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Ectopia of nodular adrenocortical tissue is very frequently found in the periadrenal region. It corresponds to accessory adrenal tissue and is a normal variant. Ectopia in more distant regions are found in inner male or female genitalia. Strong long-lasting hyperstimultions induce hyperplasia and simulate true tumors ("adrenal rest tumors"). Real autonomic tumors from ectopic adrenal tissue with or without hyperfunction are rare. Ectopia of adrenomedullary tissue are nearly exclusively found in the surroundings of normal medulla. Ectopia in the adrenals corresponds almost exclusively with thyroid tissue. Ectopic secretion of hormones, mostly ACTH, can be found in pheochromocytomas and induces hyperfunction (Cushing's syndrome).

Cushing's syndrome (CS) due to a corticotropin-releasing hormone (CRH) and adrenocorticotropin hormone (ACTH) co-secreting tumor is very rare, and diagnosis can be difficult. We describe a case of CS caused by ectopic CRH and ACTH production from a pancreatic neuroendocrine tumor (pNET) and discuss possible pitfalls in the diagnosis. A 48-year-old woman presented with gradual increase in body weight, muscle weakness, and difficult to control hypertension. Laboratory and imaging investigations revealed ACTH-dependent hypercortisolemia and a 3-cm mass at the head of the pancreas. The patient underwent partial pancreatoduodenectomy. Histological examination revealed a well-differentiated pNET, expressing both CRH and ACTH. After a follow-up period of 18 months, she remains asymptomatic with no metastatic disease. This is the fourth case report of CS in adults due to an ectopic ACTH- and CRH-secreting pNET. Co-secretion of ACTH and CRH by the same tumor may cause diagnostic problems since investigation depends on which of the two hormones is secreted in greater amounts. Measurement of plasma CRH may help in establishing the diagnosis, especially in patients in whom endocrine tests are indicative of ectopic CS, whereas imaging findings are suggestive of pituitary hyperplasia.

The management of adrenocorticotropic hormone (ACTH)-dependent Cushing's disease implies difficulties in the differential diagnosis, in the detection of minute pituitary adenomas, as well as in the radical removal of invasive adenomas. Magnetic resonance imaging (MRI) is unspecific and often negative in minute adenomas of three or less millimeters diameter. The trias of detectable ACTH, suppression of cortisol in the high-dose dexamethasone test, and stimulation in the corticotropin-releasing-hormone (CRH)-test has a high accuracy to prove pituitary dependency. In unclear cases, the use of inferior petrosal sinus sampling (IPSS) or cavernous sinus sampling (CSS) for the exclusion of ectopic ACTH-syndrome is currently advised especially in cases where cranial MRI is negative. The reliability of these methods to localize the mostly lateralized microadenomas is still discussed. Transsphenoidal microsurgical adenomectomy, the accepted primary therapy of Cushing's disease, has been published from experienced pituitary centers with remission rates ranging from 70% to 98% in the last decade. False diagnosis (pseudo-Cushing, ectopic ACTH-syndrome), incorrect adenoma localization by IPSS or CSS, and the rate of minute or non-resectable invasive tumors influence the results. The handling of minute specimen implies problems for surgeon and pathologist. Intraoperative tumor localization was improved by ACTH measurement from the cavernous sinus and the adenoma itself, by cytology, and frozen sections. The histology of the anterior lobe (rate of Crooke's cells) bears information of clinical relevance. Invasive macroadenomas may deserve repeat microsurgery, medical treatment, and radiosurgery.

Background: Microsurgical selective adenomectomy is the best established method available for the treatment of Cushing's disease. However, this surgical method warrants still more efforts to improve the results in minute microadenomas. In this paper the authors evaluate a method of intraoperative cytological investigations during transsphenoidal surgery., Method: Between January 1997 and September 1999, transsphenoidal surgery was performed in 75 patients with the diagnosis of Cushing's disease. Fifty-one cases of proven microadenomas were reviewed., Findings: Of 51 cases, 33 tumors were 3 mm or less in diameter, here after called minute adenomas. In 49 of 51 (96.1%) microadenomas, adenoma tissue was identified by intraoperative cytological techniques. Postoperatively, only 35 of 51 ACTH-secreting microadenomas (68.6%) were confirmed by immunostaining methods. This lower percentage was most probably due to the small amount of tissue obtained. Therefore, in 14 cases (including 12 minute adenomas) the presence of the adenoma was only proven by cytological preparation and clinical outcome. The sensitivity of cytological preparations in cases of confirmed Cushing's disease was 100%., Interpretation: The method described here was particularly well suited for the intraoperative discrimination and documentation of minute adenomas. Cytological preparation appears to be effective in improving the adenoma finding rate and the surgical outcome in cases of Cushing's disease.

A 32-year-old man presenting with typical features of Cushing's syndrome showed baseline cortisol and ACTH values indicating ACTH-dependent disease. Dynamic function tests (dexamethasone, corticotropin releasing hormone (CRH), desmopressin), were suggestive of paraneoplastic ectopic ACTH production. However, inferior petrosal sinus (IPS) ACTH sampling demonstrated a maximum baseline central (363 pmol/l)-peripheral (19 pmol/l) ACTH gradient of 19.1 for the right IPS, conventionally suggestive of Cushing's disease. However, again, IPS ACTH level did not increase after CRH stimulation. Magnetic resonance imaging, while showing no evidence of an intrasellar tumour, revealed an 1.5 x 1.0 cm mass in the left sphenoid sinus which was initially interpreted as most probably being a mucosal polyp. After neurosurgical removal of the tumour, transient secondary adrenal insufficiency was present. The structure and immunostaining characteristics of the tumour demonstrated an ACTH cell adenoma of the pituitary. Ectopic ACTH-secreting pituitary adenomas may cause significant difficulties in differential diagnosis, localisation and appropriate therapy. Thus, although these tumours are rare, they should be included in the list of possible causes of ACTH-dependent Cushing's syndrome.

In Cushing's disease, selective total removal of a corticotroph tumor of the pituitary regularly results in subnormal ACTH- and cortisol plasma levels. The duration of secondary adrenocortical insufficiency varies widely, with an average of 17 months in our patients. The goal of this study is to elucidate the underlying causes for the variation in duration of postoperative hypocortisolism. In this retrospective study, we evaluated 35 patients with postoperative hypocortisolism lasting more than 36 months, and compared them to 51 patients with a duration of less than 36 months. Preoperative data, intraoperative findings, and postoperative results with follow-up evaluations are presented. Extensive pituitary exploration, medial localization of the tumor, and a higher age were associated with increased risk for isolated secondary long-term hypocortisolism. The histological examination of paraadenomateous tissue identified a significantly larger amount of Crooke's cells in long-term cortisol insufficient patients. Previous pituitary surgery increased the risk for hypopituitarism. In some of our patients, the long-term adrenocortical insufficiency resolved after a period of over five years.

Simultaneous bilateral inferior petrosal sinus (IPS) sampling has been repeatedly proposed to be a highly specific approach for the diagnosis of Cushing's disease and 100% sensitivity in detecting autonomous pituitary ACTH secretion by an adenoma has been reported in a large series. We now report on a patient suffering from ACTH-dependent Cushing's syndrome in whom repeated bilateral IPS sampling failed to detect a central/peripheral gradient diagnostic for autonomous pituitary ACTH secretion during initial evaluation. Applying lysine vasopressin as the corticotroph secretatogue, the maximum central/peripheral gradient was 1.0 before and 1.1 following stimulation. Moreover, results of high dose dexamethasone and corticotrophin releasing hormone administration suggested ectopic ACTH secretion. Since thorough diagnostic procedures failed to localise a suspected carcinoid tumour, occult ectopic Cushing's syndrome was diagnosed. Eight years later, a pituitary macroadenoma was detected by magnetic resonance imaging (MRI), IPS catheterisation then revealed a maximal central/ peripheral gradient of 9.3 before and 20.4 after the intravenous administration of lysine vasopressin. Resected tumour tissue was classified as a typical densely granulated ACTH cell adenoma. We conclude that repeated MRI scans should be included in the follow-up of patients with a diagnosis of occult ectopic Cushing's syndrome to avoid the risk of overlooking 'occult eutopic Cushing's syndrome'.

Three cases of a composite sellar tumour composed of a gangliocytoma and an adenoma are presented. Two patients who showed acromegaly and hyperprolactinaemia had a gangliocytoma and a growth hormone (GH)-prolactin cell adenoma in close proximity. The gangliocytoma contained growth hormone-releasing hormone (GHRH) by immunohistochemistry. At the electron microscopical level, the gangliocytoma was characterized by numerous synaptic vesicles. The third patient, a child with Cushing's disease, presented a corticotropin-releasing hormone (CRH)-positive gangliocytoma in close contact with an adrenocorticotropic hormone (ACTH) secreting adenoma, the latter a typical densely granulated ACTH cell adenoma. Ultrastructurally, the gangliocytoma revealed synaptic vesicles and sparse secretory granules. The results suggest that gangliocytomas may promote the development of pituitary adenomas by hypersecretion of releasing hormones. Whereas 20 cases of sellar GHRH producing gangliocytomas in acromegaly are reported in the literature, the combination of a CRH-positive gangliocytoma and an ACTH cell adenoma in Cushing's disease is apparently the first case.

Cushing's disease resulting from intrasellar corticotropin-releasing hormone (CRH)-secreting gangliocytomas is very rare, and only two such cases have been reported in the literature to date. The authors present a third case in which an adrenocorticotropic hormone-secreting pituitary adenoma was found in addition to a gangliocytoma in a 10-year-old girl with clinical and endocrinological symptoms of Cushing's disease. Computed tomographic and magnetic resonance imaging scans showed a suprasellar and parasellar tumor. A green-colored, heterogeneous tumor and a small adenoma were removed transsphenoidally. Histological examination revealed a large gangliocytoma immunoreactive for CRH and a small, mucoid cell pituitary adenoma immunoreactive for ACTH. This is the first case of such a tumor causing Cushing's disease in a child. It might exemplify induction of an ACTH-secreting pituitary adenoma by means of chronic overstimulation of CRH.

A collection of 13 tumors causing an ectopic Cushing's syndrome was composed of four bronchial carcinoids, one small cell carcinoma of the bronchus, one thymic carcinoid, two islet cell tumors of the pancreas, one pheochromocytoma, two medullary carcinomas of the thyroid, one prostatic cancer and one intrasellar choristoma. By immunohistochemistry, ACTH in combination with CRH was found in one bronchial carcinoid and in one islet cell carcinoma. ACTH but not CRH was demonstrable in one bronchial carcinoid, in both medullary carcinomas of the thyroid, in the thymic carcinoid and in the pheochromocytoma. CRH without ACTH was present in the small cell carcinoma of the bronchus, one bronchial carcinoid, the prostatic cancer and the choristoma of the sellar region. Neither ACTH nor CRH could be found in one islet cell carcinoma. In the pituitary (n = 7) Crooke's cells were found except in one case with islet cell carcinoma which was treated with adrenostatic drugs. The pituitary besides the intrasellar choristoma harbored an ACTH cell adenoma. The pathophysiological correlations are discussed.

Pro-opiomelanocortin (POMC) mRNA was demonstrated in pituitary adenomas from 16 patients with Cushing's disease and 10 with Nelson's syndrome. The intensity of signal was significantly greater in Nelson's syndrome than in Cushing's disease and there was a trend towards a greater proportion of positive cells. This probably reflects inhibition of POMC gene expression by the high circulating levels of cortisol in Cushing's disease. In the para-adenomatous gland, the intensity of signal was variable in cells showing Crooke's hyaline change, ranging from negative to strongly positive, in keeping with the functional heterogeneity of corticotrophs. In one case, junctional corticotrophs were present and these were more intensely stained than anterior lobe corticotrophs in the same gland. This supports the concept that these cells are subject to different regulatory influences from corticotrophs in the anterior lobe. Whether this is related to differences in embryological origins or to local factors is at present unclear.

Adrenal tumors are usually diagnosed by clinical symptoms of hormone excess. The increasing use of ultrasound and computed tomography results in the detection of a substantial number of incidentally discovered adrenal tumors. Most of these tumors are nonfunctional adrenocortical adenomas, but a few cases of subclinical cortisol production in "incidentalomas" have been reported. We investigated prospectively the prevalence of autonomous cortisol production in 68 patients (44 females and 24 males, aged 25-90 yr) with adrenal incidentalomas at our institution. As a screening procedure all patients with incidentalomas underwent an overnight dexamethasone suppression test (1 mg). Patients who failed to suppress serum cortisol below 140 nmol/L (5 micrograms/dL) underwent more comprehensive studies (prolonged dexamethasone suppression test, determination of the diurnal rhythm of cortisol secretion in saliva, and CRH stimulation test). Eight patients (12% of all patients with incidentalomas; 5 females and 3 males, aged 25-71 yr) were finally identified as having cortisol-producing tumors, and the findings in these patients were compared with those of overt Cushing's syndrome in 8 patients (8 females, aged 26-50 yr) suffering from cortisol-producing adrenal adenomas. The tumor size of patients with cortisol-producing incidentalomas ranged from 2-5 cm. No specific signs and symptoms of hypercortisolism were present, but arterial hypertension (seven of eight subjects), diffuse obesity (four of eight subjects), and noninsulin-dependent diabetes mellitus (NIDDM; two of eight subjects) were frequently observed. Baseline cortisol levels were in the normal to upper normal range, whereas baseline ACTH levels were suppressed in five of the eight patients. In none of the patients was serum cortisol suppressible by low dose or high dose dexamethasone. The ACTH and cortisol responses to CRH were normal in two, blunted in one, and suppressed in four patients. Unilateral adrenalectomy was performed in seven patients and resulted in temporary adrenal insufficiency in four of them. After surgery, improvement of arterial hypertension, a permanent weight loss in obese subjects, and a better metabolic control of NIDDM were noted in the majority of patients. The following conclusions were reached. Incidentally diagnosed adrenal tumors with pathological cortisol secretion in otherwise clinically asymptomatic patients are more frequently observed than previously assumed. Adrenocortical insufficiency is a major risk in these patients after adrenalectomy. After surgery, hypertension, obesity, and NIDDM may improve. Patients with asymptomatic adrenal incidentalomas, therefore, should be screened for cortisol production by means of an overnight dexamethasone suppression test.

The frequency and the significance of the 3 main features of pituitary in Cushing's disease (ACTH secreting adenomas, ACTH cell hyperplasia, and Crooke's cells) are reported and discussed. In our most recent surgical series (1989-1990) the rate of demonstration of adenoma increased up to 96%. The frequency of paraadenomatous ACTH cell hyperplasia depends on the amount of resected tumor-free tissue. The significance of such peritumorous hyperplasia seems to be low. Crooke's cells as suppressed and transformed ACTH cells were present in each case and are a reliable indicator of a hypercortisolism.

Adrenocorticotrophic hormone (ACTH)-secreting adenomas of patients with Cushing's disease (undifferentiated and well-differentiated ACTH-cell adenomas) were studied ultrastructurally and analysed morphometrically by a computer-supported quantitative image-analysing system. They were compared with identically prepared ACTH tumours (undifferentiated and well-differentiated ACTH-cell adenomas) of pituitaries from bilateral adrenalectomised patients with Nelson's syndrome. The aim of our study was to look for significant differences in ultrastructure and to evaluate these findings statistically regarding adenoma types and clinical syndromes. Clinical syndromes aside, more secretory granules and larger-sized prosecretory granules were measured in the well-differentiated ACTH-cell adenomas. The undifferentiated adenomas showed a greater content of nucleoli and prosecretory granules. Within the adenoma types, comparison of well-differentiated ACTH-cell adenomas showed that the clinical group of Cushing's disease contained larger areas of cytofilaments, whereas the clinical group of Nelson's syndrome had a larger tumour size and more lysosomes. Comparing the undifferentiated adenomas of both clinical groups the adenomas in Cushing's disease contained larger nuclei and more lysosomes, whereas the adenomas in Nelson's syndrome were larger in tumour size and contained larger prosecretory granules. Comparison of well-differentiated and undifferentiated adenomas in Cushing's disease showed more secretory granules and bigger prosecretory granules in well-differentiated adenomas whereas in undifferentiated adenomas the total area of the nuclei is larger, the nucleoli increase in number and size and the lysosomes are more frequent. Comparison of well-differentiated and undifferentiated adenomas in Nelson's syndrome demonstrated more lysosomes in well-differentiated adenomas and a larger total area of the nuclei in undifferentiated adenomas. The differences between the well-differentiated adenomas (mainly more secretory granules and larger prosecretory granules) and undifferentiated adenomas (mainly more and larger nuclei and nucleoli and more prosecretory granules) prove the clear separability between the adenoma types, not demonstrated in the literature up to now. The significant differences between adenomas in Cushing's disease (mainly more cytofilaments) and Nelson's syndrome (mainly more ribosomes and larger prosecretory granules) may be interpreted as different cell reactions due to the hypercortisolism present in Cushing's disease and lacking in Nelson's syndrome following adrenalectomy. Despite the fact that both clinical syndromes are based on the same adenoma types, indistinguishable by light microscopy, significant morphometrical findings in ultrastructure allow a clear discrimination of both clinical types.

Fragments of adrenocorticotropic hormone (ACTH) cell adenomas and anterior lobes of two patients with Cushing's disease were obtained by transnasal operation. Both patients showed the typical clinical course, with postoperative ACTH deficit and all other pituitary functions intact. Equivalent specimens of tissue were investigated by immunocytology and in a superfusion system. The majority of adenoma cells were ACTH-positive, whereas ACTH-secreting cells of the anterior lobes were mostly inactive and were reduced in number. In vitro, adenomatous tissue showed high ACTH secretion into the superfusion medium, which was increased significantly after vasopressin application. Corticoid feedback was impaired Anterior lobe cells exhibited a significant spontaneous ACTH secretion that was reduced by cortisol, but not stimulated by vasopressin. These results support the concept of an impaired corticoid feedback at the adenoma level in the presence of suppressed ACTH secretion of the para-adenomatous anterior lobe.

We report a patient with hypersecretion of a high mol wt ACTH from an aggressive corticotropic pituitary tumor who did not have hypercortisolism. Basal plasma ACTH levels were clearly elevated (26-121 pmol/L), whereas basal and stimulated serum cortisol levels were in the normal range. The pituitary source of the ACTH hypersecretion was confirmed by selective venous catheterization. Gel chromatography of the patient's plasma showed two peaks of ACTH immunoreactivity, one major peak eluting near the void volume (high mol wt form of ACTH), accounting for more than 95% of the ACTH detected, and a very small peak at the expected position of ACTH-(1-39). Plasma ACTH levels were not altered by metyrapone or bromocriptine. During high dose dexamethasone administration plasma ACTH decreased, but was not fully suppressed. Immunohistochemical evaluation of tumor tissue demonstrated ACTH immunoreactivity in 40% of the tumor cells. The patient died from postoperative complications after a second operation performed after tumor recurrence. This patient's course confirms the observations of relatively rapid growth and high recurrence rate in clinically silent corticotropic pituitary adenomas.

A case of primary hyperparathyroidism and coincidental Cushing's syndrome of hypothalamic-hypophyseal origin is reported. The hyperparathyroidism was based on an adenoma of the parathyroid glands and produced a severe hypercalcaemia (4.5 mmol/l) and calcinosis of kidneys and lungs. The Cushing's syndrome was caused by a hyperplasiogenic ACTH cell-adenoma of the pituitary which had induced a regulative hyperplasia of the ACTH-dependent zones of the adrenal cortex. The ultrastructure of the zona fasciculata and reticularis showed a conspicuous activation of the steroid hormone-producing organelles. The two endocrine diseases added together in skeleton, heart, duodenum, and pancreas. As a sign of hyperparathyroidism the osteoclastic absorption of the bone was strongly increased, whereas the bone formation was reduced due to the hypercortisolism. The pancreas showed a severe acute recurrence of chronic pancreatitis which was induced by a parathyrotoxic crisis. This was the immediate cause of death.

A case of a feminizing adrenocortical tumor associated with Cushing's syndrome in a 29 year old male is presented. The ultrastructural features are compared with adrenal tumors secreting aldosterone, glucocorticoids of androgens. As in adrenal carcinomas, this tumor demonstrates nuclear pleomorphism with enlarged nucleoli and nuclear pseudoinclusions. The cytoplasmic organelles show some parallels between feminizing and androgen-secreting adrenal tumors. Different types of mitochondria occur with varying amounts of smooth endoplasmic reticulum. Numerous microbodies are present. Histological and ultrastructural signs indicating probably malignancy are discussed and it is noted that most of the feminizing adrenal tumors are carcinomata. Neither local recurrence nor distant metastases have yet been detected in this case, two years after excision of the 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.