By definition, an adrenal incidentaloma is an asymptomatic adrenal mass detected on imaging not performed for suspected adrenal disease. In most cases, adrenal incidentalomas are nonfunctioning adrenocortical adenomas, but may also represent conditions requiring therapeutic intervention (e.g. adrenocortical carcinoma, pheochromocytoma, hormone-producing adenoma or metastasis). The purpose of this guideline is to provide clinicians with best possible evidence-based recommendations for clinical management of patients with adrenal incidentalomas based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. We predefined four main clinical questions crucial for the management of adrenal incidentaloma patients, addressing these four with systematic literature searches: (A) How to assess risk of malignancy?; (B) How to define and manage low-level autonomous cortisol secretion, formerly called ‘subclinical’ Cushing’s syndrome?; (C) Who should have surgical treatment and how should it be performed?; (D) What follow-up is indicated if the adrenal incidentaloma is not surgically removed? Selected recommendations: (i) At the time of initial detection of an adrenal mass establishing whether the mass is benign or malignant is an important aim to avoid cumbersome and expensive follow-up imaging in those with benign disease. (ii) To exclude cortisol excess, a 1mg overnight dexamethasone suppression test should be performed (applying a cut-off value of serum cortisol ≤50nmol/L (1.8µg/dL)). (iii) For patients without clinical signs of overt Cushing’s syndrome but serum cortisol levels post 1mg dexamethasone >138nmol/L (>5µg/dL), we propose the term ‘autonomous cortisol secretion’. (iv) All patients with ‘(possible) autonomous cortisol’ secretion should be screened for hypertension and type 2 diabetes mellitus, to ensure these are appropriately treated. (v) Surgical treatment should be considered in an individualized approach in patients with ‘autonomous cortisol secretion’ who also have comorbidities that are potentially related to cortisol excess. (vi) In principle, the appropriateness of surgical intervention should be guided by the likelihood of malignancy, the presence and degree of hormone excess, age, general health and patient preference. (vii) Surgery is not usually indicated in patients with an asymptomatic, nonfunctioning unilateral adrenal mass and obvious benign features on imaging studies. We provide guidance on which surgical approach should be considered for adrenal masses with radiological findings suspicious of malignancy. Furthermore, we offer recommendations for the follow-up of patients with adrenal incidentaloma who do not undergo adrenal surgery, for those with bilateral incidentalomas, for patients with extra-adrenal malignancy and adrenal masses and for young and elderly patients with adrenal incidentalomas

Adrenal incidentalomas are adrenal masses detected on imaging performed for reasons other than suspected adrenal disease. In most cases, adrenal incidentalomas are non-functioning adrenocortical adenomas, but may also require therapeutic intervention including that for adrenocortical carcinoma, pheochromocytoma, hormone-producing adenoma or metastases. Here, we provide a revision of the first international, interdisciplinary guidelines on incidentalomas. We followed the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system and updated systematic reviews on four predefined clinical questions crucial for the management of incidentalomas: A) How to assess risk of malignancy? ; B) How to define and manage mild autonomous cortisol secretion? ; C) Who should have surgical treatment and how should it be performed? ; D) What follow-up is indicated if the adrenal incidentaloma is not surgically removed? Selected Recommendations: 1) Each adrenal mass requires dedicated adrenal imaging. Recent advances now allow discrimination between risk categories: Homogeneous lesions with HU ≤ 10 on unenhanced CT are benign and do not require any additional imaging independent of size. All other patients should be discussed in a multidisciplinary expert meeting, but only lesions >4 cm that are inhomogeneous or have HU >20 have sufficiently high risk of malignancy that surgery will be the usual management of choice. 2) Every patient needs a thorough clinical and endocrine work-up to exclude hormone excess including the measurement of plasma or urinary metanephrines and a 1-mg overnight dexamethasone suppression test (applying a cutoff value of serum cortisol ≤50 nmol/l (≤1.8 µg/dl)). Recent studies have provided evidence that most patients without clinical signs of overt Cushing's syndrome but serum cortisol levels post dexamethasone >50 nmol/l (>1.8 µg/dl) harbor increased risk of morbidity and mortality. For this condition, we propose the term ‘mild autonomous cortisol secretion’ (MACS). 3) All patients with MACS should be screened for potential cortisol-related comorbidities that are potentially attributably to cortisol (e.g. hypertension and type 2 diabetes mellitus), to ensure these are appropriately treated. 4) In patients with MACS who also have relevant comorbidities surgical treatment should be considered in an individualized approach. 5) The appropriateness of surgical intervention should be guided by the likelihood of malignancy, the presence and degree of hormone excess, age, general health and patient preference. We provide guidance on which surgical approach should be considered for adrenal masses with radiological findings suspicious of malignancy. 6) Surgery is not usually indicated in patients with an asymptomatic, non-functioning unilateral adrenal mass and obvious benign features on imaging studies. Furthermore, we offer recommendations for the follow-up of non-operated patients, management of patients with bilateral incidentalomas, for patients with extra-adrenal malignancy and adrenal masses, and for young and elderly patients with adrenal incidentalomas. Finally, we suggest ten important research questions for the future.

Adrenal insufficiency continues to be a challenge for patients, their physicians, and researchers. During the past decade, long-term studies have shown increased mortality and morbidity and impaired quality of life in patients with adrenal insufficiency. These findings might, at least partially, be due to the failure of glucocorticoid replacement therapy to closely resemble physiological diurnal secretion of cortisol. The potential effect of newly developed glucocorticoid drugs is a focus of research, as are the mechanisms potentially underlying increased morbidity and mortality. Adrenal crisis remains a threat to lives, and awareness and preventative measures now receive increasing attention. Awareness should be raised in medical teams and patients about adrenal insufficiency and management of adrenal crisis to improve clinical outcome.

Context: Malignant pheochromocytoma (PHEO) and paraganglioma (PGL) are rare and knowledge of the natural history is limited. Objective: We aimed to describe baseline characteristics and outcomes of patients with malignant PHEO and PGL (PPGL) and to identify predictors of shorter survival. Design: Retrospective review of patients with malignant PPGL evaluated from 1960 to 2016. Setting: Referral center. Patients: The group comprised 272 patients. Main Outcome Measures: Baseline description, survival outcomes, and predictors of shorter survival were evaluated in patients with rapidly progressive (n= 29) and indolent disease (n= 188). Results: Malignant PPGL was diagnosed at a median age of 39 (range, 7-83) years, with synchronous metastases in 96 (35%) patients. In 176 (65%) patients, metastases developed at a median of 5.5 (range, 0.3 - 53.4) years from the initial diagnosis. Median follow-up was 8.2 (range, 0.01-54.1) years. Median overall and disease-specific survivals were 24.6 and 33.7 years, respectively. Shorter survival correlated with: male sex (P=.014), older age at the time of primary tumor (P=.0011), synchronous metastases (P<0.0001), larger primary tumor size (P = 0.0039), elevated dopamine (P= 0.0195), and not undergoing primary tumor resection (P<0.0001). There was no difference in the type of primary tumor or presence of SDHB mutation. Conclusions: The clinical course of patients with malignant PPGL is remarkably variable. Rapid disease progression is associated with: male sex, older age at diagnosis, synchronous metastases, larger tumor size, elevated dopamine, and not undergoing resection of primary tumor. An individualized approach to patients with metastatic PPGL is warranted.

BACKGROUND. Adrenal aldosterone excess is the most common cause of secondary hypertension and is associated with increased cardiovascular morbidity. However, adverse metabolic risk in primary aldosteronism extends beyond hypertension, with increased rates of insulin resistance, type 2 diabetes, and osteoporosis, which cannot be easily explained by aldosterone excess. METHODS. We performed mass spectrometry–based analysis of a 24-hour urine steroid metabolome in 174 newly diagnosed patients with primary aldosteronism (103 unilateral adenomas, 71 bilateral adrenal hyperplasias) in comparison to 162 healthy controls, 56 patients with endocrine inactive adrenal adenoma, 104 patients with mild subclinical, and 47 with clinically overt adrenal cortisol excess. We also analyzed the expression of cortisol-producing CYP11B1 and aldosterone-producing CYP11B2 enzymes in adenoma tissue from 57 patients with aldosterone-producing adenoma, employing immunohistochemistry with digital image analysis. RESULTS. Primary aldosteronism patients had significantly increased cortisol and total glucocorticoid metabolite excretion (all P < 0.001), only exceeded by glucocorticoid output in patients with clinically overt adrenal Cushing syndrome. Several surrogate parameters of metabolic risk correlated significantly with glucocorticoid but not mineralocorticoid output. Intratumoral CYP11B1 expression was significantly associated with the corresponding in vivo glucocorticoid excretion. Unilateral adrenalectomy resolved both mineralocorticoid and glucocorticoid excess. Postoperative evidence of adrenal insufficiency was found in 13 (29%) of 45 consecutively tested patients. CONCLUSION. Our data indicate that glucocorticoid cosecretion is frequently found in primary aldosteronism and contributes to associated metabolic risk. Mineralocorticoid receptor antagonist therapy alone may not be sufficient to counteract adverse metabolic risk in medically treated patients with primary aldosteronism. FUNDING. Medical Research Council UK, Wellcome Trust, European Commission.