Harley S. Smyth

Acidophil stem cell adenoma of the human pituitary: Clinicopathologic analysis of 15 cases

In material of 347 surgically removed pituitary adenomas, 15 tumors (4.3%) were diagnosed as acidophil stem cell adenomas. These are immature neoplasms, assumed to derive from the common progenitor of growth hormone and prolactin cells, and usually containing both hormones by the immunoperoxidase technique. Clinically, they are regularly associated with hyperprolactinemia. Some patients may exhibit physical stigmata of acromegaly without biochemical evidence of the disease (“fugitive acromegaly”). The entity is also characterized by (1) relatively short clinical history; (2) large (grade III‐IV), locally invasive adenoma, and (3) relatively low hormonal activity. By electron microscopy, these tumors are unicellular with immature cytoplasm, exhibiting some features of adenomatous growth hormone and prolactin cells and frequently mitochondrial abnormalities as well. They are more aggressive than the well‐differentiated adenomas of the “acidophil” cell line—a fact to be considered in postoperative management.

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 adenoma of the pituitary associated with gigantism and hyperprolactinemia. A morphological study including immunoelectron microscopy

SummaryA 29-year old giantess with growth hormone excess and hyperprolactinemia underwent transsphenoidal surgery to remove her pituitary tumor. Electron microscopy revealed a mammosomatotroph adenoma composed of one cell type. Immunoelectron microscopy, using the immunogold technique, demonstrated predominantly growth hormone or prolactin or a varying mixture of both growth hormone and prolactin in the adenoma cells. The presence of growth hormone and prolactin was found not only in the cytoplasm of the same adenoma cells but also in the same secretory granules. In the nontumorous adenohypophysis, somatotrophs and lactotrophs showed ultrastructural signs of hyperactivity. This finding is in contrast with the presence of suppressed somatotrophs and lactotrophs seen in nontumorous portions of adult pituitaries harboring growth hormone or prolactin-secreting adenomas. Our morphological study reinforces the view that growth hormone-producing pituitary tumors, originating in childhood, are different from those of the adult gland.

Basic Fibroblast Growth Factor Expression by Two Prolactin and Thyrotropin-Producing Pituitary Adenomas.

We investigated the expression of basic fibroblast growth factor (bFGF) in an aggressive type of PRL and TSH-producing pituitary adenoma. Immunocytochemistry and electron microscopy were used to characterize the tumors removed from two patients. Immunoassays were used to measure hormone and bFGF levels in vitro and in vivo. Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect bFGF mRNA expression by these tumors. Morphologically, these tumors were characterized by an unusual plurihornal pattern with expression of PRL and TSH and the ultrastructural characteristics of the silent subtype 3 adenoma; in addition, both adenomas displayed marked interstitial fibrosis. bFGF was measurable in the circulation of these patients ranging from 7.5–20.5 pg/mL (normal<1 pg/mL). bFGF concentrations were reduced following surgical adenomectomy. bFGF in culture media was present in concentrations of 197–387 pg/24h/105 cells. bFGF mRNA expression was identified in both adenomas examined. bFGF levels were unaltered in the culture media and in the serum of patients following GnRH and TRH treatment. In conclusion, the expression of bFGF by these plurihormonal pituitary adenomas suggests the possiblity that it may play a role in the development of fibrosis and tumor cell proliferation of this unusual type of pituitary neoplasm.

Transsphenoidal management of Rathke's cleft cysts a clinicopathological review of 10 cases

We report detailed data on 10 patients who underwent transsphenoidal microsurgical management of histopathologically confirmed Rathkes cleft cysts. Preoperatively, pituitary dysfunction was present in 90%, headaches in 80%, hyperprolactinemia in 70%, and visual interference in 40%. Computed tomography and magnetic resonance imaging had 90% and 100% sensitivity, respectively, in disclosing the lesion. The mean follow-up duration was 22 months. There was no mortality. The only morbidity was sustained diabetes insipidus in one case. Resolution or improvement in preoperative dysfunction occurred in the majority of patients: headaches in 100%, visual deficits in 75%, normalization of hyperprolactinemia in 83%, and reversal of panhypopituitarism in 33%. We conclude that Rathkes cleft cysts can be managed safely and effectively with transsphenoidal drainage and partial excision of the wall.

The c-erbB-2/neu proto-oncogene in human pituitary tumours

OBJECTIVEThe aetiology of most pituitary tumours remains unknown. We have examined the potential role of the neu receptor proto‐oncogene in human pituitary tumorigenesis.

Distinct clonal composition of primary and metastatic adrencorticotrophic hormone-producing pituitary carcinoma

The pathogenetic mechanisms underlying pituitary tumorigenesis are largely unknown. Previous reports have suggested that aggressive pituitary adenomas and/or carcinomas may be associated with genetic alterations that are distinct from those responsible for the more common and less aggressive pituitary adenomas. Here, we describe the clonal composition of a pituitary carcinoma, its recurrence and its metastasis. The samples studied were from a 48‐year‐old woman who presented with recurrent Cushings syndrome. During the 8‐year course of her disease, she had an ACTH‐producing pituitary carcinoma requiring two transsphenoidal procedures and resection of a metastatic cervical lymph node. Her disease remained active despite surgical resection, external beam irradiation and medical treatment with ketoconazole. Ultimately, bilateral adrenalectomy was performed to control the hypercortisolism. Morphological and immunohistochemical studies revealed that the primary and recurrent pituitary tumours and the metastatic lesion were an endocrine tumour with ACTH and growth hormone immunoreactivity. Primary, recurrent and metastatic tumour DNAs were analysed for X‐chromosome inactivation and loss of heterozygosity (LOH) at several microsatellite loci on chromosomes 9,10, 11, 13 and 22. All three lesions were monoclonal in composition as suggested by the pattern of X chromosome inactivation of the PGK‐1 allele. Moreover, the primary, recurrent and metastatic lesions demonstrated LOH at the microsatellite allelic markers PYGM and D10S217. In contrast, however, the metastatic lesion showed a loss‐to‐retention pattern at two distinct loci (IFNA and D22S156) compared to the primary and recurrent pituitary tumours. These findings, while consistent with a clonal composition of the primary and metastatic pituitary lesions, show each clone to be distinct. This is the first description of a metastatic pituitary carcinoma with a distinct clonal composition from its primary source.

Growth hormone (GH) and prolactin (PRL) gene expression and immunoreactivity in GH- and PRL-producing human pituitary adenomas

Growth hormone(GH)-producing pituitary adenomas are morphologically heterogeneous and frequently contain not only GH immunoreactivity but also variable numbers of prolactin (PRL) immunopositive cells. Paraffin sections of 59 surgically removed GH- and/or PRL-producing adenomas classified by histology, immunocytochemistry (ICC) and electron microscopy were studied using in situ hybridization (ISH) for GH and PRL mRNA and combined with ICC for the coded hormones. Somatotroph adenomas (10 densely and 10 sparsely granulated tumours) and mammosomatotroph adenomas (10 cases) contained both GH mRNA and GH immunoreactivity. In 4 densely and 4 sparsely granulated somatotroph adenomas and 4 mammosomatotroph adenomas, only GH mRNA and its product were found. In 28 cases (6 densely and 6 sparsely granulated somatotroph adenomas, 10 mixed somatotrophlactotroph adenomas and 6 mammosomatotroph adenomas) both GH and PRL mRNA were present, although no PRL immunoreactivity was not in 2 densely granulated somatotroph adenomas. In these cases, ISH for PRL mRNA combined with GH immunostaining revealed the presence of variable numbers of mammosomatotrophs. In 9 acidophil stem cell adenomas only PRL mRNA and its product were found; one tumour expressed both GH and PRL mRNA and their products. Nine lactotroph adenomas contained only PRL mRNA and PRL immunoreactivity. The results show that GH and/or PRL mRNA content could not be correlated with ICC for coded proteins and ultrastructural features. The mammosomatotrophs were more numerous using ISH when compared with ICC. Somatotroph, mammosomatotroph and mixed adenomas are closely related and they can be considered to represent one basic tumour type originating in a cell committed to GH production. This may undergo clonal differentiation towards a mammosomatotroph and further to the lactotroph line. The results also indicate that lactotroph adenomas arise in a cell committed to PRL production. Acidophil stem cell adenomas seem to be more closely related to lactotroph cells than somatotroph.

Immunoreactive luteinizing hormone in functioning corticotroph adenomas of the pituitary. Immunohistochemical and tissue culture studies of two cases.

Two pituitary adenomas removed from a 37-year-old woman and a 26-year-old woman with typical Cushings disease were studied by light and electron microscopy, immunohistochemistry and radioimmunoassay of tissue culture media. Both patients had high plasma levels of cortisol and normal levels of luteinizing hormone (LH). Both tumours were monomorphous, composed of densely granulated corticotrophs; the tumour cells contained periodic acid-Schiff positivity, were arranged in a sinusoidal pattern and, ultrastructurally, contained well-developed cytoplasmic organelles. By immunohistochemistry the majority of tumour cells contained immunoreactive adrenocorticotropin (ACTH); approximately 10% of the tumour cell population contained LH immunoreactivity. The LH-positive cells tended to form clusters scattered widely throughout the tumour tissues. LH immunoreactivity was demonstrated in some ACTH-immunoreactive cells on serial sections. Large amounts of immunoreactive ACTH and smaller quantities of LH, follicle stimulating hormone and αsubunit were released into the culture media and release of the glycoprotein hormones responded in parallel to corticotropin releasing hormone stimulation or inhibition by cortisol. These findings indicate that LH can be simultaneously produced and released by ACTH-producing tumour cells of otherwise typical functioning corticotroph adenomas. The capacity for LH production may be acquired during neoplastic proliferation. This is the first detailed report of concurrent production of LH by pituitary corticotroph adenomas.

Impact of technique on cushing disease outcome using strict remission criteria.

BACKGROUND Cushing disease (CD) constitutes a challenging condition for the pituitary surgeon. Given the variety of factors affecting outcomes in CD, it is uncertain whether the newer endoscopic technique improves the results of surgery. METHODS A review was conducted of CD cases at our institution between 2000 and 2010. Analysis was done to: determine if surgical technique had an effect on outcome, identify the predictors of outcome and provide details of failed cases. Remission was defined as normal postoperative 24-hour urinary free cortisol (24-h UFC), suppression of morning serum cortisol to <50 nmol/L after 1mg of dexamethasone or being dependent on steroid replacement. RESULTS Forty-two patients met our inclusion criteria. Average follow-up period was 33 months. There were 15 macroadenomas and 27 microadenomas. Seventeen patients had an endoscopic transsphenoidal surgery and twenty-five patients had a microscopic transsphenoidal procedure. Long-term overall remission was achieved in 26 (62%) patients. There was no significant difference in remission rates between the two techniques (p value 0.757). Patients subjective symptomatic improvement and drop of morning serum cortisol in the postoperative period to less than 100 nmol/L correlated with long-term remission (p value 0.0031 and 0.0101, respectively) while repeat surgery was the only predictor of the lack of postoperative remission (p value 0.0008). CONCLUSIONS Revision surgery predicted poor remission rate for CD. Within the power of our study size, there was no difference in outcome between the endoscopic and microscopic approaches. Surgical outcomes should be reviewed in association with remission criteria used in a study.