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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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Anne Klibanski, Nicholas T. Zervas, Kalman Kovacs, and E. Chester Ridgway

✓ Hypersecretion of growth hormone (GH) was found in three women aged 25 to 35 years old, with somatotroph adenomas without clinical stigmata of acromegaly. The patients had previously been diagnosed as having nonfunctioning pituitary macroadenomas, with extrasellar extension. Concentrations of GH were elevated preoperatively in all subjects and could not be suppressed during oral glucose tolerance testing. Somatomedin-C concentrations were elevated in two patients. Immunocytochemical studies of surgically obtained tumor tissue demonstrated sparse positive staining for GH in all subjects. Gel-chromatographic analysis of serum and tumor tissue samples demonstrated that the immunoactive GH was authentic GH. On pathological examination, the tumor was cellular in all cases, consisting of partly acidophilic and partly chromophobic cells. Electron microscopic analysis of one tumor showed a cell composition not previously described. These studies further characterize GH hypersecretion in a subset of patients with clinically nonfunctioning pituitary macroadenomas.

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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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Michael D. Cusimano, Tony Q. Huang, Anthony Marchie, Harley S. Smyth, and Kalman Kovacs

OBJECTIVE

Cushing’s disease (CD) patients experience a range of debilitating symptoms that impair quality of life (QOL) as assessed using generic measures. These generic measures are inadequate to capture the disease-specific burden of illness. The development of the CD-specific QOL-CD measure of QOL using items generated by CD patients and healthcare professionals will provide a holistic assessment of patient outcomes and efficacy of novel therapies.

METHODS

A total of 96 CD patients participated. A list of 177 items (version 1.0) was generated by treated CD patients (n = 9), caregivers (n = 2), healthcare providers (n = 7), and results of a MEDLINE search. Item reduction was performed through content analysis and dual scaling. Patients’ rating of importance was incorporated to reduce to a final version of 56 items (version 3.0). Evidence for test-retest reliability was sought through administering the QOL-CD 1 week apart and Cronbach’s α of each subscale. Construct validity was assessed through extreme group analysis and comparison with the normal Canadian population. Concurrent validity was sought through comparison with the SF-36, Functional Assessment of Cancer Therapy–Brain (FACT-Br), and Karnofsky Performance Status (KPS). Perioperative testing was conducted on CD patients (n = 25) against nonfunctioning pituitary adenoma controls (n = 25) through pre- and postoperative testing.

RESULTS

A total of 96 CD patients (86 females and 10 males; mean age 45.23 ± 14.16 years) participated. The QOL-CD was feasible (mean completion time 15 minutes, with 70% believing accurate capture of QOL), reliable (CD 1 week apart: r = 0.86; control 1 week apart: r = 0.83; Cronbach’s α: general health = 0.73, emotional health = 0.85, physical health = 0.78, mental status = 0.82, social well-being = 0.63, medical treatment = 0.54), and valid (extreme group testing p < 0.001; SF-36 and QOL-CD general health: r = 0.56, social well-being: r = 0.21, emotional health: r = 0.61, total score: r = 0.58; FACT-Br and QOL-CD physical health: r = 0.47, social well-being: r = 0.21, emotional health: r = 0.34, total score: r = 0.68; KPS and QOL-CD general health: r = 0.32, total score: r = 0.14). Perioperative testing of CD patients (n = 25) demonstrated improvement in all subscales postoperatively, with a significant difference in emotional health (p < 0.001) and physical health (p < 0.001).

CONCLUSIONS

The QOL-CD questionnaire has been developed for patients with CD and has demonstrated evidence for validity and reliability.

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Bernd W. Scheithauer, Kalman T. Kovacs, Edward R. Laws Jr., and Raymond V. Randall

✓ Pituitary adenomas may remain intrasellar or infiltrate dura and bone. Invasive adenomas are not considered to be malignant; in biological behavior they are between non-infiltrative adenomas and pituitary carcinomas. The latter are defined as tumors with subarachnoid, brain, or systemic metastasis. Invasion may be defined radiologically, operatively, or histologically. On the basis of operatively assessed tumor size and gross invasion of dura and bone as well as immunocytochemical and ultrastructural analysis of 365 pituitary adenomas, the following data were obtained. There were 23 growth hormone (GH)-cell adenomas: 14% microadenomas and 86% macroadenomas; their overall frequency of invasion was 50%. There were 24 prolactin (PRL)-cell adenomas: 33% microadenomas and 67% macroadenomas, with an overall frequency of invasion of 52%. Mixed GH-cell and PRL-cell adenomas were found in 35 cases; 26% were microadenomas and 74% were macroadenomas, and the overall frequency of invasion was 31%. Sixty patients had adrenocorticotropic hormone (ACTH)-cell adenomas (Cushing's disease): 87% microadenomas and 13% macroadenomas; the overall frequency of invasion was 25% (in 8% of microadenomas and 62% of macroadenomas). Twenty patients had ACTH-cell adenomas (Nelson's syndrome): 30% microadenomas and 70% macroadenomas; the overall frequency of invasion in these cases was 50% (in 17% of microadenomas and 64% of macroadenomas). Silent ACTH-cell adenomas, 100% macroadenomas, were found in 11 patients, with an 82% frequency of invasion. There were 32 follicle-stimulating and luteinizing hormone adenomas, all macroadenomas, with a frequency of invasion of 21%. Four patients had thyroid-stimulating hormone adenomas, all macroadenomas, with a 75% frequency of invasion. Null-cell adenomas were found in 93 cases: 2% microadenomas and 98% macroadenomas, with a frequency of invasion of 42%. There were 63 plurihormonal adenomas (GH, PRL, glycoprotein): 25% microadenomas and 75% macroadenomas, with a 50% overall frequency of invasion.

Based on this study, and on their usual frequency of occurrence, the estimated rate of gross invasion by pituitary adenomas of all types is approximately 35%. It is concluded that immunocytochemical and ultrastructural characteristics of pituitary adenomas reflect the tendency of these tumors to infiltrate and hence may be of prognostic significance.

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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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Michael D. Cusimano, Kalman Kovacs, Juan M. Bilbao, William S. Tucker, and William Singer

✓ A case with the coexistence of a microprolactinoma and suprasellar craniopharyngioma lactotroph hyperplasia is presented. Loss of inhibitory hypothalamic dopaminergic input may have played a role in hyperprolactinemia and the proliferation of pituitary lactotrophs. This is believed to be the first published case of suprasellar craniopharyngioma with this association.

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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.