High-Resolution, Accurate-Mass (HRAM) Mass Spectrometry Urine Steroid Profiling in the Diagnosis of Adrenal Disorders.

BACKGROUND: Steroid profiling is a promising diagnostic tool with adrenal tumors, Cushing syndrome (CS), and disorders of steroidogenesis. Our objective was to develop a multiple-steroid assay using liquid-chromatography, high-resolution, accurate-mass mass spectrometry (HRAM LC-MS) and to validate the assay in patients with various adrenal disorders. METHODS: We collected 24-h urine samples from 114 controls and 71 patients with adrenal diseases. An HRAM LC-MS method was validated for quantitative analysis of 26 steroid metabolites in hydrolyzed urine samples. Differences in steroid excretion between patients were analyzed based on Z-score deviation from control reference intervals. RESULTS: Limits of quantification were 20 ng/mL. Dilution linearity ranged from 80% to 120% with means of 93% to 110% for all but 2 analytes. Intraassay and interassay imprecision ranged from 3% to 18% for all but 1 analyte. Control women had lower excretion of androgen and glucocorticoid precursors/metabolites than men (P < 0.001), but no difference in mineralocorticoids was seen (P = 0.06). Androgens decreased with age in both sexes (P < 0.001). Compared with patients with adrenocortical adenoma (ACA), patients with adrenocortical carcinoma (ACC) had 11 steroids with increased Z scores, especially tetrahydro-11-deoxycortisol (14 vs 0.5, P < 0.001), pregnanetriol (7.5 vs -0.4, P = 0.001), and 5-pregnenetriol (5.4 vs -0.4, P = 0.01). Steroid profiling also demonstrated metabolite abnormalities consistent with enzymatic defects in congenital adrenal hyperplasia and differences in pituitary vs adrenal CS. CONCLUSIONS: Our HRAM LC-MS assay successfully quantifies 26 steroids in urine. The statistically significant differences in steroid production of ACC vs ACA, adrenal vs pituitary CS, and in congenital adrenal hyperplasia should allow for improved diagnosis of patients with these diseases.

Simplified urinary steroid profiling by LC-MS as diagnostic tool for malignancy in adrenocortical tumors.

OBJECTIVES: Preoperative identification of malignant adrenal tumors is challenging. 24-h urinary steroid profiling by LC-MS/MS and machine learning has demonstrated high diagnostic power, but the unavailability of bioinformatic models for public use has limited its routine application. We here aimed to increase usability with a novel classification model for the differentiation of adrenocortical adenoma (ACA) and adrenocortical carcinoma (ACC). METHODS: Eleven steroids (5-pregnenetriol, dehydroepiandrosterone, cortisone, cortisol, α-cortolone, tetrahydro-11-deoxycortisol, etiocholanolone, pregnenolone, pregnanetriol, pregnanediol, and 5-pregnenediol) were quantified by LC-MS/MS in 24-h urine samples from 352 patients with adrenal tumor (281 ACA, 71 ACC). Random forest modelling and decision tree algorithms were applied in training (n = 188) and test sets (n = 80) and independently validated in 84 patients with paired 24-h and spot urine. RESULTS: After examining different models, a decision tree using excretions of only 5-pregnenetriol and tetrahydro-11-deoxycortisol classified three groups with low, intermediate, and high risk for malignancy. 148/217 ACA were classified as being at low, 67 intermediate, and 2 high risk of malignancy. Conversely, none of the ACC demonstrated a low-risk profile leading to a negative predictive value of 100% for malignancy. In the independent validation cohort, the negative predictive value was again 100% in both 24-h urine and spot urine with a positive predictive value of 87.5% and 86.7%, respectively. CONCLUSIONS: This simplified LC-MS/MS-based classification model using 24-h-urine provided excellent results for exclusion of ACC and can help to avoid unnecessary surgeries. Analysis of spot urine led to similarly satisfactory results suggesting that cumbersome 24-h urine collection might be dispensable after future validation.

Simultaneous analysis of mitotane and its main metabolites in human blood and urine samples by SPE-HPLC technique.

Adrenocortical carcinoma (ACC) is a rare malignancy with an incompletely understood pathogenesis and a poor prognosis. The adrenalytic activity of mitotane has made it the most important single drug in the treatment of ACC. Unfortunately, the exact mechanism of mitotane action is still unknown. It is believed that mitotane belongs to the class of drugs that require metabolic transformation by cytochrome P450 for therapeutic action; therefore determination of plasma levels of not only mitotane but also its metabolites would help in carrying out the treatment. The objective of this work was to develop and validate an SPE-HPLC method for simultaneous determination of mitotane and its metabolites in different biological fluids. The sample preparation consisted of a solid-phase extraction on a Discovery DSC(18) cartridge, while analysis of extracts was performed on a Symmetry C(18) column. The usefulness of the proposed method was confirmed by analysis of plasma, red cell and urine samples from patient chronically treated with 1.5 g of mitotane. The patient involved in this study had a high plasma concentration of mitotane and none of the investigated metabolites were found. In order to investigate whether the polymorphism of CYP2C9 and CYP2C19 enzymes could be related to the metabolism of mitotane, RT-PCR analysis was performed.

Clinicopathological features, biochemical and molecular markers in 5 patients with adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is a very rare malignant tumor with poor prognosis. To gain insight into the pathogenic significance of ACC, we studied clinicopathological features and gene expression profile in ACC. We analyzed five ACC cases (two men and three women) with the median age of 45-year-old who underwent adrenalectomy at our institute. Endocrine studies revealed that two cases had subclinical Cushing's syndrome (SCS) and one with concomitant estrogen-secreting tumor, while the rest of three cases had non-functioning tumors. Analysis of urinary steroids profile by gas chromatography/mass spectrometry showed increased metabolites of corticosteroid precursors, such as 17-OH pregnenolone, 17-OH progesterone, dehydroepiandorosterone (DHEA), and 11-deoxycortisol in all five cases. The pathological diagnosis of ACC was based on Weiss's criteria with its score ≥ 3. The mean size of the resected tumors was 87 mm and Ki67/MIB1 labeling index, a proliferative marker, was 3-27%. Immunohistochemical analysis revealed a disorganized expression of several steroidogenic enzymes, such as 3ß-hydroxysteroid dehydrogenase, 17α-hydroxylase, and DHEA-sulfotransferase. Among several genes determined by RT-PCR, insulin-like growth factor (IGF)-II mRNA was consistently and abundantly expressed in all 5 tumor tissues. Postoperatively, two cases with SCS developed local recurrence and liver metastasis. The present study suggests that the disorganized expression of steroidogenic enzymes and the overexpression of IGF-II by the tumor are hallmarks of ACC, which could be used as biochemical and molecular markers for ACC.

Urine Steroid Metabolomics as a Novel Tool for Detection of Recurrent Adrenocortical Carcinoma.

CONTEXT: Urine steroid metabolomics, combining mass spectrometry-based steroid profiling and machine learning, has been described as a novel diagnostic tool for detection of adrenocortical carcinoma (ACC). OBJECTIVE, DESIGN, SETTING: This proof-of-concept study evaluated the performance of urine steroid metabolomics as a tool for postoperative recurrence detection after microscopically complete (R0) resection of ACC. PATIENTS AND METHODS: 135 patients from 14 clinical centers provided postoperative urine samples, which were analyzed by gas chromatography-mass spectrometry. We assessed the utility of these urine steroid profiles in detecting ACC recurrence, either when interpreted by expert clinicians or when analyzed by random forest, a machine learning-based classifier. Radiological recurrence detection served as the reference standard. RESULTS: Imaging detected recurrent disease in 42 of 135 patients; 32 had provided pre- and post-recurrence urine samples. 39 patients remained disease-free for ≥3 years. The urine "steroid fingerprint" at recurrence resembled that observed before R0 resection in the majority of cases. Review of longitudinally collected urine steroid profiles by 3 blinded experts detected recurrence by the time of radiological diagnosis in 50% to 72% of cases, improving to 69% to 92%, if a preoperative urine steroid result was available. Recurrence detection by steroid profiling preceded detection by imaging by more than 2 months in 22% to 39% of patients. Specificities varied considerably, ranging from 61% to 97%. The computational classifier detected ACC recurrence with superior accuracy (sensitivity = specificity = 81%). CONCLUSION: Urine steroid metabolomics is a promising tool for postoperative recurrence detection in ACC; availability of a preoperative urine considerably improves the ability to detect ACC recurrence.

Use of urinary steroid profiling for diagnosing and monitoring adrenocortical tumours.

It has been suggested that urinary steroid profiling may be used to provide information aiding the diagnosis and monitoring of adrenocortical carcinoma. Nonetheless, the abnormal patterns suggestive of adrenal malignancy are not well defined. We retrospectively studied the urinary steroid profiles of five patients with adrenocortical carcinoma at presentation and at follow-up, and compared these results with those from 76 patients with benign adrenocortical adenoma and 172 healthy controls. Three abnormal patterns of urinary steroid excretion were identified in patients with adrenocortical carcinoma at presentation and/or follow-up of residual disease: (1) hypersecretion in multiple steroid axes; (2) excretion of unusual metabolites, notably 5-pregnene-3alpha,16alpha,20alpha-triol, 5-pregnene-3beta,16alpha,20alpha-triol, and neonatal steroid metabolites in the post-neonatal period; (3) increase of tetrahydro-11-deoxycortisol relative to total cortisol metabolites. These preliminary findings offer ways in which urinary steroid profiling performed using gas chromatography-mass spectrometry can be helpful in the diagnosis and monitoring of adrenocortical carcinoma.

Adipokine levels and cardiovascular risk in patients with adrenal incidentaloma.

Adrenal incidentalomas (AIs) have been associated with an increased incidence of several cardiovascular risk factors, similar to overt Cushing syndrome. Data about the involvement of the adipokines in the development of insulin resistance and atherosclerosis in AI are completely lacking. The aim of the present study was to evaluate plasma interleukin 6 (IL-6), adiponectin, resistin, tumor necrosis factor alpha (TNF-alpha), and monocyte chemoattractant protein 1 (MCP-1) levels in patients with AI. Plasma IL-6, adiponectin, resistin, TNF-alpha, and MCP-1 levels were measured in 20 healthy subjects (6 males; 14 females; age, 58.5 +/- 2.2 years; body mass index, 28.1 +/- 0.9 kg/m(2)) and in 20 patients (5 males; 15 females; age, 57.9 +/- 2.0 years; body mass index, 28.0 +/- 0.8 kg/m(2)) with AI and typical computed tomographic features of cortical adenoma, who were not affected by diabetes mellitus, hypertension, or other relevant diseases. All patients underwent anthropometric measurements and determination of basal corticotropin, cortisol, and urinary free cortisol excretion. Overnight dexamethasone test and 250-microg corticotropin test were performed in all cases. A subclinical Cushing syndrome was found in 3 patients, whereas the others had apparently nonfunctioning masses. Plasma IL-6, adiponectin, resistin, TNF-alpha, and MCP-1 levels were higher in patients than in controls (64.4 +/- 2.8 vs 5.5 +/- 0.6 pg/mL, 13.7 +/- 1.3 vs 3.6 +/- 0.5 microg/mL, 12.5 +/- 1.9 vs 5.1 +/- 0.2 ng/mL, 27.0 +/- 1.5 vs 22.2 +/- 1.5 pg/mL, 172.5 +/- 20.0 vs 104.4 +/- 19.5 pg/mL, respectively; P < .05) and apparently not affected by the presence of visceral obesity. Plasma IL-6 levels were negatively correlated with urinary free cortisol (r = -0.461, P < .05), and TNF-alpha levels were positively correlated with cortisol after the administration of 1 mg dexamethasone (r = 0.636, P < .01). In conclusion, patients with AI may show increased levels of adipokines (apparently not related to the presence of diabetes, hypertension, or obesity), which may be affected by the presence of the adrenal adenoma. For some adipokines, a direct production from the adrenal gland may be hypothesized even if other studies are needed to better investigate the role of adipokines in states of altered cortisol secretion.

Adrenal Cushing syndrome with detectable ACTH from an unexpected source.

Mixed corticomedullary adrenal tumours (MCMT) are rare. We describe the second reported case of a male patient presenting with hypertension and Cushing syndrome with MCMT. A man aged 48 years presented with hypertension and signs of Cushing syndrome. 24-hour urine cortisol was elevated, with detectable adrenocorticotropic hormone (ACTH). A high-dose dexamethasone suppression test indicated an adrenal or ectopic Cushing syndrome. Plasma metanephrines were normal. A 3 cm left adrenal mass was identified without potential ectopic sources of ACTH on imaging. After induction of anaesthesia for laparoscopic adrenalectomy, the patient developed resistant hypertension with stress-dose hydrocortisone administration. Surgery was cancelled and repeat testing revealed elevated plasma metanephrines. α-Blockade was administered for a presumed coexisting pheochromocytoma, and the patient underwent adrenalectomy. Pathology revealed an MCMT. This case highlights the importance of a thorough biochemical evaluation in patients with adrenal masses to rule out multiple hormone producing tumours.

Different Types of Urinary Steroid Profiling Obtained by High-Performance Liquid Chromatography and Gas Chromatography-Mass Spectrometry in Patients with Adrenocortical Carcinoma.

Urinary steroid profiling (USP) was studied using high-performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC-MS) methods in 108 patients with adrenocortical adenoma (ACA) and in 31 patients with adrenocortical carcinoma (ACC). Thirteen ACC and Cushing's syndrome (ACC-CS) patients had two types of USP as well as 18 ACC patients without hypercortisolism. These four types differed by androgen and glucocorticoid secretion of the adrenal cortex. Fifteen main ACC features were observed by GC-MS. Urinary excretion of dehydroepiandrosterone (DHEA) was increased in 67.7 % of ACC patients and tetrahydro-11-deoxycortisol (THS) in 74.2 %. By combination of the following parameters: THS >900 µg/24 h and/or DHEA >1500 µg/24 h with ratios of 3α,16,20-pregnentriol/3ß,16,20-pregnentriol (3α,16,20dP3/3ß,16,20dP3) less than 6.0 and 3α,17,20dP3/3ß,17,20dP3 less than 9.0 and the detection of "non-classical" 5-en-pregnens, not found in ACA and healthy persons, 100 % sensitivity and specificity of ACC and ACA differential diagnosis were achieved. Features of 21-hydroxylase and 11ß-hydroxylase deficiency were observed by GC-MS in 32.2 and 61.3 % of the ACC patients, respectively. Additional features for ACC-CS diagnostic were increased urinary excretion of 6ß-hydroxycortisol, 18-hydroxycorticosterone, the sum (UFF + UFE) obtained by HPLC, tetrahydrocorticosterone, and the sum (THF + THE + allo-THF) obtained by GC-MS.

[Specific features of diagnosis of hormonal insufficiency in patients with tumors of the adrenal cortex].

An examination of 145 patients with incidentalomas and 195 women with virale syndrome has shown that 20% of patients with incidentalomas and 23.1% of patients with steroidogenesis have disorders of the adrenal steroidogenesis characteristic of the obliterated form of congenital hyperplasia of the adrenal cortex (CHAC) with a defect of 11beta-hydroxylase on the basis of the following biochemical criteria: the elevation in blood of the basal levels of 11-desoxycortisole and 11beta-desoxycorticosterone, decreased excretion of free cortisole with urine, lower indices of hydrocortisole/cortisone in blood and free cortisole/free cortisone in urine, in the test with corticotropin - elevation in blood of the level of 11-desoxycortisole and 11-desoxycorticosterone, decreased relationships cortisole/11-desoxycortisole and cortisole/cortisone and lower growth of the levels of corticosterone and cortisole. The data obtained suggest that long-standing obliterated form of CHAC with a defect of 11beta-hydroxylase might be the cause of the formation of certain incidentalomas.

The unique steroidogenesis of the aldosteronoma in the differential diagnosis of primary aldosteronism.

18-Hydroxycortisol and 18-oxocortisol have been isolated from the urine of patients with aldosterone producing adrenocortical adenomas, but not from those with idiopathic hyperaldosteronism associated with bilateral adrenal hyperplasia. These C-18 oxygenated cortisols are biosynthesized by the substitution of cortisol for the normal substrate, corticosterone, in the terminal oxidase system required for the biosynthesis of 18-hydroxycorticosterone and aldosterone. To make use of this biochemical difference between the two groups in the preoperative diagnosis of primary aldosteronism, we have developed and utilized a specific primary standard analytical method, stable isotope dilution mass fragmentography, for quantifying 18-hydroxycortisol and the tetrahydro metabolite of 18-oxocortisol in 24-h urine samples. The normal range by this technique of 4.6 +/- 1.8 micrograms/day tetrahydro 18-oxocortisol and 43 +/- 23 micrograms/day 18-hydroxycortisol in urine was lower and narrower than previous estimates using other methods. Excretion of the 18-oxocortisol metabolite ranged from 2-12 micrograms/day in bilateral hyperplasia and 17-1203 micrograms/day in typical adenomas. 18-Hydroxycortisol excretion similarly separated bilateral hyperplasia (23-59 micrograms/day) from typical adenomas (60-2750 micrograms/day). The cortisol C-18 oxidation pathway describes a unique steroidogenic mechanism in the aldosteronoma not present in idiopathic aldosteronism due to bilateral adrenal hyperplasia and as such provides a basis for the biochemical classification of primary aldosteronism and the differentiation of these two groups. This unique biochemistry was also observed in unilateral hyperplasia but not in the renin-dependent aldosteronoma.

The regulation of urinary free 19-nor-deoxycorticosterone and its relation to systemic arterial blood pressure in normotensive and hypertensive subjects.

19-Nor-deoxycorticosterone (19-nor-DOC) is a naturally occurring, potent mineralocorticoid present in hypertensive animal models as well as man. To investigate 19-nor-DOC's regulation and possible pathogenesis in hypertension, urinary free (UF) 19-nor-DOC was measured in 14 hypertensives, correlated with other corticosteroids and systemic arterial blood pressure (BP), and compared to basal and ACTH-stimulated values in 8 normotensive subjects. Seven of the 14 hypertensives had low-renin hypertension, 2 had primary aldosteronism, 1 had an adrenal carcinoma, and another had acromegaly. These studies determined that: 1) although the mean UF 19-nor-DOC was not increased in hypertensives (588 +/- 180 vs. 428 +/- 122 ng/day), 2 low-renin hypertensives had quite elevated levels (2186 and 2018); 2) the UF 19-nor-DOC in hypertensives was correlated with BP but not with PRA, aldosterone secretion, plasma potassium, basal plasma cortisol, or 17-hydroxycorticosteroids; 3) likewise, in normotensives, UF 19-nor-DOC did not correlate with basal plasma cortisol, cortisol secretion, or 17-hydroxycorticosteroids excretion but did correlate after ACTH stimulation. Therefore, although 19-nor-DOC is activated by ACTH administration, it is not correlated with basal parameters of cortisol production, suggesting that factors other than ACTH regulate basal 19-nor-DOC secretion. Furthermore 19-nor-DOC is elevated in some hypertensive patients, and it is directly related to the elevation of mean systemic BP. This suggests that, although 19-nor-DOC could contribute to hypertensive disease in some individuals, it does not appear to be due to excess ACTH.

Deoxycorticosterone and aldosterone excretion in Cushing's syndrome.

We have used specific radioimmunoassays to measure urinary free deoxycorticosterone (DOC) and total aldosterone excretion in 15 patients with Cushing's syndrome. Free DOC excretion was increased in 6 of 8 patients with pituitary-dependent adrenal hyperplasia, in 2 of 3 patients with adrenal adenoma, and in all 4 cases with adrenal carcinoma. The most marked increase was noted in the adrenal carcinoma cases. Aldosterone excretion was high, normal, or low in each of the three types of Cushing's syndrome. The free DOC response to metyrapone in Cushing's syndrome due to adrenal adenoma was markedly different from that in patients with adrenal hyperplasia (pituitary-dependent) and may serve as a test to ascertain the etiology of the disorder. Correlations of free DOC and aldosterone excretion with free cortisol excretion, and their responses to the administration of metyrapone and dexamethasone were compatible with ACTH dependency in adrenal hyperplasia, autonomous production of steroids in adrenal adenomas and a chaotic steroidogenesis in adrenal carcinoma.

Virilizing adrenal cortical carcinoma with hypertrophy of spermatic tubules in childhood.

A review of adrenal cortical carcinoma in childhood is presented, including endocrinologic aspects. Electron microscopic features are presented, as well as the finding of hypertrophied spermatic tubules. The importance of serial steroidal determinations is stressed as a "tumor marker" that may help in early detection of recurrent disease and possibly increased long-term survival.

Adrenal cortical phaeochromocytoma: a case report of a rare entity.

Adrenal cortical phaeochromocytomas (pseudo-phaeochromocytomas) are a very rare entity and a diagnostic challenge. Of the few cases previously reported, most have incomplete data or lack clinical and biochemical follow-up documenting the cure of the excess secretion of catecholamines after resection of the tumour. We report herein a 62-year-old patient with clinical and biochemical findings diagnostic of a phaeochromocytoma associated with a 2-cm adrenal mass on CT scan. Surgery revealed the presence of an adrenal cortical adenoma with positive staining for the neuroendocrine marker synaptophysin, but negative for chromogranin, as has been previously reported for these rare cortical phaeochromocytomas. After removal of the tumour the clinical symptoms resolved and biochemical markers normalized, demonstrating the causal relationship between the cortical tumour and the excess production of catecholamines.

Urinary steroid profile in adrenocortical tumors.

Determination of the urinary steroid profile has been proposed as a sensitive tool for diagnosing adrenocortical tumors. The urinary steroid profiles were determined for patients with adrenocortical tumors. Urinary steroids were extracted, derivatized to form methyloxime-trimethylsilyl ether and analyzed by gas chromatography/mass spectrometry. Patients with adrenal adenomas from primary hyperaldosteronism had increased metabolites of 18-hydroxycorticosterone and aldosterone, and those with Cushing's syndrome had elevated excretion of 11 -deoxycortisol, cortisol, 18-hydroxycortisol, and cortisone metabolites. In patients with adrenocortical carcinomas, increased levels of metabolites of 11-deoxycortisol or 33-hydroxy-5-ene steroids were observed. The urinary steroid profiles of adrenal adenomas and adrenocortical carcinomas were quite different, suggesting the diagnostic validity for discriminating malignant from benign diseases.

[Diagnostic problems in pheochromocytoma]. / Problemi diagnostici nel feocromocitoma.

Pheochromocytoma is mainly characterized by a great deal of variability in its biological activity and in its clinical manifestations. This special feature has always to be taken into account in any diagnostic procedure. The tumor is generally suspected on clinical ground for the presence of paroxysmal hypertension but this sign is largely aspecific and often absent. The diagnosis of pheochromocytoma has to be based on laboratory tests demonstrating an excess and/or a disregulation in catecholamine (CA) secretion. CA or CA metabolites can be measured in urine or blood. Whatever the sample measured, it is important to correlate its result with the clinical picture found during its collection. Basal plasma CA concentrations are often raised also during periods of normotension but their accuracy is the highest in samples drawn during a hypertensive crisis. When basal measurements are insufficient for a final diagnosis, inhibitory (clonidine) or stimulatory (glucagon) tests can be performed. Clonidine test is recommended in patients showing slight increases in basal plasma CA. Glucagon stimulation test should be performed only in normotensive patients with an incidental adrenal mass, patients with sporadic hypertensive crises or members of families affected by MEN II. Localization procedures are mainly based on CT (or MRI) and on scintigraphy with I131-MIBG. CT possesses high sensitivity (about 96%) while I131-MIBG scintigraphy possesses a very high specificity (about 97%). Therefore, both the procedures should be performed before surgery. Rarely, it is also necessary to perform catheterization of the venous tree and plasma sampling for CA measurement to localize the tumor through the discovery of a secretory gradient.

Experience with adrenocortical neoplasms in childhood.

The experience with adrenocortical neoplasms in childhood is reviewed. During three decades, ten children with adrenocortical neoplasms were seen at the authors' institution. The literature was reviewed, and 209 patients 16.5 years or younger were found. All ten patients at Vanderbilt University Hospital (VUH) presented with endocrine manifestations of the tumor. Three patients had Cushing's, two patients had virilization, and five patients had features of both. In the literature, virilization, alone or with Cushing's, was the most common mode of presentation. Feminizing tumors were uncommon and nonfunctional tumors rare. The majority of patients were female. Features associated with malignancy included 17-KS levels greater than 40 mg/24 hr, diameter greater than 6 cm, weight greater than 500 g, and histologic evidence of diffuse growth pattern, vascular invasion, and tumor cell necrosis. Although uncommon, adrenocortical neoplasms should be suspected in children with Cushing's, virilization, feminization, or a combination of these. There has been an increased incidence reported in patients with hemihypertrophy, Beckwith-Wiedemann syndrome, hemangiomas, and nevi. Following endocrinologic evaluation, imaging studies should be performed. CT scan appears to be the most useful diagnostic tool. A posterior operative approach is recommended for suspected adenomas. An anterior thoracoabdominal approach is favored for suspected malignancies with uncompromised en bloc resection. There is no evidence that adjuvant therapy provides any additional benefit.

A functioning black adenoma of the adrenal gland.

A 53-year-old female had clinical and laboratory findings suggestive of Cushing's syndrome. In contrast to the Cushing's syndrome caused by cortical adenoma, a high level of urinary 17-ketosteroids (17-KS) was also noted. Imaging studies revealed a right adrenal tumor. Right adrenectomy was performed; the surgical specimen revealed a black adenoma consisting of compact cells with numerous pigments which seemed to be lipofuscin in nature. The present case indicates that black adenoma as well as adrenocortical carcinoma should be suspected, when patients with Cushing's syndrome show an increased level of urinary 17-KS excretion.

Exaggerated natriuresis in primary aldosteronism.

Acute response in blood pressure (BP) and natriuresis to saline infusion was evaluated in 16 patients with primary aldosteronism caused by aldosteronoma (PA) and 12 patients with salt-sensitive essential hypertension (SSEH). Salt-sensitivity was defined by a decrease in mean BP exceeding 5% at the second hour after a 20 mg furosemide injection. Plasma renin activity (PRA), plasma aldosterone concentration (PAC) and urine electrolytes in response to saline infusion were determined. During a 2-liter isotonic saline infusion, a similar degree of natriuresis and change in BP were observed in PA and SSEH patients. A significantly inverse correlation between the increase in mean BP and the degree of natriuresis at the end of the infusion was found in patients with SSEH (r = -0.80, p less than 0.01). No correlation was observed between these parameters in patients with PA (r = 0.28, p greater than 0.05). These results suggest that hypernatriuresis in SSEH may play a protective mechanism against abrupt increases in BP and volume during acute saline loading. This protective mechanism was not evident in patients with PA.