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Clinical and laboratory data, histologic, electron microscopic and immunocytochemical findings of the tumors of eight patients suffering from Cushing's syndrome and of one patient with hypercalcemia are described. The unlabeled antibody enzyme method was used for the detection of insulin, glucagon, somatostatin, pancreatic polypeptide, corticotropin, beta-lipotropin, calcitonin, parathyroid hormone, and gastrin. Ectopic Cushing's syndrome was caused by pancreatic endocrine tumors, medullary thyroid carcinoma, a bronchial, a gastric and a thymic carcinoid, and a carcinoid of the mediastinum. Hypercalcemia in one patient was related to a pancreatic endocrine tumor. After surgery the clinical symptoms disappeared in two patients, but persisted or relapsed in five patients. ACTH-immunoreactivity could be demonstrated in six of eight tumors; calcitonin-immunoreactivity was found in the tumor of the patient suffering from hypercalcemia. ACTH-immunoreactivity could be localized to secretory granules by immunoelectron microscopy, and the presence of ACTH and beta-LPH in the same tumor cells could be shown in one pancreatic tumor. A combination of production of orthotopic and ectopic hormones was found in one, and secretion of two ectopic hormones was detected in another pancreatic endocrine tumor.

Chronic stimulation of the ACTH-cells in rats was undertaken by adrenalectomy, chemical adrenostasis, by application of a CRF-analog and by non-specific means. The ultrastructural findings of the ACTH-cells were compared to those of the human pituitary gland in Cushing's disease. The pituitaries of 12 patients with the hypothalamic-hypophyseal form of Cushing's syndrome were studied by electron microscopy. A good correlation of the experimental observations to those in human pathology could be seen in the first steps of reaction. There was an enlargement of the ACTH-cells with well developed organelles and there was a simple hyperplasia. The following forms of reaction, nodular hyperplasia and adenomas, were only observed in the human pituitary glands. Chronic suppression by steroids leads to a diminution of the single ACTH-cell and their organelles and a reduction. The appearance of Crooke's cells is specific for the human pituitary and is not reproduced in animal experiments.

An 18-month old infant with Cushing's disease due to an ACTH producing pituitary tumor is presented. The case showed typical clinical and morphological sings of hypercortisolism. The infant died of pulmonary thromboembolism after transsphenoidal partial adenomectomy. The adrenals were diffusely hyperplastic. The pituitary adenoma was classified as an undifferentiated mucoid cell adenoma with sparse granulation by light microscopy. Immunoenzymatic studies demonstrated ACTH not only in granulated adenoma cells. Ultrastructurally the cells were only differentiated as typical ACTH cells or so-called follicular cells in small areas. Most of them were undifferentiated, showing pleomorphism of the relatively sparse organelles. In-vitro experiments using suspensions of adenoma cells showed a distinct enhancement of ACTH secretion after arginine-vasopressin and a further decrease ultrastructurally in the number of secretory granules. No effect of ACTH levels and no alterations of the ultrastructure were observed after cortisol. The case is representative of typical hypothalamic-hypophyseal Cushing's disease with an undifferentiated pituitary adenoma secreting ACTH in part autonomously. This constellation of Cushing's syndrome is extremely rare at the age of one year. Our case is the second one reported in the literature.

Two patients, one with malnutrition due to anorexia nervosa and one with Cushing's syndrome, showed evidence of cerebral atrophy by computed tomography (CT) of the brain. Several months after the original diagnosis of cerebral atrophy, follow-up CT studies demonstrated essentially total return to normality. It is postulated that the mechanism responsible for the described atrophic changes may be related to protein loss or fluid retention, or both. Correction of these metabolic abnormalities may be followed, as in the two cases reported here, by reversion of the CT findings to normality.

Thirty-eight patients with adrenal adenocarcinoma were reviewed. Two of 23 males and 8 of 15 females had a functioning tumor (P less than 0.005). The most striking finding in this review was the variation in survival according to histologic grade. The median survival from histologic diagnosis was for grade I tumors 54 months, for grade II tumors 26 months, for grade III tumors 1 month. The difference in survival between patients with grade I or II tumors and those with grade III tumors was significant (P less than 0.001). The majority of the patients with grade III tumors were admitted with clinical evidence of disseminated disease and died within 1 month. Among the patients with well-differentiated tumors, five who received surgical treatment of their recurrence had a median survival of 51 months, whereas seven patients who received no surgical treatment had median survival of 20 months following first recurrence (0.05 less than P less than 0.10).

58 cases of Cushing's disease were studied after selective transsphenoidal surgery, by means of histology, immunocytochemistry and morphometry. The qualitative and quantitative results, related to the clinical follow-up of the patients indicated that: 1) when a well-defined tumor was found (62% of the patients), successful outcomes occurred in 88% of the cases, 2) when a tumor could not be found, successful outcomes amounted to only 33% of the cases, a rate that might be related to a surgical exploration of the basophil cell zone "invading" the neural lobe, thus questioning a role of this zone, at least in some Cushing's diseases.

Experience with the surgical treatment of hypercorticism caused by bilateral adrenocortical hyperplasia in 16 patients is discussed. The treatment of choice is bilateral total adrenalectomy. Following subtotal adrenalectomy recurrence occurred in three of six patients; a third operation was needed in two cases, while permanent hypadrenia developed in the third. There was no operative mortality. One patient died 9 years after surgery, but the death was not related to the original disease. The clinical symptoms of hypercorticism subsided in every totally adrenalectomized patient. Indication and contraindication of adrenalectomy, the surgical method, and the problems of pre- and postoperative treatment are discussed.

Chronic excess of glucocorticoids results in Cushing's syndrome in humans. A common cause of excess cortisol secretion is the presence of an adrenocorticotropin secreting pituitary tumor which stimulates the adrenal cortex to produce excess glucocorticoids. ACTH-secreting AtT-20 mouse pituitary cells transplanted subcutaneously in oestrogenized athymic nude mice form tumors rapidly. Six weeks after receiving the tumor transplants, the mice weighed 45% more than normal mice due to the increase in body fat. The tumor-bearing mice exhibit the familial "buffalo hump" appeaance due to the abnormal distribution of body fat. The adrenal glands of the tumor-bearing animals are enlarged due to hypertrophy of the zona fasciculata. The foamy looking fasciculata cells in normal mice were converted to dense, eosinophilic cells in the tumor-bearing mice. Transplantation of normal pituitary glands to athymic nude mice with or without oestrogen treatment did not produce these morphological changes. The experimental model described here may be useful for future studies of Cushing's syndrome.

The case of a 56-year old woman with severe Cushing's syndrome due to ovarian ACTH-production is described. Both clinical picture and biochemical pattern were consistent with the ectopic ACTH syndrome. ACTH was found by specific immunohistochemical staining in a carcinoid tumor of the patient's right ovary. In contrast, pituitary cells exhibited immunoreactive ACTH to only a minimum extent.

Pituitary adenomas from 15 patients with Cushing's disease were studied histopathologically. The tumors were examined for the presence of neural axons by the Bodian silver impregnation technique and a specific immunohistologic technique based on a monoclonal antibody to axonal neurofilaments. Axons were not seen in any of the surgical specimens. This finding suggests that most, if not all, adrenocorticotropin-secreting pituitary adenomas are of anterior lobe origin.

The clinical and autopsy findings are described in two patients with Crushing's disease who died five days and 18 years following bilateral adrenalectomy. In each case tomography of the pituitary fossa was normal but examination of the pituitary revealed a 5 to 6 mm basophilic adenoma in the antero-inferior aspect of the gland. The first patient failed to show suppression of urinary oxogenic steroids during administration of high dose dexamethasone. The second patient had functioning adrenal autografts in skeletal muscle 18 years after adrenalectomy. The clinico-pathological correlation of these two patients supports modern re-emphasis on the aetiology of Cushing's disease as a primary pituitary tumour and its treatment by selective trans-sphenoidal hypophysectomy.

Adrenal pieces obtained from six female patients, three without increased adrenocortical function and three with Cushing's disease, showed, in all adrenal cortex zones, cells containing simple and complex nuclear bodies. The simple nuclear bodies were spherical or ovoid and had a filamentous structure surrounded by a clear halo. Complex nuclear bodies were more numerous and heterogeneous in patients with adrenal pathology, and they were spherical with a proteinaceous filamentous capsule surrounding a core; the core was granular, filamentous or a mixture of granular and filamentous material, sometimes with a reticular or concentric arrangement. Some bodies showed vacuolar or multilocular aspect, and others had a close relationship with the nucleolus or appeared near the interchromatin granules. The meaning of adrenal nuclear bodies is discussed as well as their relationship with ACTH stimulation.

A case of Cushing's syndrome in a 31-year-old woman is presented. The resected left adrenal gland revealed a tumor consisting of cortical cells intermingled with myelolipomatous tissue comparable to that of normal bone marrow. The adjacent cortex was atrophic. Postoperative plasma cortisol concentrations have remained quite low. Previously, 28 cases of surgically removed adrenocortical tumors with a main diagnosis of myelolipoma have been published. Of these, three cases (two pituitary Cushing's disease, one steroid 21-hydroxylase deficiency) were associated with endocrine dysfunction. The combination of a myelolipoma and a true adenoma has only been described once before (in a case of virilization) and never in connection with Cushing's syndrome. The etiology of myelolipoma is discussed, and a local trigger mechanism related to adrenocortical growth disturbances is suggested.

A 36-year-old female was admitted to Asahi General Hospital because of hypertension. Laboratory findings showed elevated levels of urine 17 (11)-hydroxycorticosteroid and blood cortisol. Computerized tomography and ultrasound sonography demonstrated a round tumor at the suprarenal region. The black tumor, 5 X 3 X 2 cm, was removed by left adrenalectomy. Microscopic findings revealed adrenal adenoma consisting of compact cells containing numerous pigmented granules. Postoperative course was uneventful. Hormonal condition was recovered 11 months after operation.

Twenty-seven patients with Cushing's disease underwent transsphenoidal pituitary surgery. After the operation 16 patients were cured, and 11 remained hypercortisolemic. In the cured patients a significantly lower incidence of paradoxical responsiveness to TRH or to LRH was found preoperatively (1 of 16) than in the failures (6 of 11; P less than 0.02, by Fisher's chi 2 test). Furthermore, responsiveness of cortisol to CRH administration was significantly lower in the failures [maximum, 0.30 +/- 0.10 mumol/L (10.8 +/- 3.6 micrograms/dL) vs. 0.50 +/- 0.07 mumol/L (18.1 +/- 2.5 micrograms/dL) in the cured patients; P less than 0.05]. There were no differences in basal plasma cortisol levels, ACTH levels, or suppressibility by dexamethasone between the 2 groups. In the 16 patients who were cured initially, 4 patients relapsed after a mean period of 4 yr. These 4 patients had significantly higher basal cortisol levels postoperatively than those who remained in remission [0.14 +/- 0.03 mumol/L (5.1 +/- 0.8 micrograms/dL) vs. 0.04 +/- 0.01 mumol/L (1.4 +/- 0.3 micrograms/dL); P less than 0.01]. Cortisol responses to CRH after the operation positively correlated with the basal cortisol levels at that time (P less than 0.05, by Spearman's rank correlation test; r = 0.64), thus, the relapsing patients had higher cortisol responses to CRH than patients who stayed in remission [maximum response, 0.31 +/- 0.07 (11.2 +/- 2.5 micrograms/dL) vs. 0.12 +/- 0.03 mumol/L (4.3 +/- 1.1 microgram/dL), respectively; P less than 0.05]. We conclude that 1) patients responding paradoxically to TRH and/or LRH have a lower chance of being cured after pituitary surgery; and 2) patients with higher cortisol levels (greater than 0.10 mumol/L; 3.6 micrograms/dL) after being cured initially have a higher chance of recurrence of their disease.

Using the immunoperoxidase method with specific antibody, we examined the presence of atrial natriuretic peptide (ANP) in adrenal tissues of a patient with primary aldosteronism and those derived from a patient with Cushing's syndrome. We found cells immunopositive for ANP in primary aldosteronism but not in Cushing's syndrome. In primary aldosteronism, we noted positively stained cells mainly but not exclusively in the adenomatous tissue. These results demonstrate for the first time the presence of immunoreactive ANP in adrenal tissues of a patient with primary aldosteronism and suggest that adrenal ANP may have potentially important impacts on aldosterone secretion in this disorder.

Conventional or electron microscopy can contribute significantly to the diagnosis of pancreatic endocrine tumours. These techniques, however, are of limited value for the classification of the tumours, which should take both clinical and morphological findings into account. In this paper a classification based on both the clinical features and on the content of peptide hormone-producing cells in the tumours is presented.