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Context: Inferior petrosal sinus sampling (IPSS) is used to diagnose Cushing's disease (CD) when dexamethasone-suppression and CRH tests, and pituitary magnetic resonance imaging (MRI), are negative or give discordant results. However, IPSS is an invasive procedure and its availability is limited., Objective: To test a noninvasive diagnostic strategy associated with 100% positive predictive value (PPV) for CD., Design: Retrospective study., Setting: Two university hospitals., Patients: A total of 167 patients with CD and 27 patients with ectopic ACTH-syndrome investigated between 2001 and 2016., Main Outcome Measure(s): Performance of a strategy involving the CRH and desmopressin tests with pituitary MRI followed by thin-slice whole-body computed tomography (CT) scan in patients with inconclusive results., Results: Using thresholds of a cortisol increase > 17% with an ACTH increase > 37% during the CRH test and a cortisol increase > 18% with an ACTH increase > 33% during the desmopressin test, the combination of both tests gave 73% sensitivity and 98% PPV of CD. The sensitivity and PPV for pituitary MRI were 71% and 99%, respectively. CT scan identified 67% EAS at presentation with no false-positives. The PPV for CD was 100% in patients with positive responses to both tests, with negative pituitary MRI and CT scan. The Negative Predictive Value was 100% in patients with negative responses to both tests, with negative pituitary MRI and positive CT scan. Using this strategy, IPPS could have been avoided in 47% of patients in whom it is currently recommended., Conclusions: In conjunction with expert radiologic interpretation, the non-invasive algorithm studied significantly reduces the need for IPSS in the investigation of ACTH-dependent Cushing's syndrome., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: The per-operative hemodynamic behavior of normotensive incidentally discovered pheochromocytomas is poorly documented., Objective: To compare the per-operative hemodynamic instability and early postoperative outcome of normotensive pheochromocytomas, hypertensive pheochromocytomas, and benign non-pheochromocytoma adrenal incidentalomas (AIs)., Design: Retrospective cohort treated in a single center., Patients and Methods: Fifty patients (10 normotensive pheochromocytomas, 24 hypertensive pheochromocytomas, and 16 AIs) were anesthetized and operated on by the same team, using laparoscopy in 78% of cases. Before surgery, 60% of normotensive and 95.8% of hypertensive pheochromocytomas received pretreatment with α-receptor or calcium channel blockers. All of the patients received the same intraoperative hemodynamic monitoring, including continuous direct intra-arterial pressure recording., Results: All the features of hemodynamic instability, with the exception of the diastolic pressure nadir and fluid volume requirements, differed between hypertensive pheochromocytomas and AIs. Conversely, all features of hemodynamic instability were similar in hypertensive and normotensive pheochromocytomas. More specifically, by comparison with AIs, normotensive pheochromocytomas displayed higher maximal systolic pressure; more hypertensive, severe hypertensive, and hypotensive episodes; and a higher minimal heart rate, and also required more interventions to treat undesirable blood pressure elevations. Postoperative complications, all of which were mild, were more frequent in hypertensive pheochromocytomas than in normotensive pheochromocytomas (P < .03)., Conclusions: Normotensive pheochromocytomas have roughly comparable per-operative hemodynamic instability to hypertensive pheochromocytomas and differ markedly from non-pheochromocytoma AIs. It is therefore crucial to identify normotensive pheochromocytomas among AIs when surgery is scheduled and to apply the standard of care for pheochromocytoma anesthesia.

Context: A number of incidentally discovered pheochromocytomas are not associated with hypertension. The characteristics of normotensive incidentally discovered pheochromocytomas (NIPs) are poorly known., Objective: The purpose of this work was to assess the clinical, hormonal, histological, and molecular features of NIPs., Design: This was a retrospective cohort recruited from 2001 to 2011 in 2 tertiary care medical departments., Patients and Methods: Clinical, biological, and radiological investigations performed in 96 consecutive patients with sporadic unilateral pheochromocytomas were examined; 47 patients had overt pheochromocytomas responsible for hypertension. Among the patients with incidental pheochromocytomas, 28 had hypertension and 21 were normotensive (NIPs). A total of 62 tumors were examined to determine the Pheochromocytoma of the Adrenal Gland Scale Score, and 29 were studied for the expression of 16 genes involved in chromaffin cell function., Results: Tumor size and metaiodobenzylguanidine (MIBG) scintigraphy results were similar for hypertensive pheochromocytomas (HPs) and NIPs. Patients with NIPs displayed reduced summed levels of urinary catecholamines and metanephrines and, more specifically, reduced levels of adrenaline and metadrenaline compared with those of patients with HPs (P < .001). Urinary metanephrines had 98% diagnostic sensitivity in patients with HPs and only 75% in patients with NIPs (P < .01). Tumor diameter positively correlated with the total amount of urinary concentrations of metanephrines in patients with HPs (P < .001) but not in patients with NIPs. NIPs displayed global decreased chromaffin gene expression (reaching significance for 5 of them) and 2 corresponding proteins (phenylethanolamine N-methyltransferase and secretogranin II) and a significant increase in the cellularity, mitotic activity, and presence of atypical mitosis (P < .05)., Conclusions: NIPs differ from pheochromocytomas responsible for hypertension and display features of altered chromaffin differentiation. These tumors may be misdiagnosed with the use of the usual biological diagnostic tools.

Context: Neither precise evaluation of pertinent thresholds nor comparison of the diagnostic performance of late-night salivary cortisol (NSC) between inpatient and outpatient settings has been conducted. The usefulness of NSC for the screening of "subclinical" Cushing's syndrome is still unknown., Objectives: The aim of the study was to compare the influence of inpatient and outpatient settings on the diagnostic performance of NSC and assess its usefulness as a screening test for subclinical Cushing's syndrome., Design: Consecutive patients were investigated prospectively with two salivary collections, first as inpatients and then as outpatients., Participants: Forty-two obese subjects participated in the study, as well as nine patients cured of Cushing's disease, 13 with overt Cushing's syndrome, 14 showing mild recurrence of Cushing's disease, and 48 with adrenal incidentalomas [23 subclinical cortisol-secreting adenomas (SCSA), 25 nonsecreting adenomas]., Main Outcome Measures: Reproducibility of NSC and diagnostic performance were measured using receiver operating characteristic analysis., Results: NSC in controls was similar between inpatient and outpatient settings. The diagnostic performance of NSC across the different patient groups was similar irrespective of the setting. A threshold of 12 nmol/liter yielded 100% sensitivity and specificity in overt Cushing's syndrome. Optimal performance in subclinical Cushing's syndrome required lower thresholds. NSC showed acceptable performance in diagnosing recurrence of Cushing's disease (90% sensitivity, 91.8% specificity). On the contrary, NSC was similar between patients with SCSA and nonsecreting adenomas., Conclusions: Our data validate the outpatient bed sampling strategy for NSC with no need for specific outpatient threshold. NSC may be helpful to detect mild recurrence of Cushing's disease after surgery but is of little value in identifying SCSA amongst adrenal incidentalomas.

Context: The diagnostic accuracy of the combined dexamethasone suppression test (DST)-CRH test for the differential diagnosis between Cushing's disease (CD) and pseudo-Cushing syndrome (PCS) has recently been debated., Objective: Our objective was to reevaluate the performance of the DST-CRH test to differentiate CD from PCS and compare it with that of midnight plasma cortisol measurement., Setting: The study took place at three specialized tertiary care university hospitals., Design: Fourteen patients with PCS and 17 patients with CD matched for 24-h urinary free cortisol were retrospectively studied., Main Outcome Measure: Diagnosis or exclusion of CD was the main outcome measure., Results: A 55 nmol/liter cortisol concentration after dexamethasone (DST) yielded 94% sensitivity, 86% specificity, and 90% diagnostic accuracy. Using the historical 38 nmol/liter threshold for plasma cortisol 15 min after CRH administration, the DST-CRH test achieved 100% sensitivity, 50% specificity, and 77% diagnostic accuracy. Increasing the threshold to 110 nmol/liter improved the specificity and diagnostic accuracy to 86 and 93.5%, respectively. However, diagnostic accuracy was not significantly different from that of the DST. A midnight plasma cortisol concentration of more than 256 nmol/liter was consistent with the diagnosis of CD with 100% sensitivity, specificity, and diagnostic accuracy., Conclusion: The diagnostic performance of the DST-CRH test for the differential diagnosis between PCS and mild CD was lower than previously reported. Although the specificity of the test is improved using a revised cortisol threshold, its diagnostic accuracy is not better than that of the standard DST. Our study supports the preferential use of the DST and midnight plasma cortisol measurement as first-line diagnostic tests in equivocal cases.