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Shozo Yamada, Kalman Kovacs, Eva Horvath, and Tadashi Aiba

✓ Clinically nonsecreting pituitary adenomas removed at surgery from 69 patients under 40 years of age were studied by histological, immunocytochemical, and transmission electron microscopic examination. By morphological analysis. 19 tumors were found to be null-cell adenomas. 17 silent gonadotroph adenomas, 14 silent subtype 3 adenomas of unknown cellular origin, 13 silent subtype 1 or subtype 2 corticotroph adenomas, three oncocytomas, and three silent thyrotroph adenomas. These results indicate that the incidence of null-cell adenomas and oncocytomas, which are known to be the most common types of nonsecreting pituitary adenomas in patients over 40 years of age, is relatively low in younger patients. This trend is even more obvious in patients younger than 30 years of age.

It can be concluded that clinically nonsecreting pituitary adenomas represent a heterogeneous group morphologically, and that the incidence of the different tumor types varies depending on the patient's age. These findings underline the importance of careful morphological studies. It is proposed that, in order for the correct morphological diagnosis to be made, tumors removed surgically from patients with clinically nonsecreting pituitary adenomas (especially younger patients) should be investigated not only by histological means but also by immunocytochemical and electron microscopic examination. The information obtained from such analysis may be useful in assessing prognosis and deciding on the appropriate treatment.

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Multiple adenomas of the human pituitary

A retrospective autopsy study with clinical implications

George Kontogeorgos, Kalman Kovacs, Eva Horvath, and Bernd W. Scheithauer

✓ In a review of autopsy material from two centers, 20 pituitary glands were found containing multiple adenomas. In total, 44 adenomas were identified histologically; 16 glands contained double tumors and in four glands triple adenomas were found. Size was measured in 30 tumors, all of which were microadenomas. Thirty-four adenomas were located in the lateral wings and 10 lay in the median wedge. Forty-one tumors were chromophobic and three were basophilic. Immunocytochemical analysis of the 44 tumors demonstrated the presence of prolactin in 11, adrenocorticotropic hormone in three, growth hormone in one, and α-subunit as well as follicle-stimulating hormone and luteinizing hormone in one.

Of the 20 patients studied, there were 11 men and nine women, with an average age of 69 years. All patients died from various nonendocrine causes. With the exception of one patient who appeared mildly acromegalic, no correlation was observed between pituitary morphology and clinical data. This study found a 10.4% frequency of adenomas in pituitaries studied randomly at autopsy. Multiple tumors were encountered in 0.9% of cases. Despite its low frequency, adenoma multiplicity may underlie surgical failure in cases in which one adenoma is removed and the other is left behind.

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Kalman Kovacs, Lucia Stefaneanu, Eva Horvath, Michael Buchfelder, Rudolph Fahlbusch, and Wolfgang Becker

✓ A 14-year-old girl presented with a rapidly growing, invasive prolactin-producing pituitary tumor that failed to respond to dopamine agonist medication. Histological, immunocytochemical, and ultrastructural studies of the surgically removed tissue revealed a pleomorphic, chromophobic, or slightly acidophilic pituitary tumor that was immunoreactive for prolactin and that, according to electron microscopy, consisted of atypical lactotrophs showing no evidence of cell shrinkage.In situ hybridization demonstrated large amounts of prolactin messenger ribonucleic acid (mRNA), moderate amounts of estrogen receptor mRNA and dopamine (D2) receptor mRNA, and an absence of growth hormone mRNA in the tumor cells. Because D2 receptor mRNA was present in the tumor, causes other than D2 receptor loss may have been responsible for the resistance of the lactotrophs to dopamine agonist administration.

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Mubarak Al-Gahtany, Juan Bilbao, Kalman Kovacs, Eva Horvath, and Harley S. Smyth

✓ Ectopic pituitary adenomas (EPAs) are rare and their association with orthotopic corticotroph hyperplasia has not been published.

The case of a 30-year-old woman with clinical and biochemical evidence of Cushing disease (CD) is reported. A magnetic resonance image obtained preoperatively revealed asymmetrical inhomogeneity of the pituitary gland, which was suggestive of localized adenoma. It also showed what was thought to be a small sphenoid polyp. Postoperatively the latter lesion was found to be an ectopic corticotroph adenoma. The pituitary gland, which was free from any tumor, exhibited diffuse unilateral corticotroph hyperplasia. Clinical, radiological, laboratory, and histopathological findings are presented. A review of the literature and a discussion of possible causes of this unique association between the ectopic corticotroph adenoma and the pituitary hyperplasia are provided.

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Daniel L. Barrow, George T. Tindall, Kalman Kovacs, Michael O. Thorner, Eva Horvath, and James C. Hoffman Jr.

✓ Bromocriptine inhibits prolactin secretion and causes size reduction of prolactin-secreting adenomas. The effect of the drug upon pituitary tumors other than prolactinomas is uncertain. The authors report a prospective series of 12 patients with pituitary macroadenomas in whom bromocriptine was administered for 6 weeks prior to transsphenoidal surgery. Five of the patients had computerized tomographic documentation of significant reductions in tumor size (Group A) and six had no change (Group B) during 3 and 6 weeks of bromocriptine administration. One patient who demonstrated size reduction in his tumor was not assigned to either group as he was treated with high-dose dexamethasone concurrently with the bromocriptine. Pathological examination (light and electron microscopy and immunocytochemistry) indicated that all Group A patients harbored tumors with prolactin granules whereas all Group B tumors lacked such granules. Adenoma cells in the responsive tumors were involuted with reduced cytoplasmic, nuclear, and nucleolar areas. Neither widespread cell necrosis, infarction, nor vascular injury was observed. Two of the five Group A patients discontinued bromocriptine prior to completion of the 6-week protocol and had a rapid return of their tumors to pre-treatment size.

Although bromocriptine has been reported to cause shrinkage of nonfunctional tumors, there was no radiological evidence of size reduction or pathological changes in the nonfunctional tumors of this series. Interestingly, serum levels of prolactin were modestly elevated (84 and 113 ng/ml) in two of the six Group B patients, an elevation due to stalk compression rather than secretion by adenoma cells. This finding underscores the fact that failure of bromocriptine to reduce pituitary tumor size in the presence of hyperprolactinema may occur because the tumor is other than a prolactinoma.

This is the first moderate-sized group of patients in whom pathological changes in responsive prolactinomas during bromocriptine therapy have been demonstrated. As bromocriptine is not tumoricidal, and thus not curative, there is insufficient evidence to recommend this drug as primary therapy for either prolactin-secreting or nonfunctional macroadenomas, but the drug may have potential as a preoperative adjunct to effect shrinkage of prolactinomas and theoretically, at least, make excision easier and possibly more complete.

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Kalman Kovacs, Eva Horvath, Lucia Stefaneanu, Juan Bilbao, William Singer, Paul J. Muller, Kamal Thapar, and Elaine Stone

✓ The authors report on the morphological features of a pituitary adenoma that produced growth hormone (GH) and adrenocorticotropic hormone (ACTH). This hormone combination produced by a single adenoma is extremely rare; a review of the available literature showed that only one previous case has been published. The tumor, which was removed from a 62-year-old man with acromegaly, was studied by histological and immunocytochemical analyses, transmission electron microscopy, immunoelectron microscopy, and in situ hybridization. When the authors used light microscopy, the tumor appeared to be a bimorphous mixed pituitary adenoma composed of two separate cell types: one cell population synthesized GH and the other ACTH.

The cytogenesis of pituitary adenomas that produce more than one hormone is obscure. It may be that two separate cells—one somatotroph and one corticotroph—transformed into neoplastic cells, or that the adenoma arose in a common stem cell that differentiated into two separate cell types. In this case immunoelectron microscopy conclusively demonstrated ACTH in the secretory granules of several somatotrophs. This was associated with a change in the morphological characteristics of secretory granules. Thus it is possible that the tumor was originally a somatotropic adenoma that began to produce ACTH as a result of mutations that occurred during tumor progression.

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Federico Roncaroli, Vania Nosé, Bernd W. Scheithauer, Kalman Kovacs, Eva Horvath, William F. Young Jr., Ricardo V. Lloyd, Mary C. Bishop, Bradley Hsi, and Jonathan A. Fletcher

✓ The authors report on two gonadotropic carcinomas of the adenohypophysis that occurred in a 55-year-old man (Case 1) and a 53-year-old woman (Case 2), with signs of mass effect and amenorrhea, respectively. Both lesions were macroadenomas. The tumor in Case 1 metastasized to dura mater, skull, nasal sinus, and larynx 2 years after patient presentation, whereas that in Case 2 spread to vertebral bodies and ribs after a 19-year latency. Histologically, the primary, recurrent, and metastatic lesions in Case 1 featured brisk mitotic activity and high MIB-1 levels as well as p53 labeling indices. Immunoreactivity for HER-2/neu was assessable only in rare neoplastic cells of the second recurrence and in 80% of cells of the dural metastasis. Low-level HER-2/neu gene amplification was evident in the recurrent tumors and metastasis. The sellar and metastatic tumors in Case 2 resembled benign gonadotropic adenoma with oncocytic change; p53 accumulation, HER-2/neu overexpression, and HER-2/neu gene amplification were not present. The results indicate that low-level amplification of the HER-2/neu gene might be associated with pituitary carcinomas in which more aggressive behavior is seen. Further studies are needed to determine whether HER-2/neu plays a role in the pathogenesis of pituitary carcinoma.

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Fateme Salehi, Kalman Kovacs, Michael D. Cusimano, Eva Horvath, C. David Bell, Fabio Rotondo, and Bernd W. Scheithauer

Object

The aim of this work was to investigate the immunohistochemical expression of nestin, a member of the intermediate filament family, in adenohypophysial vasculature during development and progression of pituitary infarction.

Methods

Forty-five nontumorous adenohypophyses and 34 pituitary adenomas of various types, all exhibiting acute or healing infarcts, were examined immunohistochemically using the streptavidin-biotin-peroxidase complex method.

Results

In both adenohypophyses and pituitary adenomas without infarction, nestin was expressed in only a few capillaries and endothelial cells. In acute infarcts without a vascular response, no nestin was demonstrable within necrotic capillaries (50 cases). In organizing infarcts, newly formed vessels spreading into necrotic zones showed nestin expression in all capillaries and practically every endothelial cell (25 cases). In the hypocellular, fibrotic scar phase, only a few vessels (4) were apparent, and immunoreactivity was focal and mild.

Conclusions

Nestin is strongly expressed in newly formed capillaries and is downregulated when infarcts transform to fibrous tissue. Nestin expression may provide valuable insight into the process of pituitary angiogenesis.

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Thomas A. Gaffey, Bernd W. Scheithauer, Ricardo V. Lloyd, Peter C. Burger, Peter Robbins, Forouzandeh Fereidooni, Eva Horvath, Kalman Kovacs, Takao Kuroki, William F. Young Jr., Thomas J. Sebo, Darren L. Riehle, and Allan J. Belzberg

✓ To understand the relationship between pituitary adenoma and carcinoma, four adrenocorticotropic hormone—producing pituitary adenomas and corresponding metastatic carcinomas were studied. All were functional macroadenomas (three cases of Nelson syndrome and one of Cushing disease) that initially invaded the sella turcica and occurred in women ranging in age from 17 to 66 years (mean 45 years). Metastases (two craniospinal and two systemic) occurred after latency periods of 6 to 13 years. Histological specimens were immunostained for pituitary hormones, Ki-67 antigen (MIB-1), p53 and p27 proteins, D-type cyclins, and glucocorticoid receptor messenger (m)RNA. The DNA content of the specimens was assessed using Feulgen stain. Reactivities were quantified by digital image analysis. Primary/recurrent lesions and metastatic tumors differed according to their respective mean mitotic indices (1.2/10 hpf compared with 4.3/10 hpf), MIB-1 labeling (1.7% compared with 8%), p53 staining (37.3% compared with 49.9%), and p27 labeling (48% compared with 25%). Cyclin D3 immunoreactivity provided no prognostically significant information. Glucocorticoid receptor mRNA was detected in all cases. Results of a ploidy analysis were variable and nonprognostic. In keeping with the 2000 World Health Organization classification of endocrine neoplasms, our findings support the concept that primary tumors that exhibit mitotic activity, an increased (> 3%) MIB-1 labeling index, and/or p53 immunoreactivity should be termed “atypical adenomas” to denote their aggressive potential and the possibility of future malignant transformation.