence of a pituitary adenoma and lymphocytic hypophysitis and also because the hypophysitis preceded her first pregnancy.

Pathology of growth hormone-producing tumors of the human pituitary.

This paper reviews the morphologic features of growth hormone-producing tumors of the human pituitary. These tumors are associated with elevated blood growth hormone levels and acromegaly or gigantism and can be classified into the following morphologically distinct entities by the combined application of histology, immunocytology, and electron microscopy: densely granulated growth hormone cell adenoma; sparsely granulated growth hormone cell adenoma; mixed growth hormone cell- prolactin cell-adenoma; acidophil stem cell adenoma; mammosomatotroph cell adenoma; growth hormone cell carcinoma; plurihormonal adenoma with growth hormone production.

Mammosomatotroph cell adenoma of the human pituitary: a morphologic entity

Nine cases of a hitherto undescribed morphologic entity, termed mammosomatotroph cell adenoma of the human pituitary, are reported. These tumors, occurring mostly in men, are invariably associated with acromegaly (or gigantism) and high-normal or slightly elevated blood prolactin levels, and it cannot be distinguished clinically from well-differentiated growth hormone cell or mixed growth hormone cell-prolactin cell adenomas. They show a slow growth rate and usually exhibit a diffuse pattern and intense cytoplasmic acidophilia by histology. The immunoperoxidase technique detects both growth hormone and prolactin within the same cells. Electron microscopy reveals monomorphous tumors with a fine structure markedly similar to that of well-differentiated, densely granulated growth hormone cell adenomas. An added feature and diagnostic marker of mammosomatotroph cell adenoma is the presence of extracellular deposits of secretory material. One tumor shows a marked abnormality of hormone packaging and storage, resulting in the cytoplasmic accumulation of pleomorphic bodies containing semicrystalline secretory material.

Mammosomatotroph Cell Adenoma of the Human Pituitary

In the morphologic study of surgically-removed pituitary adenomas, histology, electron microscopy as well as immunocytochemistry at the light microscopic and ultrastructural level were used. In material of 370 adenomas, 226 tumors (61.7%) were found to derive from the “acidophil” cell line. Thirty-one of these were densely granulated growth hormone cell adenomas; 38 were sparsely granulated growth hormone cell adenomas; 1 was composed of densely granulated prolactin cells and 114 of sparsely granulated prolactin cells. The latter represent the most common tumor type in the human pituitary. Twentyone adenomas were mixed, consisting of growth hormone cells and prolactin cells; 17 tumors were classified as acidophil stem cell adenomas. The latter are immature, aggressive neoplasms assumed to originate in the common precursor of growth hormone cells and prolactin cells.

Pituitary growth hormone cell adenoma with cytoplasmic tubular aggregates in the capillary endothelium

Electron microscopy revealed the presence of cytoplasmic tubular aggregates in the capillary endothelium of a sparsely granulated growth hormone cell adenoma removed surgically from a 25-year-old female patient with acromegaly. To our knowledge, this is the second publication describing these structures in hypophysial growth hormone cell adenomas.