Basophilic Adenoma Research Articles

Cushing’s Disease: 50 Years Later

The recent improvements in transsphenoidal microsurgery have once again placed the emphasis on the basophilic adenoma of the pituitary as the etiology of the disease originally described by Harvey Cushing fifty years ago. In 75 operated cases, tumors were found in 60 cases: 52 were microadenomas, 4 were larger adenomas and 4 were invasive. In 15 cases, no tumor was found at surgery; a selective partial central hypophysectomy was performed in 11 cases and a total hypophysectomy in 4. Among the latter, 3 additional microadenomas were found at pathology. The majority of the microadenomas were located in the center of the gland most often near or within the neural lobe. In 59 patients with a non invasive tumor, initial cure was obtained in 52 (88%); only 1 of the 4 patients with an invasive tumor was cured. In the 12 cases without surgical or pathological tumor, partial or total hypophysectomy resulted in 10 cures (83%).

Cushing's disease: management by transsphenoidal pituitary microsurgery.

Over 15 yr, 24 patients underwent transsphenoidal pituitary surgery for Cushing's disease with a median follow-up of 12 months. Cures included 7 patients with normal sella turcicas (6 microadenomas), 6 patients with focal depressions (6 microadenomas) of the sella (grade I), and 3 patients (3 adenomas) with enlarged sellas (grade II). Three patients with sella destruction (grades III and IV), 2 with normal sellas, and 1 with focal sella depression (grade I) were not cured. Two apparent cures (microadenomas) recurred. Tumor histology revealed 19 basophilic adenomas; electron microscopy (14 tumors) and immunochemical studies (10 tumors) revealed only ACTH cells. Circadian rhythm returned in 6 cured patients. Impotence (in 2), amenorrhea (in 7), and galactorrhea (in 3) resolved in affected cured patients. The major surgical complication was hemorrhage at the operative site (3 patients). Transsphenoidal pituitary surgery is a valuable method for managing Cushing's disease in many patients.

Cushing's disease revisited

Harvey Cushing [I] presented and subsequently published his extraordinary study of basophilic pituitary adenomas in 1932. Validation of these observations followed long after his death through the fortunate coincidence of two developments: first, conclusive biochemical definition of pituitary-based hypercortisolism, for the first time differentiating this distinct clinical entity from other causes of hypercortisolism [2,3], and second, the evolution of transsphenoidal microsurgery not only providing an effective means of treating the disease but also permitting unequivocal documentation of ACTH-secreting microadenomas as a distinct entity [4]. Because it is now possible, in one simultaneous maneuver, to detect and remove minute adenomas situated in a pituitary gland of normal dimensions, the management of Cushing’s disease has undergone a revolutionary change. Until a superior form of treatment evolves, microsurgical removal of these remarkably occult adenomas offers the highest probability of restoring normal pituitary function to patients affected with the disease. The endocrinologic data from our initial series of patients were reported earlier [5]. When presented with a patient with Cushing’s disease, the surgeon can assume that the pituitary gland contains an ACTH-secreting adenoma. In a series of 44 intrasellar explorations in patients with Cushing’s disease, an adenoma was removed in every case. Three tumors, the smallest in the series, were missed at exploration and identified subsequently in serial sections of the excised glands. Microadenomas (diameter less than 10 mm) constituted the majority of adenomas.

CUSHING'S SYNDROME, NODULAR ADRENAL HYPERPLASIA AND VIRILIZING CARCINOMA

A 48-year-old hypertensive diabetic woman rapidly became virilized. Urine 17-oxo-and oxogenic steroids and plasma testosterone, androstenedione, DHEA, DHEA-sulphate and androstenediol were greatly elevated. Plasma cortisol was constantly high and was not suppressed by dexamethasone. Circulating immunoreactive ACTH was consistently detectable at 18-24 ng/l. A 450 g carcinoma arising from a nodular hyperplastic right adrenal gland was resected. Production by the tumour of 17a-hydroxypregnenolone, 17a-hydroxyprogesterone and five C-19 steroids, but very little prenenolone, progesterone or cortisol, was shown by blood sampling, tumour culture and dramatic falls after operation. The plasma cortisol fell to half, with no diurnal variation, consistent with persistent Cushing's syndrome, and the plasma ACTH rose to 55 ng/l. She died 3 months later from a myocardial infarction. Autopsy revealed a pituitary basophil adenoma at a site where radiologically there had been an indentation in the fossa floor for at least 7 years. The left adrenal gland showed nodular hyperplasia. Therefore we conclude that mild pituitary-dependent Cushing's syndrome may have been present for many years before development of a virilizing carcinoma. This case demonstrates that adrenal carcinoma in man can sometimes develop as a consequence of nodular adrenal hyperplasia which may in turn be due to long-standing trophic hyper-stimulation.

Cushing's Disease

We undertook trans-sphenoidal microsurgical pituitary exploration in 20 consecutive patients with Cushing's disease, eight of whom had normal sellar polytomography. Pituitary adenomas were selectively resected in 17 and histologically confirmed in 14. In one patient total hypophysectomy revealed a 1.5-mm basophilic adenoma, and in two patients vascular anomalies prevented sellar exploration. Hypercortisolism was corrected in 17 patients (i.e., in 16 of the 17 undergoing selective tumor removal and in the one with total hypophysectomy). Panhypopituitarism occurred only in this patient, and transient diabetes insipidus occurred in five. Most patients became glucocorticoid deficient and required replacement therapy. We conclude that pituitary tumors are present in the great majority of patient with Cushing's disease, even in the absence of demonstrable tomographic changes in the sella turcica, and that selective removal corrects hypercortisolism with little morbidity.

Staining of human pituitary glands with lead hematoxylin in comparison with other histochemical procedures, including the immunoenzyme technique

Human pituitary glands and pituitary adenomas, obtained by surgery or at autopsy, have been stained with lead hematoxylin and the results were compared with those of other histochemical procedures, including the immunoperoxidase technique. Lead hematoxylin positivity was found in the cytoplasm of melanocorticotroph, thyrotroph as well as gonadotroph cells, indicating that lead hematoxylin has no selective affinity for melanocorticotroph cells. Lead hematoxylin positive cells also stained with the PAS technique. Lead hematoxylin positivity was not revealed in growth hormone cells or in prolactin cells. Basophilic adenomas, composed of melanocorticotroph cells and associated with Cushing's disease or with Nelson's syndrome or unaccompanied by hormonal hypersecretion, showed intense lead hematoxylin positivity. Thus, no correlation was evident between lead hematoxylin positivity and secretory activity. Acidophilic or chromophobic adenomas consisting of growth hormone cells, prolactin cells, stem cells, undifferentiated cells or oncocytes, however, were negative. It can be concluded that the lead hematoxylin staining techniques a reliable, easy and reproducible histochemical method, and its use can be recommended in studies related to adenohypophysial cytology.

Pituitary adenomas and craniopharyngiomas: Analysis of 99 cases treated with radiation therapy

A total of 85 cases of pituitary adenomas and 14 of craniopharyngiomas were treated in the Department of Therapeutic Radiology at the Yale-New Haven Hospital from 1958 to 1973. The over-all control rate of the chromophobe adenomas were 86% at 5 years and 73% at 10 years. The results were similar in the groups treated with surgery followed by postoperative radiation and the group treated initially with radiation therapy alone, with surgery for the radiation failures. This report discusses 13 patients with eosinophilic adenomas; of these, half obtained control of the disease. In 4 of the 6 basophilic adenomas, endocrine abnormalities appear to be arrested. The results in the fourteen patients with craniopharyngioma were disappointing. The incidence of visual field loss after therapy was high. Complications were few and those attributed to the radiation therapy were present in patients who received unusually high fractions and often high total doses.

Effect of salicylates on renal gluconeogenesis

important etiologic cause. In this work, 12 patients were studied under basal conditions and during tests of pituitary and adrenal function with the objective of making a differential diagnosis. The 12 patients were divided by age into two subgroups of six patients each. The prepubertal group had tumors, with the exception of one child with bilateral hyperplasia: one basophil adenoma, one adenocarcinoma, two ectopic ACTH-producing tumors (thymoma and embryoma), and one adrenal adenoma. The pubertal group consisted of five with bilateral hyperplasia and one with an adrenal adenoma. The tumors did not respond to stimulation or suppression tests, except for the adrenal adenoma which showed a hyperresponsiver}ess to the infusion of ACTH. The results of attempts at inhibition of the bilateral hyperplasia were as follows: four inhibited with a small dose of dexamethasone, one partially inhibited with a large dose, and no inhibition in one patient. The last patient also did not respond to intravenous ACTH stimulus, presenting with a very high secretion of cortisol (156 mg/day/m2). This marked adrenal hyperactivity explains its tumor-like behavior. TREATMENT. Two patients with bilateral hyperplasia received conventional 4,000 r pituitary radiotherapy with no result; five patients had bilateral adrenalectomy with no deaths. The three 9 patients with adrenalectomy who had had no previous hypophyseal radiotherapy developed a syndrome of hyperpigmentation, one with enlargement of the sella turcica and diplopia. All patients received rotating 5,000 r pituitary cobalt therapy. The results suggest that optimum therapy would be bilateral adrenalectomy plus radiotherapy.

Glaucoma Secondary to Benign Adrenal Adenoma

Cushing, in 1932, demonstrated that the signs and symptoms previously considered to be due to hyperactivity of the adrenal cortex could result from a basophilic adenoma of the pituitary body. It has since been established that the clinical manifestations of this are due to a secondary hypercortisolism re­ sulting from excess ACTH production. Currently, the term is used to describe the signs and symptoms of endogenous hypercortisolism whether caused by an adrenal adenoma, an adrenal carcinoma, or the ectopic ACTH syndrome^ while the term disease is applied to hyper­ cortisolism secondary to hasnpViilir adejjpma of the pnify gland. Although references to the retinal and vas­ cular changes in Cushing's syndrome are fre­ quent, the effects of this disorder on the ocu­ lar pressure have received scant attention. The earliest reference to elevation of the ocular pressure in a case of Cushing's syndrome ap­ peared in 1937. In 1968, Neuner and Dardenne reported seven of 29 patients with Cushing's syndrome whose ocular pressure rose above 23 mm Hg. Three patients showed visual field defects. The purpose of this paper is to report a classical case of Cushing's syndrome secon­ dary to a benign adrenal adenoma, which af­ forded an unusual opportunity to evaluate the mechanism of the markedly elevated ocu­ lar prggsjire.

Pitfalls of functional tests for the establishment of the etiology of Cushing's syndrome in childhood and adolescence.

ABSTRACT The clinical course and results of steroid measurements before and during different tests of pituitary adrenal function are presented in 3 boys and 1 adolescent girl with Cushing's syndrome. Two of the boys had bilateral adrenal hyperplasia even though their cortisol production rates and pituitary adrenal function tests were typical of adrenal tumors. One of them developed central nervous system hemorrhages and died. At autopsy a basophilic adenoma of the pituitary was found. The third boy had a malignant thymoma which was probably secreting an ACTH-like substance. His cortisol production rate was also very large and it could not be suppressed with dexamethasone. The adolescent girl had a moderate hypercorticism. Functional tests were typical of Cushing's syndrome due to bilateral adrenal hyperplasia. Surprisingly, she improved markedly without any specific treatment.

Cushing's syndrome with a paradoxical response to dexamethasone.

Abstract A paradoxical response to dexamethasone was observed in a patient with Cushing's syndrome due to bilateral adrenal hyperplasia. Postoperatively the patient died and was found to have a basophil adenoma of the pituitary. In two separate tests the administration of dexamethasone caused increases in urinary 17-hydroxysteroids and 17-ketosteroids. After the administration of dexamethasone, plasma ACTH activity appeared slightly increased and urinary 17-hydroxysteroid metabolites were similar to those found after the administration of ACTH. Metyrapone caused an initial rise in urinary 17-hydroxysteroids due to an increase in tetrahydro-11-deoxycortisol, as would be expected, but a much larger increase in adrenal corticoid excretion occurred on the second and third days after metyrapone treatment and was associated with the reappearance of urinary cortisol metabolites. Incubation of adrenal slices in the presence of dexamethasone did not stimulate the conversion of labeled acetate to cortisol. These findings implicate the pituitary adenoma in the paradoxical response, and suggest that it was mediated by ACTH. The early response to metyrapone indicates that there was an intact positive feedback mechanism, the late rise in cortisol metabolites suggests that ACTH secretion was also paradoxically stimulated by endogenous adrenal corticoids.

INTERFERENZMIKROSKOPISCHE UNTERSUCHUNGEN AN ZELLEN VERSCHIEDENER HYPOPHYSENADENOME

ABSTRACT The dry mass of the cells of a chromophobic, eosinophilic and basophilic adenoma of the pituitary gland is calculated with the use of a Zeiss interference microscope. The dry weights per unit area of the eosinophilic cells are the largest, followed by the chromophobic and the basophilic. The dry weights are compared with the activity of the cells. The errors based on the method are discussed.

Roentgen Aspects of Pituitary Tumors Manifested after Bilateral Adrenalectomy for Cushing's Syndrome

In 1958, Nelson et al. (13) first described an ACTH-secreting chromophobe adenoma after bilateral adrenalectomy in a patient with Cushing's syndrome. Since that time other cases in which previously unsuspected pituitary tumors became manifest after adrenalectomy have been reported (1–3, 5, 6, 8, 9, 11, 14, 15, 17). In these, the pituitary tumor was diagnosed in from one to ten years after adrenalectomy. Most of the patients were women, reflecting the predilection of Cushing's syndrome for females. The pituitary tumors in these patients were chromophobe adenomas, basophil adenomas, or mixed basophil and chromophobe adenomas, and carcinomas composed of either basophilic or chromophobic components. Cushing's syndrome resulting from adrenocortical hyperfunction is frequently treated by bilateral total or subtotal adrenalectomy. Since it has become apparent that in some of these patients evidence of pituitary tumor may develop after adrenalectomy, routine follow-up roentgenograms are essential. Report of Cases...

Symposium on pituary tumours (4) Unusual pathological features

Some aspects of tumour pathology in the pituitary region are discussed. Material from 83 cases of anterior lobe tumours is reviewed and the range of histological appearances illustrated. The massive suprasellar extension of the chromophobe adenomas, often more to one side than the other, is stressed. Eosinophil and basophil adenomas were encountered infrequently. Of the tumours of the posterior lobe, a few gliomas have been described, whilst those resembling in structure the infundibulum, involve the pituitary stalk and adjacent floor of the third ventricle, into which they protrude. Intrasellar and suprasellar cystic tumours form the third group in this review and evidence is presented confirming the similarity in pathogenesis of craniopharyngioma to other intracranial epidermoids.

Zytologische Beobachtungen an der hyperplastischen Nebennierenrinde des Menschen

Clinical observations and the light and electron microscopic appearance of the adrenal cortex are described in a case of Cushing's disease associated with adrenocortical hyperplasia and a basophilic adenoma of the pituitary gland. The electron microscopic investigation concentrates upon the occurrence of osmiophil material in the different cytoplasmic compartments of the cell type rich in organelles and relatively poor in paraplasmic inclusions. It seems that the observation of osmiophil material in the perinuclear space, the mitochondrial matrix, Golgi vacuoles, and cytoplasmic vesicles has been made possible by a rather long fixation in Wohlfarth-Bottermann's chromium-osmium fixative. Mitochondria and related particles (named X-Einschlusse) may contain a light center with a few dense filaments and masses resembling those described by other authors as being of deoxyribonucleic acid nature. Relatively large Golgi complexes are found, sometimes in close topographic relation with a centriole. A large population of osmiophil bodies (lipid droplets, pigment granules, microbodies) is described. Apart from these findings the cytoplasmic organization in the tissue studied is similar to that of the adrenal cortex as described in other mammals. The observations are discussed with respect to hypotheses about lipid droplet formation and to the possibility of artifacts due to preparation procedures.

The Basophil Adenomas of the Pituitary Body and Their Clinical Manifestations (Pituitary Basophilism)

The Basophil Adenomas of the Pituitary Body and Their Clinical Manifestations (Pituitary Basophilism)

Form of Conjugation of Steroids in Urine and in the Adrenal Glands of a Patient with Cushing's Syndrome Owing to Adrenal Cortical Hyperplasia and a Basophilic Adenoma of the Pituitary Gland

Several steroids in the urine and adrenal tissue of a boy with Cushing's syndrome and a basophilic adenoma of the pituitary gland have been studied. The outstanding observation was that large quantities of free cortisol were excreted; a considerable amount of this hormone was also found in the adrenal tissue. There appeared to be deficiencies in the mechanisms for conjugation with glucuronic acid, for the reduction of the Δ4-3-keto grouping and for the dehydrogenation of 11β-hydroxysteroids. In this paper we also report the identification and isolation of 6β,17α,21-triol-4-pregnene-3,11,20-trione (6β-hydroxycortisone).

INVASIV GEWACHSENES BASOPHILES ADENOM DES HYPOPHYSENVORDERLAPPENS BEI CUSHING-SYNDROM

ABSTRACT A case report is presented of a female patient with an invasive basophil adenoma of the anterior pituitary gland and with Cushing's syndrome. Following a review of the literature of Cushing's syndrome with expanding and invasive pituitary tumours with and without metastases we have divided these tumours into three groups: Pituitary tumours, which arise with no surgical treatment of the adrenals. Tumours of category 1, the growth of which is accelerated following adrenalectomy. Tumours whose growth is accelerated following adrenalectomy, but which are recognized clinically only after surgical treatment of the adrenals. Most of these tumours are now considered to be »hyperplasiogenic« growths, which continue to remain under the influence of hypothalamic factors. Primary autonomous, ACTH-secreting tumours are on the contrary seldom seen. Histological criteria are insufficient to differentiate between autonomous and regulated pituitary ACTH-producing tumours. It is assumed that this differentiation may be only possible by means of function-tests.

Steroids and the skeleton.

Harvey Cushing in 1932 first described the syndrome of obesity, hypertension, weakness, and depression of sexual function which has since become classically designated by his name. The condition was attributed by him to overproduction of pituitary adrenocorticotrophic hormone in association with the presence of a basophil adenoma. Although he postulated that the consequent stimulation of the adrenal cortex resulted in endogenous overproduction of the adrenocortical steroids, it has since been shown, largely as a result of the work of Albright, Parson, and Bloomberg (1941), that the presence of such an adenoma is not essential for the development of the syndrome. Primary disease of the adrenal cortex itself, either simple hyperplasia or benign or malignant neoplasia, is the more common cause, without stimulus from the pituitary. The hormones responsible for the skeletal changes in this condition are cortisone and hydrocortisone. During the last decade, these substances and similar steroids have been made available for therapeutic use and a number of instances of iatrogenic disease have resulted from their employment. These untoward sequelae are relatively uncommon, and individual radiologists may not encounter personally all the varieties that may occur. That such therapy may result in fully developed Cushing's syndrome, with its principal skeletal manifestations of osteoporosis, pathological fractures, and abnormal callus formation, is now well recognised. Study of the literature, however, indicates that certain lesser changes may be observed, particularly in connection with intraarticular injections. Diminution of pain sense and suppression of inflammatory reaction as a result of a surfeit of these hormones, whether natural or therapeutic, may cause the diagnosis of such lesions to be delayed. Radiological Changes in the Skeleton in Cushing's Syndrome (a) Osteoporosis: The generalised increase of translucency affecting the bony structures in the majority of patients suffering from Cushing's syndrome results from inability to lay down the osteoid tissue or protein matrix, which is an essential preliminary to the formation of new bone. Such bone as is present is normally calcified. This condition, therefore, is a true example of osteoporosis. In a minority of patients, and in early cases, no radiological bone abnormality can be detected. When only minimal changes of osteoporosis are present, differentiation on radiological grounds from osteoporosis of other origin cannot be made. Cushing recognised osteoporosis as a fundamental feature of the syndrome and this observation was confirmed by Eisenhardt and Thompson (1939) and by Sussman and Copleman (1942). The condition is usually first visible in the spine, where a fine, vertical linear striation becomes apparent, with consequent prominence of the vertebral plates. The skull, ribs, and pelvis become similarly affected.

Ocular manifestations of pituitary tumor in Cushing's syndrome.

The series of cases to be reported in this paper represent a most unusual group. Not only did the patients have an interesting association of pituitary tumor with Cushing's syndrome,1but we think that the ocular findings are unusual enough to warrant presentation in the ophthalmic literature. From discussions with colleagues and a review of the literature, it appears that ophthalmologists are not aware of the association of pituitary tumor with Cushing's syndrome. Furthermore, the belief still exists that a pituitary tumor in conjunction with Cushing's syndrome must be a basophil adenoma rather than a chromophobe adenoma. The opinion that basophil adenomas occur in Cushing's syndrome stems from the original observations made by Cushing,2in 1932, on small basophilic tumors of the pituitary. He emphasized their possible role in the production of the syndrome bearing his name. Interest has continued in the relationship between the anterior pituitary and