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The purpose of the study is to evaluate the positive predictive value of the combined pituitary dynamic enhanced MRI (dMRI) and high-dose dexamethasone suppression tests (HDDST) in the diagnosis of Cushing's disease (CD) bypassing bilateral inferior petrosal sinus sampling (BIPSS). A total of 118 patients with Cushing's syndrome (CS), who underwent pituitary dMRI, HDDST and BIPSS were included. Positive predictive value of pituitary dMRI, HDDST, BIPSS and the combined test were calculated and tumor lateralization accuracy was further analyzed. The positive predictive value of the combined pituitary dMRI and HDDST was 98.6%, higher than that of BIPSS. There were 96.8% of patients, who had either negative findings in pituitary dMRI or HDDST, showing centralizing BIPSS results. For tumor lateralization, the accuracy by pituitary dMRI was 88.6%, whereas BIPSS was 57.5%. Therefore, CS patients with both positive findings in pituitary dMRI and HDDST need no further invasive evaluation to establish the definite diagnosis of CD. BIPSS will improve the diagnostic accuracy when negative findings were found in either pituitary dMRI or HDDST.

Background: Spontaneous hypercortisolism or Cushing's syndrome in dogs is either pituitary or adrenal dependent, but concurrent pituitary and adrenal hypercortisolism also has been reported., Objective: To determine how often concurrent pituitary and adrenal lesions are present in dogs with spontaneous hypercortisolism., Animals: Two hundred one client-owned dogs with spontaneous hypercortisolism., Methods: Retrospective study. Pre- and post-contrast computed tomography (CT) scans of the pituitary and adrenal glands were performed in dogs with confirmed hypercortisolism., Results: In dogs with dexamethasone-suppressible hypercortisolism (122/201), 78 dogs (64%) had an enlarged pituitary gland (median pituitary height/brain area [P/B], 0.43 × 10 -2 mm -1 ; range, 0.32-1.21 × 10 -2 mm -1 ). Two of these 78 dogs had concurrent adrenal lesions. In the remaining dogs (44/122; 36%), the pituitary gland was not enlarged. In the dexamethasone-resistant group (79/201), the pituitary gland was enlarged in 47 dogs (59%; median P/B, 0.57 × 10 -2 ; range, 0.32-1.50 × 10 -2 mm -1 ). Eight of these 47 dogs (17%) had concurrent adrenal lesions. In the remaining 32 dexamethasone-resistant dogs (41%), the pituitary gland was not enlarged. Among them, 27 dogs had adrenal lesions and suppressed ACTH concentrations consistent with adrenal-dependent hypercortisolism and 5 dogs were diagnosed with pituitary-dependent hypercortisolism., Conclusions and Clinical Importance: Concurrent pituitary and adrenal lesions were present in 5% of all dogs with hypercortisolism and in 10% of the dexamethasone-resistant dogs. Diagnostic imaging of both pituitary and adrenal glands should be included in the diagnostic evaluation of every dog with spontaneous hypercortisolism to obtain information needed for estimation of prognosis and choosing the optimal treatment., (© 2018 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Purpose: The majority of cases of Cushing's disease are due to the presence of a corticotroph microadenoma. Less frequently no adenoma is found and histology shows either corticotroph hyperplasia, or apparently normal pituitary. In this study we have used molecular pathology to determine whether the tissue labeled histologically as "normal" is indeed abnormal., Experimental Design: Tissue from 31 corticotroph adenomas and 16 nonadenomatous pituitaries were subject to methylation-sensitive PCR to determine the methylation status of the p16 gene CpG island. The proportion of methylated versus unmethylated CpG island was determined using combined bisulphite restriction analysis. Methylation status was correlated with immunohistochemical detection of p16., Results: Seventeen of 31 adenomas (54.8%), 4 of 6 cases of corticotroph hyperplasia, and 7 of 10 apparently normal pituitaries showed p16 methylation. Ten of 14 (71%; P = 0.01) adenomas and 2 of 3 cases of corticotroph hyperplasia, which were methylated, failed to express p16 protein. However, only 2 of 7 apparently normal pituitaries that were methylated failed to express p16 protein. Quantitative analysis of methylation using combined bisulphite restriction analysis showed only unmethylated CpG islands in postmortem normal pituitaries; however, in adenomas 80-90% of the cells within a specimen were methylated. The reverse was true for corticotroph hyperplasia and apparently normal pituitaries where only 10-20% of the cells were methylated. Thus, the decreased proportion of cells that were methylated, particularly in those cases of apparently normal pituitary, is the most likely explanation for the lack of association between this change and loss of cognate protein in these cases., Conclusions: To our knowledge this is the first report that describes an intrinsic molecular change, namely methylation of the p16 gene CpG island, common to all three histological patterns associated with Cushing's disease. Thus, the use of molecular pathology reveals abnormalities undetected by routine pathological investigation. In cases of "apparently" normal pituitaries it is not possible to determine whether the change is associated with adenoma cells "scattered" throughout the gland, albeit few in number, or with the ancestor-clonal origin of these tumor cells.

Cushing's syndrome (CS) is associated with low fat-free mass, but it is unclear whether hypercortisolism causes a loss of whole body protein. Body composition was studied prospectively in 15 patients with untreated CS (n = 14 pituitary adenoma; n = 1 adrenal adenoma), in 15 nonobese healthy controls, and in 15 weight-matched obese controls by 3 different methods: total body potassium counting (TBP), bioelectrical impedance analysis (BIA), and anthropometry. In 6 patients, body composition was studied before and within 6 months after pituitary surgery. In CS patients and weight-matched controls, body weight and total body fat were significantly higher than in nonobese controls. In CS patients, TBP was 18.4% lower than predicted, whereas in weight-matched controls TBP was 7.1% higher than predicted. As compared with nonobese and weight-matched controls, in CS patients TBP indicated a significant loss of body cell mass (BCM) of -20.2 and -21.1%, respectively. A significantly reduced arm muscle area of -21.3% compared with weight-matched controls also indicated a loss of whole body protein. In CS, however, BIA overestimated BCM when compared with TBP by +18% and agreement between BIA and TBP in the individual patient was poor (limits of agreement plus minus 27.6%), indicating the invalidity of standard BIA equations in this population. Measurements performed before and 6 months after successful pituitary surgery demonstrated a significant loss of body weight (-11%) and body fat (-33%), but BCM and muscle mass remained on a constant low level. In conclusion, this study shows that, in patients with CS, a significantly reduced BCM indicates a true protein loss. The second interesting finding is that in the early recovery after successful treatment of hypercortisolism patients lose body fat without gaining BCM or muscle mass.

Pituitary gland is an uncommon site of a primary cancer. Of more than 600 cases of pituitary tumors seen at the KFSH&RC between 1975 to 1998 only 3 patients had primary pituitary cancer. We have previously reported a case of pituitary fibrosarcoma arising as a rare complication of external radiotherapy (ERT) for GH-secreting pituitary adenoma (PA) [1]. We report now 2 cases of ACTH-producing primary pituitary carcinoma (ACTH-PPC); their follow-up data provide information on the natural history of this cancer. Patient #1; a 46 year old lady with Cushing's disease (CD) presented with an enlarged right cervical lymph node (LN) 2 years after having undergone a partial hypophysectomy through transsphenoidal surgery (PHYPX/TSS) and ERT for an invasive pituitary tumor. Patient #2; a 26 year old man presented with CD and underwent bilateral adrenalectomy (ADx) and pituitary ERT. Thirty-nine months later he developed Nelson's syndrome and a PHYPX/TSS was performed. Incidentally discovered hepatic metastases in this patient and an excisional biopsy of the LN in patient #1 showed histological features very similar to the pituitary tumor, and they stained strongly positive for ACTH. Perinuclear spherical hyalinized cytoplasmic inclusions were seen in the LN biopsy that corresponded to bundles of type 1 microfilaments (specific for pituitary ACTH-producing cells) seen by electron microscopy. A whole body 18-Fluoro-2-Deoxy-D-Glucose positron emission (FDG-PET) scanning, showed an intense uptake in the neck mass. A trial of octreotide did not change the exceedingly high levels of ACTH in patient #2, further supporting the diagnosis of ACTH-PPC. The clinical course of 102 months prior to his demise showed continued progression of the primary and the metastatic tumor. Patient #1, is alive at 15 months follow-up; hypercortisolemia is controlled using ketoconazole. ACTH-PPC should be entertained in a patient with CD presenting with persistent cervical lymphadenopathy. The clinical course in our patients suggests that the emergence of PC may involve a proliferative continuum from a pre-existing PA to an invasive tumor, culminating in a carcinoma. Adjunctive events such as ERT/ADx may predispose to the evolution of PC in genetically susceptible individuals. Because ERT is an effective treatment for PA its use will continue; it is important to be aware of the possible complication of primary pituitary carcinoma.

Purpose: Evaluate the MR sensibility for detection and localisation of ACTH-secreting microadenomas of the pituitary gland., Patients: and method. The MRI studies of the pituitary gland, performed before transsphenoidal surgical exploration, about 14 patients who present clinical and biological signs of Cushing disease, were reviewed retrospectively. We have always used unenhanced sagittal and coronal spin-echo T1 sequences, and coronal T1 after injection of gadolinium (1 Tesla)., Results: The global sensibility for detection of an adenoma was 100% (84 to 92% when the lesional localisation was considered). The injection of gadolinium increased the sensibility of 38 to 42% according the readers. 7 to 14% of the lesions were isointense after injection. The estimation of lesional size after injection was the nearer to the surgical results. The indirect sign most frequently seen (35.7 to 64.3%) was focal bulging of the sellar diaphragm. The only differences between the different radiologists, statistically significant, concerned the lesional size before injection and location of the lesion in the sagittal plane., Conclusion: This study confirmed the good sensibility of contrast-enhanced MRI in detection of ACTH-secreting microadenomas. The anatomo-radiological correlations are nevertheless incomplete.

The case histories of two young ladies with Cushing's disease are described. Both patients were treated first with Gamma Knife radiosurgery and subsequently by microsurgery. The radiosurgery caused a marked reduction in tumour volume but only a partial relief of the endocrinopathy. Comparison of the histological findings with the radiological findings following radiosurgery indicates that confluent necrosis is not a prerequisite for a reduction in tumour volume. It seems more likely that the reduction in tumour volume is related to changes in cellular dynamics.

Cushing disease in children and adolescents is connected with many technical difficulties in operations for removal of pituitary adenoma from the approach through the sphenoid bone which is connected with anatomical conditions specific for that age group. The greatest difficulty is related to incomplete development of the sphenoidal sinus, which is sometimes spongy or presellar. Besides that, the size of the sphenoidal sinus and sella is small. The surgical methods are analysed which make possible overcoming of these difficulties.

It is unclear whether Cushing's disease results from a primary pituitary disorder or arises in response to abnormal hypothalamic control of the pituitary gland. Clonal analysis can provide information as to whether neoplastic tissue is derived from a monoclonal proliferation of a genetically altered cell or from a polyclonal expansion of a group of cells affected by a common stimulus. We used X-linked restriction fragment length polymorphisms at the phosphoglycerate kinase, hypoxanthine phosphoribosyltransferase, and DXS255 loci in 11 women with biochemically and pathologically confirmed Cushing's disease to determine the clonal origins of corticotroph adenomas and corticotroph hyperplasia. Tumor tissue from all 10 women with morphologically and immunohistochemically confirmed ACTH-secreting pituitary microadenomas demonstrated a monoclonal pattern. Pathologically confirmed corticotroph hyperplasia in a patient with a CRH-secreting bronchial carcinoid was found to be polyclonal. We conclude that corticotroph microadenomas in Cushing's disease are monoclonal, supporting the theory that a spontaneous somatic mutation is the primary pathogenetic mechanism in this disorder. In addition, the demonstration of polyclonality in corticotroph hyperplasia implies that excess of hypothalamic hormones is an etiologic mechanism in cases of Cushing's syndrome associated with ectopic CRH-secreting tumors.

Objective: We assessed pituitary histology in patients with Cushing's disease., Design: Systematic histological assessment of pituitary tissue removed at surgery., Patients: Thirty-six consecutive patients cured from Cushing's disease by transsphenoidal neurosurgery., Measurements: Microscopical examination of all available tissue removed at operation., Results: After selective removal of tissue supposed to represent an adenoma in 25 patients this could be histologically verified in 18. In the 11 patients who had undergone a total hypophysectomy an adenoma could be demonstrated in three patients only, despite a systematic search of the entire pituitary gland. Only in 21 of the 36 cured patients (58%) could an adenoma be verified., Conclusions: Combining the present results with previous reports there is strong reason to believe that in some patients with Cushing's disease no histological lesion in the pituitary is verifiable.

Study of biopsies from 120 pituitary adenomas from the Hospital de Especialidades, Centro Médico Nacional, and the Hospital 20 de Noviembre, ISSSTE, were studied over a period of 55 months. 70 cases were female and 50 male. Ages varied between 18 and 67 years of age (with an average of 31 years). Histologically 41 tumors were chromophobes, 34 acidophilic, 37 mixed and 8 basophilic. 101 patients were operated by trans-sphenoidal (84.5%) and 19 were operated (15.5%) by trans-cranial approaches. 99 tumors were macroadenomas (81.1%) and 21 were microadenomas (18.9%). More than one hormone was found in the cytoplasm of 69 adenomas, although only 20 fulfilled the criteria of being plurihormonal. Those adenomas classified as "non-functional", mostly produced glycoprotein hormones corresponding to oncocytomas and null cell adenomas, from an ultrastructural point of view. 85 patients developed different degrees of visual impairment, with 30 tumoral relapses, of which 10 received radiotherapy. 40 adenomas produced prolactin, although only 29 patients developed clinical signs of hyperprolactinemia; 38 tumors contained growth hormone, of which only 25 had acromegaly; 8 tumors contained ACTH in the cytoplasm, although only 7 developed Cushing's Syndrome and 57 patients (47.5%) were classified as nonfunctional and did not show any endocrinological data. All the cases are studied with a light microscope, electron microscope, and they were all submitted to a complete set of adenohypophyseal hormone with immunoperoxidase technique.

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.

Twenty-eight patients underwent transsphenoidal pituitary surgery for Cushing's disease. Selective surgical procedures were performed in 26. In 19 patients pituitary adenoma was confirmed histologically and 5 had clumps or clusters of ACTH-staining cells. At follow-up after 22.3 (range 5-56) months 21 (75%) patients remained in clinical and biochemical remission. The 24-h urinary free cortisol performed between 1 and 4 weeks postoperatively while patients took replacement doses of dexamethasone (0.5 to 0.75 mg per day) was found to predict outcome. All patients with suppressed urinary free cortisol excretion have remained in remission, 3 with levels in the normal range have suffered late relapse after initial remission, and 4 with elevated urinary free cortisol excretion were regarded as having failed to remit. Furthermore, all patients with unsuccessful outcomes had no pituitary adenoma and 3 had features consistent with corticotrope nodular hyperplasia at histological examination compared to only 2 and 1, respectively, of patients still in remission. We conclude that 24-h urinary free cortisol performed at 1 to 4 weeks postoperatively whilst on low-dose dexamethasone and the histological findings may predict outcome following transsphenoidal pituitary surgery in Cushing's disease.

Fifty-seven patients with pituitary-dependent Cushing's syndrome and eight with Nelson's syndrome underwent transsphenoidal pituitary exploration, with removal of macroscopically abnormal tissue in 64 patients and detailed histology of this in 63. The cure rate by stringent criteria 1 month later was 48 (83%) of the 58 with assessable data, who were followed for 225 patient-years. Two patients relapsed later, a rate of one per 112 patient-years of follow-up. In 27% of patients, the macroscopically abnormal tissue removed was histologically indistinguishable from normal pituitary gland but the cure rate was 82%, and a quarter of the patients in this group assessable for recovery of normal ACTH function gained it. Another 53% of biopsies showed corticotroph adenomas, and the cure rate in these was 89% though rather more (69%) recovered normal ACTH function. The remaining 20% of biopsies were consistent with corticotroph hyperplasia. The cure rate varied little whether the lesion was diffuse or localized, whether or not it was in the invasion zone/interlobar cleft, whether or not there was pituitary enlargement, or whether the surgery was radical or selective. Six patients, of whom three are cured, showed surgical or radiological evidence of invasion outside the pituitary fossa. The data are consistent with the idea that pituitary adenoma is merely the end stage of some other process in the corticotrophs, and cure often follows removal of a lesion other than adenoma. Of patients who were permanently cured, 47% regained normal ACTH function within 3 years of operation (none later), 53% remaining ACTH-deficient at 3 years or more. Of all patients 48% acquired gonadotrophin deficiency, 28% have TSH deficiency and 25% permanent diabetes insipidus. All these pituitary function deficits were more common after radical surgery and in patients with normal histology, The literature contains so little objective data on these functions that we cannot say whether the endocrine damage in our patients is exceptional or not.

This review summarizes current knowledge on pathology of proliferative lesions of the human pituitary. The morphologic classification of pituitary adenomas--based on histology, immunohistochemistry and electron microscopy--has now been firmly established. It has been conclusively proven that all presently recognized adenohypophysial cell types give rise to adenoma and all known pituitary hormones may be secreted in excess. Evidence is accumulating that hyperplasia of various adenohypophysial cell types can lead to hypersecretory syndromes similar to those associated with the corresponding adenomas. Owing to the rarity of studies on pituitary hyperplasia, the condition is still incompletely defined. The difficulties regarding morphologic diagnosis of pituitary hyperplasia are discussed. Despite major advances in the field of pituitary pathology, several problems concerning structure-function relationship, as well as pathogenesis of proliferative lesions are still unresolved. There is strong circumstantial evidence suggesting that the cytological mapping of the pituitary is incomplete and there are still cell types waiting to be discovered.

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.

There is little evidence for a separate functional or anatomical intermediate lobe in the adult human pituitary gland. Nevertheless, Lamberts et al. (1982) proposed that a subgroup of corticotroph adenomas in Cushing's disease arise in that lobe and can be identified by the presence of argyrophil (? neural) fibres, and that these tumours are more often associated with corticotroph hyperplasia and hyperprolactinaemia than those arising in the anterior lobe. We have examined a series of corticotroph adenomas from patients with Cushing's disease for evidence of argyrophil fibres, and have correlated this with tumour site, corticotroph distribution in the para-adenomatous gland, serum PRL levels and PRL immunoreactive cells in the tumour. Argyrophil fibres were identified not only in tumours adjacent to the posterior lobe, but also in tumours situated deep in the anterior lobe. There was no correlation between the presence of fibres or the site of the tumour and corticotroph hyperplasia. Whilst the two patients with the highest serum PRL levels did have argyrophil fibres they also had a subpopulation of PRL immunoreactive cells in the tumour. On the basis of these results, we propose that the 'intermediate lobe' hypothesis as outlined above should not be accepted.

The term Cushing's disease is applied to those cases of Cushing's syndrome in which hypercortisolism is secondary to inappropriate secretion of ACTH by the pituitary. Studies on control of ACTH secretion in these patients reveal: (a) that the episodic secretion of ACTH is similar to the normal; however, frequency and amplitude of the secretory episodes lack the normal circadian rhythm; (b) that ACTH release can be stimulated by vasopressin and metyrapone in a normal or above-normal manner; and (c) that it can be suppressed by large doses of corticosteroids. When the dynamic aspects of the ACTH response to corticosteroid administration are studied, it appears that the normally negative differential feedback mechanism is converted into a positive one, whereas the delayed, integral mechanism is undisturbed. Patients with Cushing's disease in the presence of obvious pituitary tumors cannot be distinguished from those without pituitary tumors by studying only the pituitary function. All these and other well-known facts would favor the concept that ACTH secretion in Cushing's disease is under hypothalamic control whether or not a pituitary tumor is present. Moreover, there are observations that suggest that brain centers superior to the hypophysiotropic area of the hypothalamus are involved in the pathophysiology of Cushing's disease. This concept has led to the discovery of neurotropic drugs that are able to induce complete remission of Cushing's syndrome in a cerain percentage of patients. In some patients with severe psychiatric diseases, neuroendocrine abnormalities are present that resemble closely those characteristic for Cushing's disease. With the most refined neuroradiological methods, pituitary microadenomas are demonstrable in approximately 70% of patients with Cushing's disease, and this number compares well with those of earlier autopsy findings (70 to 80%). In a small number of patients (4 to 10%), these tumors are large and can easily be detected by standard roentgenograms of the head. Recent studies on the frequency of these large tumors do not support the hypothesis that adrenalectomy accelerates the progression of these tumors. In this case the term "Nelson's syndrome" would be uncessary. It is established that complete cure of Cushing's disease can be obtained in most patients with selective removal of a microadenoma from the pituitary gland. The current experience with this microsurgical procedure caused a renewed interest in Cushing's original suggestion that the disease is primarily a pituitary disorder. However, there are already a number of enigmatic observations. Possibly, the recent ultrastructural studies using immunocytochemical methods will resolve some of these problems. At this moment it is impossible to decide whether Cushing's disease is primarily a CNS or a pituitary disorder, when all arguments for one or the other hypothesis are taken into account...

The overall anatomical distribution of specifically stained corticotropic cells has been studied in pituitaries obtained at autopsy from 9 patients with Cushing's disease. Three patterns have been demonstrated consistent with the theory that it is not a single entity, but that some cases are of primary pituitary aetiology, whereas others are the result of hypothalamic or central nervous system dysfunction. The junctional corticotropic cells appear to react differently from those in the anterior pituitary to some stimuli, supporting the hypothesis that these cells may represent the remnants of the pars intermedia in the human adult, and suggesting that they may have some as yet unidentified physiological function.

Pituitaries of 137 cases with Cushing's disease were microscopically and immunohistologically studied. Many alterations and parameters (sex, age, anamnesis, cortisol plasma levels, tumor size, invasiveness, localization, differentiation of adenomas, immunohistological hormone content, capillarity, recurrences, peritumorous ACTH cell hyperplasia, and Crooke's cells) were analyzed and compared. Whereas most parameters were not correlated, we found some important statistically significant correlations: Undifferentiated adenomas are more frequently invasive than differentiated ones. Invasive adenomas recur more frequently than non-invasive adenomas. Extremely laterally localized adenomas are more often invasive. Larger adenomas are more frequently invasive than micro-adenomas. ACTH cell hyperplasia are more often demonstrable in specimens from total hypophysectomies (confined to our earlier series) than from partial hypophysectomies and adenomectomies. Recurrences of adenomas are more frequent in pituitaries with periadenomous ACTH cell hyperplasia. Very rarely ACTH cell hyperplasia are the only source of ACTH hyperfunction. The more Crooke's cells are demonstrable, the longer the post-operative replacement dose of Cortisol is required. Adenomas in Cushing's disease and adenomas in Nelson's syndrome differ significantly in the following points: Adenomas in Nelson's syndrome are larger and contain more plurinuclear cells. In the ultrastructure, adenomas in Cushing's disease show more cytofilaments. Paraadenomous Crooke's cells are lacking in Nelson's syndrome.

At present it is not established whether lateralization of pituitary venous drainage occurs in humans. To explore this possibility, we performed bilateral simultaneous inferior petrosal sinus sampling for ACTH in three patients with surgically proven ACTH-secreting pituitary microadenomas laterally located in the pituitary gland. In each patient, a gradient for ACTH correctly identified the location of the tumor. This finding suggests that pituitary venous drainage in humans is lateralized. These data also demonstrate that inferior petrosal sinus sampling needs to be bilateral before the pituitary origin of ACTH hypersecretion can be safely excluded in patients with Cushing's syndrome. In at least one and possibly two patients, the pituitary origin of ACTH excess would have been missed had we only sampled one inferior petrosal sinus. Finally, the demonstration of a left to right central gradient for PRL in addition to ACTH in one patient suggests that this technique may be useful in lateralizing functioning pituitary tumors other than ACTH-secreting tumors.

The cytoplasmic secretory granules of corticotrophs in the anterior pituitary are basophil in trichrome stains and periodic acid-Schiff positive in the histochemical stain for glycoprotein due to their content of the glycosylated 16 000 N-terminal fragment of the precursor protein proopiomelanocorticotrophin (POC). The granules show a positive immunocytochemical reaction to antibodies raised against ACTH, beta-endorphin and N-terminal fragments of POC. A small subset of corticotrophs contains immunoreactive alpha MSH in addition. Immunocytochemistry shows the corticotrophs to constitute about 15-20% of the anterior pituitary cells arranged both singly and in clumps. They are distributed in the median wedge and anteriorly, laterally and posteriorly adjacent to the pars nervosa which is often 'invaded' by corticotroph basophils. The alpha MSH subset is prominent in the rudimentary intermediate lobe and is scattered anteriorly in the pituitary of the human fetus. Crooke cell hyalinization is associated with pathologically maintained hypercortisolaemia and with glucosteroid therapy. The hyalinization is demonstrated in ultrastructure to be due to massive accumulation of intermediate cytoplasmic filaments 7-8 nm in diameter that are normally present in only small number. The change is associated with a varying degree of loss of secretory granules. In untreated Addison's disease there is a marked increase in the number of corticotrophs, many of which are arranged in distended alveoli to form micronodules. The vast majority of cases of pituitary-dependent Cushing's disease and all cases of Nelson's syndrome are associated with a basophil or chromophobe adenoma. These give a positive immunocytochemical reaction with anti-ACTH, beta-endorphin and N-terminal POC. In ultrastructure the cells of the chromophobe adenomas are seen to contain sparse secretory granules that are usually smaller than those in the chromophil adenomas. There are only very few reports of pituitary-dependent Cushing's disease found to be due to immunocytochemically confirmed corticotroph hyperplasia with or without a corticotroph adenoma. A few cases have been described in which the adenoma cells show Crooke's hyalinization, associated in one example with secretion of a big ACTH found more typically in ectopic ACTH-secreting tumours. A group of cases due to corticotroph adenoma has been reported whose excessive ACTH secretion is reduced by treatment with the dopamine agonist bromocriptine, in which it is suggested that the tumour cells arise from a subset of corticotrophs of pars intermedia origin.(ABSTRACT TRUNCATED AT 400 WORDS)

Pituitary adenomas were found in 21 (84%) of 25 dogs with spontaneous pituitary-dependent hyperadrenocorticism. Six dogs had pars intermedia adenomas, whereas 15 had tumours of the pars distalis. Diffuse corticotroph cell hyperplasia was found in 1 of the 4 pituitaries without adenoma; in 2 dogs with pituitary adenoma, coexisting hyperplasia of the surrounding corticotrophs was also present. Immunocytochemical staining of the pituitaries revealed positive staining for ACTH, beta-lipotrophin, and beta-endorphin in the majority of both pars distalis and pars intermedia adenomas. The most frequent and intense staining was found with anti-beta-endorphin. In most part intermedia tumours, many cells stained strongly for alpha-MSH; double immunostaining of one pars intermedia adenoma for ACTH and alpha-MSH showed that some tumour cells stained only for ACTH or alpha-MSH whereas others contained both peptides. Only occasional cells stained for alpha-MSH in pars distalis adenomas.

The endocrinological, radiological, surgical, and pathological experience with 34 consecutive patients operated on for Cushing's disease is presented. Preoperative endocrine evaluation demonstrated that 19 patients had "typical" endocrine patterns for pituitary adrenocorticotropic hormone (ACTH)-dependent hypercortisolism and 11 had "atypical" testing. Pituitary pathology was found in 95% of the patients with typical preoperative endocrine testing but in only 55% of those with atypical testing. Eight of 34 preoperative computerized tomography scans demonstrated tumors, which correlated in all instances with the surgical findings. Microadenomas were removed from 25 patients, 22 of whom achieved postoperative remission of endocrine symptoms. Macroadenomas were found in three patients, only one of whom achieved remission after surgery. One patient had removal of an adenoma in the pharyngeal pituitary, and in another an ectopic lung carcinoid was excised; both of these patients were in postoperative remission. Four patients underwent transsphenoidal exploration but no definitive explanation was found for their hypercortisolism; these patients were not in remission. Immunohistochemical staining was performed on every specimen and all tumors showed excessive ACTH-secreting cells. A new rapid stain of the fibrovascular stroma is described.

The distribution of specifically stained corticotrophic cells has been studied in the pituitary glands of 11 dogs with pituitary-dependent hyperadrenocorticism. The results suggest that the disease is not a single entity, and that some cases are caused by primary abnormality of the pituitary gland whereas others appear to be the result of dysfunction of the hypothalamus or central nervous system. The patterns correspond closely to those demonstrated in the human pituitary gland in Cushing's disease, and confirm that the canine disease is a useful model for the study of the pathogenesis of the variants of the condition.

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.

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.

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.

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.