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Adrenal cortical carcinoma is a rare diagnosis and may present with hormone secretion. A histological differentiation between an adrenal cortical adenoma and carcinoma can be very difficult. However, a fast diagnosis including staging and complete surgical resection is pivotal for the prognosis of an adrenal cortical carcinoma. Metastasing adrenal cortical carcinoma should be treated with a mitotane based chemotherapy, and inclusion in the "firm-act study" is highly recommended. The present case report demonstrates the diagnostic pitfalls in a female patients with Cushing's syndrome who suffered from metastasing adrenal cortical carcinoma.

Adrenal tumors can be primary or secondary entities. Primary tumors are able to secrete hormones which may cause significant effects clinically. Typical tumor-related adrenal diseases are Conn's syndrome (hyperaldosteronism), Cushing's syndrome (hypercortisolism), and pheochromocytoma (catacholamine excess). Primary adrenal tumors are rarely malignant, but adrenocortical neoplasias show a relation between tumor size and rate of malignancy. Diagnostic methods for adrenal tumors include hormone tests and imaging. The first choice of treatment is surgical removal, today preferably by minimally invasive approaches.

Introduction: Conventional adrenalectomy still plays an important role, even in the era of minimally invasive endocrine surgery. It was the aim of our study to analyse the indications for conventional adrenalectomy in our own patients since the introduction of the minimally invasive technique in the year 1994 - laparoscopically and retroperitoneoscopically., Patients and Methods: Between January 1994 and September 2006, a total of 412 adrenalectomies were performed in 380 patients. Out of these, 106 operations (25.7 %) were carried out conventionally in 98 patients, and 306 operations (74.3 %) endoscopically in 282 patients., Results: Indications for conventional adrenalectomy were - as compared with the minimally invasive procedure - significantly more frequent adrenocortical carcinomas (ACC), especially in the context of multivisceral resections, as well as adrenal metastases (synchronous and metachronous). In contrast, adrenal Cushing's disease (including 19 patients with bilateral tumours), pheochromocytoma, incidentaloma and Conn's syndrome constituted a more frequent indication for minimally invasive adrenalectomy. Conventionally operated adrenal pathologies with on average 6.0 (range: 1.2-19.0) cm diameter were significantly larger than the endoscopically removed tumours with on average 3.3 (range: 0.2-9.2) cm diameter (p < 0.0001). The side localisation and the frequency of bilateral adrenal tumours did not differ significantly in the two groups., Conclusion: Since the establishment of the minimally invasive technique in 1994, conventional adrenalectomy has been selected for 26 % of all resected adrenal pathologies at our clinic and, therefore, still plays an important role even in the era of laparoscopic surgery. The benefit of the laparoscopic procedure in the case of malignant pheochromocytoma, adrenocortical carcinoma, and isolated adrenal metastases at a locally confined stage is still unclear and requires prospective, randomised studies.

ACTH-independent macronodular bilateral adrenal hyperplasia (AIMAH) is a rare cause of endogenous Cushing's syndrome. Here, massive bilateral adrenal enlargement is accompanied by ACTH-independent hypercortisolism. The detection of ectopic hormone receptors which, according to a new concept, control the cortisol production in AIMAH, offers the opportunity of normalizing the hypercortisolism by pharmacologically influencing the receptor or its ligand. We here present the case of a 46 year old male patient. Using clinical and pharmacological tests we found evidence of ectopic receptors in the AIMAH. After suspicion was erroneously raised that a malignant lesion could be inside of the right adrenal mass, the decision was made to resect both adrenals instead of trying to treat the hypercortisolism by pharmacological means. This surgical approach (bilateral adrenalectomy) has been the standard way of treatment for AIMAH until the new concept of the ectopic receptors was developed.

Adrenocortical tumours have to be differentiated from cortical hyperplasias, medullary tumours and extra-adrenal tumours or metastases. These diagnoses are mostly possible using routine paraffin sections. In some cases, immunostaining for differing cortical and medullary tumours and metastases are necessary. Adrenal hyperplasias can be congenital or acquired. They are diffuse, micronodular or macronodular and may be inactive or induce a cortical hyperfunction. Very rarely, macronodular hyperplasias may transform into autonomous adenomas. Primary, pigmented adrenocortical disease is a rare, special type of primary adrenal Cushing's syndrome, showing many small tumours with pleomorphic cells and an atrophic surrounding cortical tissue. Adrenal adenomas are mostly unilateral and solitary tumours weighing less than 50 g. Adrenal cortical carcinomas are mostly larger. Like the adenomas, they may be inactive and may induce a hypercortisolism, a hyperandrogenism or (very rarely in carcinomas) a hyperaldosteronism. Differentiating cortical adenomas and carcinomas is difficult in some cases but is possible using a diagnostic algorithm. Myelolipomas are benign, inactive tumours composed of mature fat cells and bone marrow cells. They have to be differentiated from adenomas with myelolipomatous metaplasia. Further, rare primary cortical tumours are mentioned.

A 19-year old patient was admitted to our hospital with the typical stigmata of a prolonged Cushing's syndrome. He presented first at another hospital with elevated ACTH values and the diagnosis of pituitary Cushing's syndrome was made. A partial hypophysectomy was performed, but neither this nor a therapy with ketokonazole could influence the cortisol levels. Because of this background the diagnosis of ectopic ACTH-production was established. Since we were not able to locate a source of ACTH, we recommended a bilateral adrenalectomy, after which the symptoms of Cushing's syndrome disappeared within a few months. About one year after the operation a CT-scan demonstrated an intrapulmonary mass, which was removed surgically. There were neither signs of local infiltration nor of lymphogenic metastasis. The histological and immunhistochemical diagnosis was typical of bronchial carcinoid with ACTH-production. The follow up so far did not reveal a recurrence.

Endoscopic techniques are used increasingly in adrenal gland surgery. In this paper the indications and results of the laparoscopic and retroperitoneoscopic approach are compared to the results of the conventional trans- and extraperitoneal approach. Endoscopic adrenalectomy can be performed safely and with the benefits associated with minimally invasive surgery. Disadvantages of the laparoscopic, transperitoneal approach are the risk of an intraabdominal injury and the problems caused by adhesions after abdominal operations. The retroperitoneoscopic approach avoids these disadvantages. Anatomical orientation is more difficult using the retroperitoneoscopic access. In case of large tumors of the adrenal gland suspected for malignancy we see the indication for the conventional transperitoneal approach.

History and Clinical Findings: A 29-year-old woman was found to have arterial hypertension (175/115 mm Hg). The 24-hour profile showed no diurnal cortisol variations with normal concentrations and 24-hour urinary cortisol was normal. 14 months later there was definite hypercortisolism with discrete Cushing signs and no amenorrhoea. She also had signs of depression., Investigations: Routine laboratory tests were unremarkable. ACTH and dehydroepiandrosterone levels were reduced and there was marked hypercortisolism (600 micrograms/24h). Bone densitometry showed osteoporosis. The low- and high-dose dexamethasone inhibition tests showed no suppression of 24-hour urinary cortisol, raising the suspicion of adrenal cortical adenoma or carcinoma. Magnetic resonance imaging (MRI) of both adrenals was normal, and scintigraphy showed physiological storage. MRI of the skull was normal., Treatment and Course: As ACTH-independent hypercortisolism had been proven, unilateral adrenalectomy was performed. The specimen showed primary pigmented nodular adrenocortical dysplasia (PPNAD). While cortisol levels and blood pressure were at first normal, hypercortisolism had recurred 5 months postoperatively. The other adrenal was removed and showed a similar histology. A malignant melanoma of the shoulder was also found, perhaps part of a Carney syndrome., Conclusion: PPNAD should be included in the differential diagnosis of an ACTH-independent Cushing's syndrome with normal adrenal on imaging, perhaps as part of a Carney syndrome.

Fifty patients with adrenal tumors (18 men and 32 women, average age 51.8 years) underwent laparoscopic adrenalectomy from February 1992 to October 1995. Clinical diagnosis included pheochromocytoma in 3 patients, primary aldosteronism (including 1 with a 11-OH-corticosterone-producing tumor) in 15, Cushing's syndrome (including 7 with pre-Cushing's syndrome) in 13, non-functioning tumors in 17, 1 metastatic adrenal carcinoma, and 1 adrenal tuberculosis. Transperitoneal laparoscopic adrenalectomy was performed by the method reported previously. Extraperitoneal laparoscopic adrenalectomy was performed with the patient under general anesthesia in the lateral position. A working space was created by inserting a balloon dissector through a small skin incision. A total of four trocars were inserted. Three of the 50 patients were switched to open surgery, including 1 with metastatic adrenal carcinoma and 1 with adrenal tuberculosis. Laparoscopic tumor removal was successful in the other 47 patients. The average operating time and blood loss were 209 min and 177 ml, respectively. Blood loss was greater in the patients with pheochromocytoma. In patients with Cushing's syndrome, postoperative recovery tended to take longer. Postoperative complications occurred in 40% of the patients in this group, but all complications were minor and successfully treated without any surgical procedures. In the 10 patients undergoing retroperitoneal laparoscopic adrenalectomy, operative courses were excellent, excluding 1 patient with adrenal tuberculosis. Although laparoscopic adrenalectomy is considered to be appropriate for patients with pheochromocytoma and Cushing's syndrome, it appears unsuitable for the removal of malignant and inflammatory lesions.

We present a patient with an ACTH producing neuroendocrine tumor of the hepatic bile duct which was detected by chance during abdominal surgery for Cushing's syndrome. Diagnostic strategy and surgical therapy in patients with neuroendocrine tumors are discussed. The diagnostic problems caused by combination with an endocrine function disorder like Cushing's syndrome are pointed out.

A 59-year-old female patient with mild clinical features of a Cushing syndrome underwent surgery for a suspected hormonally active tumor of the left adrenal gland. Surprisingly, the adrenal gland was unremarkable, however, a tumor in the pancreatic tail was found. A left pancreatic resection with splenectomy resulted in curative removal of the tumor. The pathohistological examination of the tumor established the diagnosis of an ACTH-producing pancreatic carcinoid. Morphology and pathogenesis of pancreatic carcinoids which are tumors of the APUD-cell-system are discussed in detail.

A 36-year-old patient developed marked pigmentation, marked myopathy and severe hypokalaemic alkalosis which at first pointed towards an ectopic ACTH syndrome. The dexamethasone test at a high dose indicated cortisol suppression. A mediastinal tumour was seen radiologically, but the sella was of normal size. Computed tomography provided indirect signs of a sellar space-occupying lesion which suggested an ectopic production of corticotropin-releasing factor (CRF) as cause of the Cushing's syndrome. CRF concentration in antecubital venous blood was markedly elevated to 280 ng/l. The mediastinal tumour was excised and proved to be a carcinoid histologically. Postoperatively the CRF concentration fell to 70 ng/l. An extract of the carcinoid contained 15.5 ng/g wet-weight of CRF and 254 ng/g wet-weight of beta-endorphin. The patient died 5 weeks postoperatively of sepsis with bilateral pneumonia. At autopsy the hypophysis was of normal size but showed nodular ACTH-cell hyperplasia. This was thus a case of Cushing's syndrome resulting from ectopic CRF production in a mediastinal carcinoid tumour.

Electron-microscopic investigations on two human adrenal gland tumors have been carried out. The glucocorticoid and androgen producing tumor predominantly showed mitochondria similar to those of normal human zona fasciculata and zona reticularis. On the other hand, the non hormone producing tumor failed to imitate typical adrenal gland mitochondria. "Light" and "dark" cells were seen like in the normal adrenal cortex. Although a few liposomes were found in nearly all cells only 6 to 8% of the cells contained liposome numbers comparable to normal adrenal gland. A possible explanation is discussed.

98 biopsies of the paraadenomatous adenohypophysis in acromegaly, galactorrhea combined acromegaly, isolated galactorrhea, hypothalamic-hypopphysial Cushing's disease. Nelson's syndrome, and in nonfunctional adenomas were studied by light microscopic methods in order to find evidence for a possible hyperplasiogenic origin of the different types of adenomas. It was hoped that the numerical relations and structures of hypophysial cells might provide significant information. Nodular ACTH cell-hyperplasia was found frequently apart from ACTH cell-tumors in Cushing's disease and Nelson's syndrome and on this basis we suggest that the adenomas in both diseases arise from hyperplasia. During their further development these adenomas seem to become autonomous, since the number of paraadenomatous ACTH cells decreased in bigger tumors. Some of the cases with isolated galactorrhea showed hyperplasia of acidophil and chromophobe cells in the paraadenomatous adenohypophysis. It can thus be assumed that porlactin cell-tumors also develop from prolactin cell-hyperplasia. Both the adenomas and the nonfunctional tumors in acromegaly seem to grow autonomously from the beginning, since paraadenomatous hyperplasia is seldom seen.

This paper reports the results of 42 CT-aided fine needle biopsies of adrenal masses in 40 patients (26 were smaller than 3 cm., six smaller than 1 cm.). There were 25 adenomas, seven metastases, one primary carcinoma, one case of tuberculosis, two phaeochromocytomas and four post-inflammatory lesions. Diagnostic material was obtained in 88%. There was one incorrect diagnosis and on five occasions the result was indefinite, leading to an accuracy of 73%. Exclusion or demonstration of malignancy was, however, correct in 85%. There were no complications except for one unimportant pneumothorax.

The presented paper includes the medical records of two girls with adrenal cortical carcinomas on the one hand and the detailed analysis of a collected series of 150 equal cases in pediatric literature on the other hand. In our patients there were a primarily metastatic, non-functioning tumour and a locally invasive, hormone-secreting neoplasm respectively. The latter one produced a Cushing's syndrome with signs of virilization. In this case surgical removal was followed by postoperative irradiation and adjunctive cytostatic therapy with cyclophosphamide and adriamycin for one year. But tumour recurrence occurred within 6 months. A treatment with the antitumour agents aminogluthetimide and o,p' DDD was transiently effective. However drug-induced side effects necessitated the stop of this regimen after 5 months. The analysis of 150 case reports revealed a peak between 1 and 3 years of age, a striking prevalence of the female sex in all age groups, and a metastasizing rate of about 30% at the time of diagnosis. Regional structures, liver and lung were the main locations of metastatic lesions. The occurrence of second primary neoplasms and the association with a group of other conditions particularly congenital disorders have proved to be a remarkable feature of the disease. In primary adrenal cortical tumours the determination of the neoplasm's biological behaviour by morphologic criteria alone can often be very problematical. This fact is especially stressed.

Pituitary adenomas are usually classified according to the nature of their proper hormonal production. Silent adenomas of the pituitary are tumors without clinical and biochemical evidence of overproduction of any known adenohypophyseal hormones. The proportion of such seemingly nonfunctioning tumors is 20 to 30%. Silent corticotropic adenomas are able to synthesize some normal or abnormal sequences of proopiomelanocortin precursor without any signs of hypercorticism. These tumors were divided into basophilic adenomas with strong periodic acid-Schiff (PAS) positivity and chromophobic adenomas with moderate or no PAS positivity. All of our cases were chromophobic adenomas. Two of the cases were positive for beta-endorphin by immunofluorescence. ACTH immunoreactivity was not present in the cells. Electron microscopic study of the adenoma cells showed small secretory granules with a halo. The diameter of these granules varied from 50 to 250 nm. Automated morphometric and densitometric investigations of silent corticotropic adenomas and adenomas from patients with Cushing's disease gave different karyometric results. The most important practical problem arising from the present investigation was the high frequency of recurrence of silent corticotropic tumors.

This paper reports ultrastructural comparision of the adrenal gland zones of a rare case of a combination from Cushing's syndrome and hyperaldosteronism with a pure Cushing's syndrom and with a normal human adrenal gland. Whilst between the zona glomerulosa of the normal adrenal gland and of the Cushing's syndrom there are no differences, the morphological state of the glomerulosa cells of the Cushing's syndrom in combination with hyperaldosteronism is interpreted as an inhibition of the activity of these cells. In the cells of the hyperplastic zona fasciculata of Cushing's syndrom in combination with hyperaldosteronism, there are no electronmicroscopical characteristics, who are morphological equivalent of the production of aldosterone. The abundant quantity of steroid producing organells in these cells point to a high function. The cells of the adenoma of Cushing's syndrom contain abundant vacuols of lipids, in which presumable are stored steroid hormones.

Bilateral adrenalectomy was performed in a 27-year-old male because of Cushing's syndrome. After 7 years a peripheral bronchial carcinoid was diagnosed; ACTH values went back to normal only after removal of the carcinoid. In the literature, there are 31 case reports on bronchial carcinoids associated with Cushing's syndrome. The Cushing's syndrome precedes the diagnosis of a tumor for months to years in at least half of the cases. Most of these patients first underwent adrenalectomy and/or hypophysectomy for their primarily endocrine symptoms and signs.

A set of 131 pituitary adenomas has been investigated morphometrically and densitometrically by use of a system for automatical microscope picture analysis (AMPA). About 500 nuclei per adenoma have been scanned for estimating 20 nuclear and tissue parameters (5 and 10 min per adenoma). Endocrine inactive adenomas differ significantly by some parameters from active adenomas. The cell nuclei of inactive tumors are smaller, of more spherical and have higher extinction values on an average. The nuclei of adenomas from patients with Cushing's syndrome differ from the nuclei of prolactinomas and acromegalics because of their lower similarity to spheres. We found no correlation between the nuclear and tissue parameters analyzed in this study and the blood hormone levels.

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.

Pituitary adenomas should be classified by the grade of differentiation in undifferentiated (acidophil or mucoid cell type) and in highly differentiated types. Corresponding to their structural identify, the latter are separated into GH cell-, prolactin cell-, TSH cell-, or ACTH cell-adenomas. Chromophobe adenomas which are nearly ungranulated tumors, were divided into small cell- and large cell-adenomas and into oncocytic adenomas. Undifferentiated acidophil and GH cell-adenomas mostly induce an acromegaly. Undifferentiated mucoid and ACTH cell-tumors result exclusively in a hyperfunction of ACTH. The morphological correlate of a hyperprolactinemia is variable. Chromophobe adenomas of small cell type and oncocytic adenomas are on the whole endocrinologically inactive. Studies of the paraadenomatous adenohypophysis let us assume that prolactin cell- and ACTH cell-adenomas develop from hyperplasias of the specific cells. In animal experiments, pituitary adenomas can be classified into highly differentiated (prolactin cell-, TSH cell-, or ACTH cell-adenomas) and also into undifferentiated adenomas. The highly differentiated ones develop hyperplasiogenic and are monohormonally active. They are on the whole structurally identical with the human adenomas. The undifferentiated ones are the consequence of a process of dedifferentiation. They show in part a plurihormonal activity.