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Background: Surgical treatment of pheochromocytomas is associated with circulatory dynamics instability, necessitating systemic management of the patient in the intensive care unit after surgery. Early mobilization after pheochromocytoma surgery is not described in the guidelines, and to our knowledge, no reports have specifically focused on circulatory dynamics during early mobilization after surgery., Case Presentation: A 31-year-old Japanese woman was diagnosed with bilateral pheochromocytoma and underwent a second-stage adrenalectomy for bilateral pheochromocytoma at our hospital. We evaluated circulatory dynamics during a passive upright posture on postoperative days 1 and 4. She was placed on a tilt bed in the supine position (0° head) for 15 min, passive upright posture (60°) for 15 min, and supine position again for 10 min. In the passive upright posture, both systolic and diastolic blood pressure decreased, and the heart rate increased by 10 bpm over approximately 10 minutes. After the postural change from the passive upright posture to the supine position, the heart rate decreased to a level lower than in the supine prior to the passive upright posture. The same measurements were taken on postoperative day 4. Systolic blood pressure decreased in the passive upright posture, but diastolic blood pressure remained unchanged. The heart rate also increased earlier after passive upright posture compared with that on the day after surgery. When the patient returned to the supine position from the passive upright posture, the heart rate decreased even further compared with its level prior to the passive upright posture, as observed on the day after surgery., Conclusion: Circulatory dynamics may fluctuate after surgery for pheochromocytoma due to a relative decrease in epinephrine and norepinephrine secretion. In this case, the patient's response may be close to normal by the fourth postoperative day, but circulatory dynamics fluctuations were noted on both the first and fourth postoperative days when the patient was supine after passive upright posture. Although the substantial variability of perioperative circulatory dynamics in patients with pheochromocytoma has improved considerably with the development of perioperative management guidelines, circulatory dynamics should be carefully monitored during early mobilization and after its completion., (© 2024. The Author(s).)

The majority of incidentally discovered adrenal tumours are benign adrenocortical adenomas and the prevalence of adrenocortical adenomas is around 1-7% on cross-sectional abdominal imaging. These can be non-functioning adrenal tumours or they can be associated with autonomous cortisol secretion on a spectrum that ranges from rare clinically overt adrenal Cushing syndrome to the much more prevalent mild autonomous cortisol secretion (MACS) without signs of Cushing syndrome. MACS is diagnosed (based on an abnormal overnight dexamethasone suppression test) in 20-50% of patients with adrenal adenomas. MACS is associated with cardiovascular morbidity, frailty, fragility fractures, decreased quality of life and increased mortality. Management of MACS should be individualized based on patient characteristics and includes adrenalectomy or conservative follow-up with treatment of associated comorbidities. Identifying patients with MACS who are most likely to benefit from adrenalectomy is challenging, as adrenalectomy results in improvement of cardiovascular morbidity in some, but not all, patients with MACS. Of note, diagnosis and management of patients with bilateral MACS is especially challenging. Current gaps in MACS clinical practice include a lack of specific biomarkers diagnostic of MACS-related health outcomes and a paucity of clinical trials demonstrating the efficacy of adrenalectomy on comorbidities associated with MACS. In addition, little evidence exists to demonstrate the efficacy and safety of long-term medical therapy in patients with MACS., (© 2024. Springer Nature Limited.)

Purpose: Surgery is the only way to cure pheochromocytoma; however, postoperative hemodynamic instability is one of the main causes of serious complications and even death. This study's findings provide some guidance for improved clinical management., Patients and Methods: This study was to investigate the factors leading to postoperative hemodynamic instability in the postoperative pathology indicated pheochromocytoma from May 2016 to May 2022. They were divided into two groups according to whether vasoactive drugs were used for a median number of days or more postoperatively. The factors affecting the postoperative hemodynamics in the perioperative period (preoperative, intraoperative, and postoperative) were then evaluated., Results: The median number of days requiring vasoactive drug support postoperatively was three in 234 patients, while 118 (50.4%) patients required vasoactive drug support for three days or more postoperatively. The results of the multivariate analysis indicated more preoperative colloid use (odds ratio [OR]=1.834, confidence interval [CI]:1.265-2.659, P=0.001), intraoperative use of vasoactive drug (OR=4.174, CI:1.882-9.258, P<0.001), and more postoperative crystalloid solution input per unit of body weight per day (ml/kg/d) (OR=1.087, CI:1.062-1.112, P<0.001) were risk factors for predicting postoperative hemodynamic instability. The optimal cutoff point of postoperative crystalloid use were 42.37 ml/kg/d., Conclusion: Hemodynamic instability is a key issue for consideration in the perioperative period of pheochromocytoma. The amount of preoperative colloid use, the need for intraoperative vasoactive drugs, and postoperative crystalloid solution are risk factors for predicting postoperative hemodynamic instability (registration number: ChiCT2300071166)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Liu, Shang, Zhuang, Su, Li, Sun and Long.)

Objective: Primary adrenal lymphoma (PAL) is a rare form of adrenal mass. We summarize our experience in its clinical presentation, biochemical indexes, radiological features, pathological information, therapy regimens, and outcomes., Methods: This was an institutional review board-approved retrospective review of medical records and surgical pathology specimens of patients with a diagnosis of PAL at the Chinese People's Liberation Army General Hospital and the First Affiliate Hospital of Xiamen University between July 2007 and July 2017., Results: Twenty-six patients were identified. The mean age at presentation was 60.84 ± 13.14 years with a male-to-female ratio of 2.25:1 (18:8). The most common presenting symptoms were loss of appetite (65%, 17/26), weight loss (62%, 16/26), abdominal pain (58%, 15/26), and fatigue (58%, 15/26). The levels of lactate dehydrogenase (75%, 15/20), β 2 -microglobulin (100%, 10/10), C-reactive protein (82%, 14/17), and ferritin (88%, 7/8) and the erythrocyte sedimentation rate (83%, 10/12) were elevated. Bilateral involvement was seen in 21 of 26 patients (81%); 12 of 19 evaluated patients with bilateral lesions (63%) were confirmed to have adrenal insufficiency. On computed tomography (CT), the mean tumor diameter was 7.31 ± 3.35 cm and the median Hounsfield density was 37.0 HU (range: 31.0-45.0 HU); 67% (10/15) and 27% (4/15) of lesions presented with mild and moderate enhancement after injection of contrast medium. 18 F-fluorodeoxyglucose positron emission tomography (FDG PET)-CT revealed not only an adrenal tumor but also extra-adrenal lesions. Diffuse large B-cell lymphoma (DLBCL) was the most common phenotype (92%, 24/26). Ninety-two percent (24/26) of patients received chemotherapy while 8% (2/26) received unilateral adrenalectomy plus chemotherapy. The prognosis of PAL was poor, with a general survival time of 7.20 ± 5.18 months., Conclusion: PAL is a rare disease. The clinical characteristics of PAL include loss of appetite and weight loss. Endocrine evaluation should be performed to determine whether patients have adrenal insufficiency, especially patients with bilateral lesions. FDG-PET appears to be more accurate than other imaging modalities in revealing extra-adrenal sites. Better therapy is required to improve the poor prognosis of PAL., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zeng, Yan, Chen, Zang, Chen, Lyu, Dou, Mu, Lin and Yang.)

Purpose: Surgical removal of pheochromocytoma (PCC), including open, laparoscopic, and robot-assisted adrenalectomy, is the cornerstone of therapy, which is associated with high risk of intraoperative and postoperative life-threatening complications due to intraoperative hemodynamic instability (IHD). This study aims to develop and validate a nomogram based on clinical characteristics as well as computed tomography (CT) features for the prediction of IHD in pheochromocytoma surgery., Methods: The data from 112 patients with pheochromocytoma were collected at a single center between January 1, 2010, and December 31, 2019. Clinical and radiological features were selected with the least absolute shrinkage and selection operator regression analysis to predict IHD then constitute a nomogram. The performance of the nomogram was assessed in terms of discrimination, calibration, and clinical utility., Results: Age, tumor shape, Mayo Adhesive Probability score, laterality, necrosis, body mass index, and surgical technique were identified as risk predictors of the presence of IHD. The nomogram was then developed using these seven variables. The model showed good discrimination with a C-index of 0.773 (95% CI, 0.683-0.862) and an area under the receiver operating characteristic curve (AUC) of 0.739 (95% CI, 0.642-0.837). The calibration plot suggested good agreement between predicted and actual probabilities. Besides, calibration was tested with the Hosmer-Lemeshow test (P = 0.961). The decision curve showed the clinical effectiveness of the nomogram., Conclusions: Our nomogram based on clinical and CT parameters could facilitate the treatment strategy according to assessment of the risk of IHD in patients with pheochromocytoma., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhang, Ye, Yu, Liao, Pan, Guo, Jiang, Luo and Zheng.)

Objective: Reliable results of wash-out CT in the diagnostic workup of adrenal incidentalomas are scarce. Thus, we evaluated the diagnostic accuracy of delayed wash-out CT and determined thresholds to accurately differentiate adrenal masses., Design: Retrospective, single-center cohort study including 216 patients with 252 adrenal lesions who underwent delayed wash-out CT. Definitive diagnoses based on histopathology (n = 92) or comprehensive follow-up., Methods: Size, average attenuation values of the adrenal lesions in all CT scan phases, and absolute and relative percentage wash-out (APW/RPW) were determined by an expert radiologist blinded for clinical data. Adrenal lesions with unenhanced attenuation values >10 Hounsfield units (HU) built a subgroup (n = 142). Diagnostic accuracy was calculated., Results: The study group consisted of 171 adenomas, 32 other benign tumors, 11 pheochromocytomas, 9 adrenocortical carcinomas, and 29 other malignant tumors. All (potentially) malignant and 46% of benign lesions showed unenhanced attenuation values >10 HU. In this most relevant subgroup, the established thresholds of 60% for APW and 40% for RPW misclassified 35.9 and 35.2% of the masses, respectively. When we applied optimized cutoffs (APW >83%; RPW >58%) and excluded pheochromocytomas, we missed only one malignant tumor by APW and none by RPW. However, only 11 and 15% of the benign tumors were correctly identified., Conclusions: Wash-out CT with the established thresholds for APW and RPW is insufficient to reliably diagnose adrenal masses. Using the proposed cutoff of 58% for RPW, malignant tumors will be correctly identified, but the added value is limited, namely 15% of patients with benign tumors can be prevented from additional imaging or even unnecessary surgery.

Purpose: Adrenal incidentalomas (AIs) are incidentally discovered adrenal masses, during an imaging study undertaken for other reasons than the suspicion of adrenal disease. Their management is not a minor concern for patients and health-care related costs, since their increasing prevalence in the aging population. The exclusion of malignancy is the first question to attempt, then a careful evaluation of adrenal hormones is suggested. Surgery should be considered in case of overt secretion (primary aldosteronism, adrenal Cushing's Syndrome or pheochromocytoma), however the management of subclinical secretion is still a matter of debate., Methods: The aim of the present narrative review is to offer a practical guidance regarding the management of AI, by providing evidence-based answers to frequently asked questions., Conclusion: The clinical experience is of utmost importance: a personalized diagnostic-therapeutic approach, based upon multidisciplinary discussion, is suggested., (© 2021. The Author(s).)

Aim: Information on systolic dysfunction, as assessed by left-ventricular (LV) mechanics, in patients with pheochromocytoma after surgical treatment is scanty. We performed a systematic meta-analysis of speckle tracking echocardiographic studies to provide an updated comprehensive information on this issue., Methods: The PubMed, OVID-MEDLINE, and Cochrane library databases were analyzed to search for articles published from the inception up to May 31st 2021. Studies were identified using MeSH terms and crossing the following search items: "myocardial strain" "left ventricular mechanics", "speckle tracking echocardiography", "systolic dysfunction", "pheochromocytoma", and "paraganglioma"., Results: A total of 92 surgically treated patients with pheochromocytoma/paraganglioma were included in 3 longitudinal studies. Successful surgical treatment was associated with a decrease in relative wall thickness (SMD - 0.25 ± 0.10, CI - 0.45/- 0.05, p < 0.01) and an improvement in global longitudinal strain (SMD - 0.45 ± 0.10, CI - 0.66/- 0.24, p < 0.0001). The favorable effects of treatment on LV geometry and mechanics were not accompanied by significant changes in ejection fraction (SMD - 0.07 ± 0.10, CI - 0.27/0.12, p = 0.44)., Conclusions: This meta-analysis adds a new piece of evidence, suggesting that surgical treatment of patients with pheochromocytoma impacts favorably on LV geometry and LV mechanics, and, more importantly, the assessment of LV changes in this setting can no longer rely on conventional echocardiographic parameters such as ejection fraction., (© 2021. Italian Society of Endocrinology (SIE).)

Purpose: There are no data regarding periodontal derangements in patients with adrenal incidentalomas (AI). We assessed the frequency and severity of periodontitis in patients with AI [non-functioning adrenal incidentaloma (NFAI) and possible autonomous cortisol secretion (ACS)] and compared with individuals with normal adrenal., Methods: A cross-sectional study evaluated thirty-five individuals with AI and 26 controls. NFAI and possible ACS diagnosis was based on the current guidelines: NFAI [cortisol levels after 1 mg dexamethasone suppression test (1 mg-DST) ≤ 1.8 µg/dL (≤ 50 nmol/L)]; possible ACS [cortisol levels after 1 mg-DST 1.9-5.0 µg/dL (51-138 nmol/L)]. Sociodemographic data were collected, and a full-mouth periodontal evaluation was performed., Results: There was no significant difference between groups regarding age, sex, income, ethnicity, education level, smoking, body mass index, dysglycemia, and arterial hypertension. Patients with AI exhibited worse periodontal conditions than controls for the following periodontal clinical parameters: mean percentage of probing pocket depth (PPD) and clinical attachment level (CAL) ≥ 5 mm (p < 0.001 and p = 0.006, respectively). Patients with NFAI and possible ACS showed higher gingival bleeding index (p = 0.014), bleeding on probing (p < 0.001), and CAL (p < 0.001) means compared to controls. The frequencies of periodontitis were 72.7% in patients with NFAI, 84.6% in possible ACS, and 30.8% in controls (p = 0.001). Periodontitis was more severe in patients with possible ACS than NFAI and controls. Patients with NFAI and possible ACS exhibited odds ratio for periodontitis of 4.9 (p = 0.016) and 8.6 (p = 0.02), respectively., Conclusion: Patients with AI have higher frequency and severity of periodontitis than controls. The presence of AI was an independent predictive factor for periodontitis., (© 2021. Italian Society of Endocrinology (SIE).)

Context: While adrenal adenomas have been linked with cardiovascular morbidity in convenience samples of patients from specialized referral centers, large-scale population-based data are lacking., Objective: To determine the prevalence and incidence of cardiometabolic disease and assess mortality in a population-based cohort of patients with adrenal adenomas., Design: Population-based cohort study., Setting: Olmsted County, Minnesota, USA., Patients: Patients diagnosed with adrenal adenomas without overt hormone excess and age- and sex-matched referent subjects without adrenal adenomas., Main Outcome Measure: Prevalence, incidence of cardiometabolic outcomes, mortality., Results: (Adrenal adenomas were diagnosed in 1004 patients (58% women, median age 63 years) from 1/01/1995 to 12/31/2017. At baseline, patients with adrenal adenomas were more likely to have hypertension [adjusted odds ratio (aOR) 1.96, 95% CI 1.58-2.44], dysglycemia (aOR 1.63, 95% CI 1.33-2.00), peripheral vascular disease (aOR 1.59, 95% CI 1.32-2.06), heart failure (aOR 1.64, 95% CI 1.15-2.33), and myocardial infarction (aOR 1.50, 95% CI 1.02-2.22) compared to referent subjects. During median follow-up of 6.8 years, patients with adrenal adenomas were more likely than referent subjects to develop de novo chronic kidney disease [adjusted hazard ratio (aHR) 1.46, 95% CI 1.14-1.86], cardiac arrhythmia (aHR 1.31, 95% CI 1.08-1.58), peripheral vascular disease (aHR 1.28, 95% CI 1.05-1.55), cardiovascular events (aHR 1.33, 95% CI 1.01-1.73), and venous thromboembolic events (aHR 2.15, 95% CI 1.48-3.13). Adjusted mortality was similar between the 2 groups., Conclusion: Adrenal adenomas are associated with an increased prevalence and incidence of adverse cardiometabolic outcomes in a population-based cohort., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

For pheochromocytoma and sympathetic paraganglioma (PPGL), surgery can be used as a curative treatment; however, the life-threatening risk of perioperative hemodynamic instability (HI) presents challenges. This study aimed to analyze the incidence and predictive factors of perioperative HI. The electronic medical records of 114 consecutive patients who underwent surgery for PPGLs at our institution were retrospectively reviewed. HI was defined as one or more episodes of systolic blood pressure > 200 mmHg or mean blood pressure < 60 mmHg during surgery. The factors predictive of perioperative HI were determined using both univariate and multivariate analyses. Intraoperative HI occurred in 79 (69.3%) patients. In multivariate analysis, α-adrenergic receptor blocker duration (days) (odds ratio, 1.015; 95% confidence interval, 1.001-1.029) was a predictor for intraoperative HI. Postoperative hypotension occurred in 36 (31.6%) patients. Higher urine epinephrine levels, and greater preoperative highest heart rate (HR) were predictive factors for postoperative hypotension in PPGL patients. Caution should be taken in perioperative management for PPGL, especially with long duration of α-adrenergic receptor blocker use, higher urine epinephrine levels, and greater preoperative highest HR., (© 2021. The Author(s).)

Context: Preoperative blockade with α-blockers is recommended in patients with pheochromocytoma/paraganglioma (PPGL). The data on calcium channel blockade (CCB) in PPGL are scarce., Objective: We aimed to compare the efficacy of CCB and α-blockers on intraoperative hemodynamic instability (HDI) in PPGL., Methods: In the interim analysis of this monocentric, pilot, open-label, randomized controlled trial, patients with solitary, secretory, and nonmetastatic PPGL were randomized to oral prazosin gastrointestinal therapeutic system (GITS) (maximum 30 mg, n = 9) or amlodipine (maximum 20 mg, n = 11). The primary outcomes were the episodes and duration of hypertension (systolic blood pressure ≥ 160 mmHg) and hypotension (mean arterial pressure < 60 mmHg) and duration of HDI (hypertension and/or hypotension) as a percentage of total surgical time (from induction of anesthesia to skin closure)., Results: The median (IQR) episodes (2 [1-3] vs 0 [0-1]; P = 0.002) and duration of hypertension (19 [14-42] vs 0 [0-3] minutes; P = 0.001) and intraoperative HDI duration (22.85 ± 18.4% vs 2.44 ± 2.4%; CI, 8.68-32.14%; P 0.002) were significantly higher in the prazosin GITS arm than the amlodipine arm, whereas episodes and duration of hypotension did not differ between the 2 groups. There was no perioperative mortality. One patient had intraoperative ST depression on the electrocardiogram. The drug-related adverse effects were pedal edema (1 in amlodipine), dizziness (1 in prazosin GITS), and tachycardia (6 in prazosin GITS and 3 in amlodipine)., Conclusion: Preoperative blockade with amlodipine is an efficacious alternative to prazosin GITS in preventing intraoperative HDI in PPGL. Larger studies that compare preoperative blockade by amlodipine with other α-blockers like phenoxybenzamine and/or doxazosin in PPGL patients are warranted., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

This study is the first to assess redox balance, glutathione metabolism, and oxidative damage to RNA/DNA, proteins, and lipids in the plasma/serum and urine of patients with adrenal masses. The study included 70 patients with adrenal tumors divided into three subgroups: incidentaloma ( n = 30), pheochromocytoma ( n = 20), and Cushing's/Conn's adenoma ( n = 20), as well as 60 healthy controls. Blood and urine samples were collected before elective endoscopic adrenalectomy. Antioxidant defense capacity was significantly decreased (serum/plasma: superoxide dismutase (SOD), catalase (CAT) and reduced glutathione (GSH), uric acid (UA); urine: SOD, GSH, UA) in patients with adrenal masses. The oxidative damage to proteins (advanced glycation end products (AGE), advanced oxidation protein products (AOPP)) and lipids (lipid hydroperoxides (LOOH), and malondialdehyde (MDA)) was higher in the plasma and urine of these patients. Plasma MDA and DNA/RNA oxidation products, with high sensitivity and specificity, can help to diagnose pheochromocytoma. This biomarker differentiates patients with pheochromocytoma from Cushing's/Conn's adenoma as well as from heathy controls. Plasma RNA/DNA oxidation was also positively correlated with urine metanephrine. Oxidative stress can play a crucial role in adrenal tumors. However, further studies are required to clarify the role of redox signaling in adrenal masses., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Barbara Choromańska et al.)

Stress cardiomyopathy (SCM) is a syndrome characterized by transient regional systolic dysfunction of the left ventricle in the absence of angiographic evidence of coronaropathy. This abnormality is associated with high levels of catecholamines. Stress cardiomyopathy is also called Takotsubo (TS) cardiomyopathy. Pheochromocytoma crisis can occur spontaneously or can be precipitated by manipulation of the tumor, trauma, certain medications or stress for example during non-adrenal surgery. The main drugs leading to pheochromocytoma crisis include D2 dopamine receptor antagonists, noncardioselective β-adrenergic receptor blockers, tricyclic antidepressants and related neurotransmitter uptake blockers, sympathomimetics, certain peptide and steroid hormones and several agents used during induction of anesthesia. Patients can develop symptoms of heart failure associated with tachyarrhythmia, cardiogenic shock with hypotension and collapse, or apparent acute coronary syndromes. This review describes pathophysiology, epidemiology, diagnosis criteria and management of SCM., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Background: Cortisol levels in response to stress are highly variable. Baseline and stimulated cortisol levels are commonly used to determine adrenal function following unilateral adrenalectomy. We report the results of synacthen stimulation testing following unilateral adrenalectomy in a tertiary referral center., Methods: Data were collected retrospectively for 36 patients who underwent synacthen stimulation testing one day post unilateral adrenalectomy. None of the patients had clinical signs of hypercortisolism preoperatively. No patient received pre- or intraoperative steroids. Patients with overt Cushing's syndrome were excluded., Results: The median age was 58 (31-79) years. Preoperatively, 16 (44%) patients had a diagnosis of pheochromocytoma, 12 (33%) patients had primary aldosteronism and 8 (22%) patients had non-functioning adenomas with indeterminate/atypical imaging characteristics necessitating surgery. Preoperative overnight dexamethasone suppression test results revealed that 6 of 29 patients failed to suppress cortisol to <50 nmol/L. Twenty (56%) patients achieved a stimulated cortisol ≥450 nmol/L at 30 minutes and 28 (78%) at 60 minutes. None of the patients developed clinical adrenal insufficiency necessitating steroid replacement., Conclusions: Synacthen stimulation testing following unilateral adrenalectomy using standard stimulated cortisol cut-off values would wrongly label many patients adrenally insufficient and may lead to inappropriate prescriptions of steroids to patients who do not need them., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zaman, Almazrouei, Sam, DiMarco, Todd, Palazzo, Tan, Dhillo, Meeran and Wernig.)

It is recommended that adrenal incidentaloma patients should be monitored for radiological changes, increase in size and new functionality that may occur in the future, even if they are benign and nonfunctional at the initial evaluation. Our aim is to evaluate the key clinical characteristics of adrenal incidentaloma patients focusing on changes during follow-up and associated clinical outcomes. A total of 755 patients (median age: 56 years), with an adrenal incidentaloma > 1 cm and underwent functionality tests, were included in the study. Clinical characteristics, functionality status and follow-up durations were recorded. During the course of follow-up, any changes in size and development of new functionality, and clinical consequences thereof were evaluated. In 71.8% of patients, incidentalomas were non-functional. Most frequent functionality (15.8%, n=119) was subclinical hypercortisolemia (SH) [10.9% (n=82) possible autonomous cortisol secretion (PACS) and 4.9% (n=37) autonomous cortisol secretion (ACS)] of all incidentalomas. Frequencies of Cushing's syndrome (CS), pheochromacytoma and primary hyperaldosteronism were 4.9% (n=37), 3.8% (n=29) and 3.7% (n=28), respectively. Adrenocortical carcinoma frequency was 1.5% (n=11). Of 755 patients, 43% (n=325) were followed up regularly more than 6 months. Median follow-up duration was 24 months (6-120). A total of 17 (5.2%) patients, which had non-functional incidentalomas at baseline had developed new functionality during follow-up, of which 15 (4.6%) were SH [13 patients (4%) PACS and 2 patients (0.6%) ACS] and 2 (0.6%) were CS. During follow-up, 24% (n=78) of the patients had an increase in mass size between 5-9 mm, while 11.7% (n=38) of the patients had an increase of ≥10 mm. During follow-up, 4% (n=13) of the patients developed a new lesion with a diameter ≥10 mm on the opposite side. In patients with a follow-up duration of more than 2 years, frequencies of size increase and new lesion emerging at the opposite adrenal gland were higher. 14 patients (4.3% of the patients with regular follow-up) underwent surgery due to increase in size or development of new functionality during follow-up. Our study demonstrated that a necessity for surgery may arise due to increase in size and development of functionality during follow-up period in adrenal incidentaloma patients, and thus continuing patient follow-up, even with wider intervals, will be appropriate., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Pheochromocytoma, as a neuroendocrine tumor with the highest genetic correlation in all types of tumors, has attracted extensive attention. Von Hipper Lindau (VHL) has the highest mutation frequency among the genes associated with pheochromocytoma. However, the effect of VHL on the proteome of pheochromocytoma remains to be explored. In this study, the VHL knockdown (VHL-KD) PC12 cell model was established by RNA interference (shRNA). We compared the proteomics of VHL-KD and VHL-WT PC12 cell lines. The results showed that the expression of 434 proteins (VHL shRNA/WT > 1.3) changed significantly in VHL-KD-PC12 cells. Among the 434 kinds of proteins, 83 were involved in cell proliferation, cell cycle and cell migration, and so on. More importantly, among these proteins, we found seven novel key genes, including Connective Tissue Growth Factor (CTGF), Syndecan Binding Protein (SDCBP), Cysteine Rich Protein 61 (CYR61/CCN1), Collagen Type III Alpha 1 Chain (COL3A1), Collagen Type I Alpha 1 Chain (COL1A1), Collagen Type V Alpha 2 Chain (COL5A2), and Serpin Family E Member 1 (SERPINE1), were overexpressed and simultaneously regulated cell proliferation and migration in VHL-KD PC12 cells. Furthermore, the abnormal accumulation of HIF2α caused by VHL-KD significantly increased the expression of these seven genes during hypoxia. Moreover, cell-counting, scratch, and transwell assays demonstrated that VHL-KD could promote cell proliferation and migration, and changed cell morphology. These findings indicated that inhibition of VHL expression could promote the development of pheochromocytoma by activating the expression of cell proliferation and migration associated genes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gao, Liu, Li, Pang, Shi and Zhu.)

Background and Aims: Pheochromocytoma and paraganglioma (PPGL) are associated with dysglycemia and diabetes mellitus (DM) much of which improves post operatively. In this study, we set out to ascertain pre and post-operative prevalence of DM in patients with PPGL based on oral glucose tolerance test (OGTT) and HbA1c and to evaluate effect of insulin secretion and sensitivity indices on DM pre-operatively., Methods: Clinical and anthropometric data collection, HbA1c, 75 g OGTT with serum insulin estimation were done pre-operatively (n = 34) and at follow-up after successful surgery (n = 24) in patients with PPGL., Results: Pre and post-operative prevalence of DM were 48%(18/37) and 17% (4/24) respectively. Comparison of patients with highest (Q4) and lowest (Q1) quartiles of insulinogenic index (IGI),a parameter of insulin secretion, revealed trends towards higher prevalence of DM in patients with lower IGI (Q4 to Q1: 29% versus 71%,n = 28, p = 0.24)but no association was observed with HOMA-IR (Q4 to Q1:50% versus 57%, n = 28, p = 1.00), an insulin sensitivity index. DM remitted in 77% patients post-operatively, predicted by duration of DM of<3 years., Conclusion: There is high prevalence of DM in PPGL, with marked remission post-operatively, especially predicted by shorter duration of DM. Impaired insulin secretion is more strongly associated with pre-operative DM than increased insulin resistance., Competing Interests: Declaration of competing interest None., (Copyright © 2020. Published by Elsevier Ltd.)

Cardiomyopathy is a frequent complication of pheochromocytoma, and echocardiography is the most accessible method for its evaluation. The objective of this study was to assess the clinical significance of classical and novel echocardiographic parameters of cardiac function in 24 patients with pheochromocytomas (PPGL) compared to 24 subjects with essential hypertension (EH). Fourteen PPGL patients were reassessed after successful surgery. Left ventricular hypertrophy was four times more prevalent in patients with PPGL vs EH (75% vs 17%; P = 0.00005). Left ventricular mass index (LVMi) significantly correlated with urine metanephrine (MN) (rs = 0.452, P = 0.00127) and normetanephrine (NMN) (rs = 0.484, P = 0.00049). Ejection fraction (EF) and endocardial fractional shortening (EFS) were normal in all participants and did not correlate with urine metanephrines. Global longitudinal strain (GLS) was significantly lower in PPGL compared to EH group (-16.54 ± 1.83 vs -19.43 ± 2.19; P < 0.00001) and revealed a moderate significant positive correlations with age (rs = 0.489; P = 0.015), LVMi (rs = 0.576, P < 0.0001), MN (rs = 0.502, P = 0.00028) and NMN (rs = 0.580, P < 0.0001). Relative wall thickness (RWT) showed a strong positive correlation with urine MN (rs = 0.559, P < 0.0001) and NMN (rs = 0.689, P < 0.00001). Markedly decreased LVMi (118.2 ± 26.9 vs 102.9 ± 22.3; P = 0.007) and significant improvement in GLS (-16.64 ± 1.49 vs -19.57 ± 1.28; P < 0.001) was observed after surgery. ΔGLS depended significantly on the follow-up duration. In conclusion, classical echocardiographic parameters usually used for assessment of systolic cardiac function are not reliable tests in pheochromocytoma patients. Instead, GLS seems to be a better predictor for the severity and the reversibility of catecholamine-induced myocardial function damage in these subjects. RWT should be measured routinely as an early indicator of cardiac remodeling.

Competing Interests: Competing interests: None declared.

Context: Catecholamines and adrenocortical steroids are important regulators of blood pressure. Bidirectional relationships between adrenal steroids and catecholamines have been established but whether this is relevant to patients with pheochromocytoma is unclear., Objective: This study addresses the hypothesis that patients with pheochromocytoma and paraganglioma (PPGL) have altered steroid production compared with patients with primary hypertension., Design: Multicenter cross-sectional study., Setting: Twelve European referral centers., Patients: Subjects included 182 patients with pheochromocytoma, 36 with paraganglioma and 270 patients with primary hypertension. Patients with primary aldosteronism (n = 461) and Cushing syndrome (n = 124) were included for additional comparisons., Intervention: In patients with PPGLs, surgical resection of tumors., Outcome Measures: Differences in mass spectrometry-based profiles of 15 adrenal steroids between groups and after surgical resection of PPGLs. Relationships of steroids to plasma and urinary metanephrines and urinary catecholamines., Results: Patients with pheochromocytoma had higher (P < .05) circulating concentrations of cortisol, 11-deoxycortisol, 11-deoxycorticosterone, and corticosterone than patients with primary hypertension. Concentrations of cortisol, 11-deoxycortisol, and corticosterone were also higher (P < .05) in patients with pheochromocytoma than with paraganglioma. These steroids correlated positively with plasma and urinary metanephrines and catecholamines in patients with pheochromocytoma, but not paraganglioma. After adrenalectomy, there were significant decreases in cortisol, 11-deoxycortisol, corticosterone, 11-deoxycorticosterone, aldosterone, and 18-oxocortisol., Conclusions: This is the first large study in patients with PPGLs that supports in a clinical setting the concept of adrenal cortical-medullary interactions involving an influence of catecholamines on adrenal steroids. These findings could have implications for the cardiovascular complications of PPGLs and the clinical management of patients with the tumors., (© Endocrine Society 2020.)

Context: Multiple endocrine neoplasia type 2B (MEN2B) is a rare cancer predisposition syndrome resulting from an autosomal-dominant germline mutation of the RET proto-oncogene. No prior studies have investigated pulmonary function in patients with MEN2B., Objective: This study characterized the pulmonary function of patients with MEN2B., Design: This is a retrospective analysis of pulmonary function tests (PFTs) and chest imaging of patients enrolled in the Natural History Study of Children and Adults with MEN2A or MEN2B at the National Institutes of Health., Results: Thirty-six patients with MEN2B (18 males, 18 females) were selected based on the availability of PFTs; 27 patients underwent at least 2 PFTs and imaging studies. Diffusion abnormalities were observed in 94% (33/35) of the patients, with 63% (22/35) having moderate to severe defects. A declining trend in diffusion capacity was seen over time, with an estimated slope of -2.9% per year (P = 0.0001). Restrictive and obstructive abnormalities were observed in 57% (20/35) and 39% (14/36), respectively. Computed tomography imaging revealed pulmonary thin-walled cavities (lung cysts) in 28% (9/32) of patients and metastatic lung disease in 34% (11/32) of patients; patients with metastatic lung lesions also tended to have thin-walled cavities (P = 0.035)., Conclusions: This study characterized pulmonary function within a MEN2B cohort. Diffusion, restrictive, and obstructive abnormalities were evident, and lung cysts were present in 28% of patients. Further research is required to determine the mechanism of the atypical pulmonary features observed in this cohort., (Published by Oxford University Press on behalf of the Endocrine Society 2020.)

Purpose: Evaluate the safety and efficacy of adrenal microwave ablation performed with continuous intra-arterial blood pressure monitoring (IABPM) and without alpha-adrenergic blockade (AAB) as pretreatment., Material and Methods: A single-center, retrospective review of all percutaneous adrenal microwave ablation performed between 2011 and 2018. Microwave ablation was completed on 11 patients, with a total of 15 adrenal tumors with a mean size of 3.3 cm (1.4-6.9 cm) treated metastatic RCC, HCC, esophageal carcinoma, adrenal adenoma. Cases were performed without prior AAB, but with continuous IABPM and rapid intervention using short-acting antihypertensive medications., Results: There were no post-procedural episodes of hypertension, no neurological or cardiovascular complications, and no SIR moderate or worse adverse event complications. Mean intraprocedural maximum systolic blood pressure (SBP) was 211 mmHg (range: 132-288), with an average increase in SBP of 100 mmHg (range: 23-180). A hypertensive crisis (SBP ≥ 180 and/or DBP ≥ 120) occurred in 9 of the 15 procedures (60%) with a mean length of 3.0 min (range: 1-12). The technical success rate was 100% (15/15 procedures). The mean follow-up time was 2.4 years (range: 0.9-7.7 years), with primary and secondary efficacy rates of 77% and 87%, respectively, and an overall survival of 82%., Conclusion: In this single-center retrospective study, microwave ablation of adrenal tumors without AAB was safe and effective when performed with continuous arterial line monitoring of vital signs and the use of short-acting, rapid-onset antihypertensive medications., Level of Evidence: Level 4, Case Series.

Objectives: The purpose of this study was to compare the effects of combined epidural-general anesthesia with those of general anesthesia alone on hemodynamic instability (intraoperative hypotension and hypertensive crisis) during pheochromocytoma and sympathetic paraganglioma surgery. Methods: A total of 119 patients' medical records were reviewed who were diagnosed as having pheochromocytoma and sympathetic paraganglioma on the basis of histological findings. Intraoperative hypotension was defined as a mean blood pressure < 60 mmHg or a decrease > 30% in baseline systolic blood pressure after adrenal vein ligation. Hypertensive crisis was defined as a systolic blood pressure > 200 mmHg or an increase > 30% in baseline systolic blood pressure during the operation. The predictor variables for intraoperative hypotension and hypertensive crisis were analyzed with logistic regression models. Data were presented as adjusted odds ratio with 95% confidence interval. Results: The independent predictors of intraoperative hypotension were an increased attenuation number on unenhanced computed tomography (1.112 [1.009-1.226], p = 0.033), a high baseline mean blood pressure (1.063 [1.012-1.117], p = 0.015), and the combined epidural-general anesthesia (5.439 [1.410-20.977], p = 0.014). In contrast, an increased attenuation number on unenhanced computed tomography was the only independent predictor of hypertensive crisis (1.087 [1.021-1.158], p = 0.009). Conclusions: The combined epidural-general anesthesia was not effective in attenuating hypertensive responses, but could have exacerbated intraoperative hypotension. These findings should be taken into account before selecting the anesthetic technique in pheochromocytoma and sympathetic paraganglioma surgery., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Dapagliflozin (DAPA) or canagliflozin (CANA), Na + -dependent glucose co-transporter type 2 (SGLT2) inhibitors, were used for treatment of type II diabetes mellitus. Addition of DAPA or CANA suppressed M-type K + current (I K(M) ) in pituitary tumor (GH 3 ) and pheochromocytoma PC12 cells. The IC 50 value for DAPA- or CANA-mediated inhibition of I K(M) in GH 3 cells was 0.11 or 0.42 μM, respectively. The presence of DAPA (0.1 μM) shifted the steady-state activation of I K(M) to less depolarized potential without changing the gating charge of the current. During high-frequency depolarizing pulses, I K(M) magnitude was reduced by DAPA; however, DAPA-induced block of I K(M) remained effective. The amplitude of neither erg-mediated K + current nor hyperpolarization-activated cation current in GH 3 cells was modified in the presence of 1 μM DAPA. Alternatively, addition of DAPA, CANA, phlorizin or chlorotoxin effectively suppressed α-methylglucoside-(αMG-) induced current (I αMG ) in GH 3 cells, albeit inability of tefluthrin (activator of I Na ) to suppress this current. DAPA shifted the charge-voltage relation of presteady-state I αMG in a rightward and downward direction with no change in the gating charge of the I αMG . Under current-clamp recordings, subsequent additions of DAPA, but still in the continued presence of αMG, increased the firing rate of spontaneous action potentials stimulated by αMG. Our results suggested that activity of SGLT was expressed functionally in GH 3 and PC12 cells. Therefore, inhibitory actions of DAPA or CANA on the amplitude and gating of I K(M) might provide a yet unidentified mechanism through which the SGLT1 or SGLT2 activity were attenuated in unclamped cells occurring in vivo., Competing Interests: Declaration of competing interest We declare no conflict of interest that would prejudice its impartiality., (Copyright © 2020 Elsevier B.V. All rights reserved.)

A 63-year-old woman with multiple endocrine neoplasia type 2A (MEN2A) presented with recurrent spells of headaches, sweats and palpitations decades after right adrenalectomy for phaeochromocytoma, and total thyroidectomy for medullary thyroid cancer. She was hypertensive and in sinus rhythm. DOTA-TATE positron-emission tomography (PET) demonstrated a 12mm enhancing left adrenal incidentaloma. 24 hours urine catecholamines, and multiple plasma metanephrine and normetanephrine measurements were all within normal reference ranges. Based on her symptoms and imaging findings, left adrenalectomy was performed and found a 40 mm phaeochromocytoma. Her symptoms have since completely resolved and plasma metanephrine is now undetectable MEN2-associated phaeochromocytomas are often bilateral and may be metachronous. Patients at high risk of phaeochromocytoma who develop symptoms of catecholamine excess should be carefully evaluated even if plasma or urinary metanephrines are within the normal reference range. Biochemical reference ranges for metanephrines need to be adjusted accordingly in patients who have had prior unilateral total adrenalectomy., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

This first part of a two-part review of pheochromocytoma and paragangliomas (PPGLs) addresses clinical presentation, diagnosis, management, treatment, and outcomes. In this first part, the epidemiology, prevalence, genetic etiology, clinical presentation, and biochemical and radiologic workup are discussed. In particular, recent advances in the genetics underlying PPGLs and the recommendation for genetic testing of all patients with PPGL are emphasized. Finally, the newer imaging methods for evaluating of PPGLs are discussed and highlighted.

Pheochromocytomas and paragangliomas (PPGLs) generally grouped together are rare catecholamine-secreting endocrine tumors. Symptoms of catecholamine excess are non-specific and therefore a high index of suspicion in children with sustained hypertension, family history of endocrine tumors, or features of syndromes associated with PPGLs leads to a timely diagnosis and treatment. Free metanephrines in the plasma or 24-h urine are the preferred tests to establish catecholamine excess. Considerations for false-positive conditions improve diagnostic yield and accuracy. Functional imaging, targeting either specific cell membrane transporters or vesicular catecholamine transport systems, is indicated for incidental lesions suspicious for PPGLs with inconclusive biochemical testing, assessment of regional extension or multifocality, and exclusion of metastases. Surgery is the mainstay of treatment for PPGLs. Preoperatively, sequential use of alpha adrenergic receptor blockade and volume expansion followed by beta blockade is mandatory to reduce intraoperative intravascular instability and blood pressure fluctuation due to tumor manipulation. Since genetic mutations have been reported in tumor susceptibility genes in nearly 50% of patients with PPGLs, genetic counselling and testing should be considered in all patients with a confirmed tumor.

Introduction: Adrenal incidentalomas are lesions that are incidentally identified while scanning for other conditions. While most are benign and hormonally non-functional, around 20% are malignant and/or hormonally active, requiring prompt intervention. Malignant lesions can be aggressive and life-threatening, while hormonally active tumours cause various endocrine disorders, with significant morbidity and mortality. Despite this, management of patients with adrenal incidentalomas is variable, with no robust evidence base. This project aimed to establish more effective and timely management of these patients., Methods: We developed a web-based, electronic Adrenal Incidentaloma Management System (eAIMS), which incorporated the evidence-based and National Health Service-aligned 2016 European guidelines. The system captures key clinical, biochemical and radiological information necessary for adrenal incidentaloma patient management and generates a pre-populated outcome letter, saving clinical and administrative time while ensuring timely management plans with enhanced safety. Furthermore, we developed a prioritisation strategy, with members of the multidisciplinary team, which prioritised high-risk individuals for detailed discussion and management. Patient focus groups informed process-mapping and multidisciplinary team process re-design and patient information leaflet development. The project was partnered by University Hospital of South Manchester to maximise generalisability., Results: Implementation of eAIMS, along with improvements in the prioritisation strategy, resulted in a 49% reduction in staff hands-on time, as well as a 78% reduction in the time from adrenal incidentaloma identification to multidisciplinary team decision. A health economic analysis identified a 28% reduction in costs., Conclusions: The system's in-built data validation and the automatic generation of the multidisciplinary team outcome letter improved patient safety through a reduction in transcription errors. We are currently developing the next stage of the programme to proactively identify all new adrenal incidentaloma cases., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Microabstract: The effect of smoking on adrenal cancer is poorly understood. A clear association of adrenal adenoma and adrenocortical carcinoma with smoking among the United States population is observed. This association points to the possibility of environmental carcinogenic and/or lifestyle factors contributing to adrenal cancer formation. Our results support the association of tobacco use with adrenal adenomas and adrenal cortical carcinoma., Background: Smoking has been suggested as a risk factor for adrenal cortical carcinoma (ACC), but this hypothesis has only been inferred from a single study using all types of adrenal cancers including pheochromocytoma, neuroblastoma, as well as ACC. Given the high rate of tobacco use in West Virginia, we hypothesized that smoking might contribute to increased prevalence of ACC., Materials and Methods: De-identified institutional review board-exempted records were analyzed in the Surveillance, Epidemiology, and End Results (SEER) Program from 2001-2016 and in patients from the United States nationwide, multicenter TriNetX database of 41,063,707 patients from 2008-2018. In addition, the state-level ratio of smoking to ACC prevalence was computed in all 50 states using data from SEER and the Center for Disease Control. West Virginia Health System data from 2008-2018 was extracted to confirm population-level findings. Melanoma was used as a cancer control in both databases., Results: 6,946 ACC cases were identified. West Virginia had the highest smoking rate and the second highest rate of ACC. A significant association was found between smoking and ACC (Pearson correlation coefficient r = 0.4887, p=.0004). From 2008 to 2018 using TriNetX, 846 ACC and 36,434 AA were extracted. Both adrenal neoplasm cohorts had increased prevalence of tobacco use compared with melanoma controls, where 23.5% were smokers compared to 36.4% and 33.9% in the ACC and AA groups, respectively (p<0.0001 each)., Conclusion: To our knowledge, this is the first United States population-based study supporting smoking as a risk factor for adrenal carcinogenesis and ACC., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Hemodynamic instability is frequently observed during adrenalectomy for pheochromocytoma (PCC). Guidelines recommend liberal preoperative volume administration. However, it is unclear whether fluid deficiency or vasoplegia causes shifting hemodynamics and whether minimally invasive hemodynamic monitoring with esophageal Doppler (EDM) can help visualize intraoperative changes avoiding volume overload and complications., Methods: Ten patients with biochemically verified PCC and five patients with hormonally inactive adrenal tumors (HIAT; control group) were treated following a strict protocol. During laparoscopic adrenalectomy, goal-directed fluid therapy was performed using EDM. Hemodynamic and biochemical data were documented. The primary outcome variables were fluid requirement and hemodynamic parameters., Results: Applying EDM, total intraoperative fluid administration was slightly higher in PCC patients than in patients with HIAT (2100 ± 516 vs. 1550 ± 622 ml, p = 0.097; 12.9 ± 4.8 vs. 8.3 ± 0.7 ml kg -1 h -1 , p = 0.014). Hemodynamics varied considerably within the PCC group and was associated with type and level of secreted catecholamines. Arterial blood pressure and systemic vascular resistance index reached their minimum in the 10-min period after resection of PCC. Without liberal fluid administration, an increase in cardiac index was observed in both groups comparing baseline measurements to end of surgery. This increase was statistically significant only in PCC patients (PCC: 2.31 vs. 3.15 l min -1 m -2 , p = 0.005; HIAT: 2.08 vs. 2.56 l min -1 m -2 , p = 0.225)., Conclusions: As vasoplegia, but not hypovolemia, was documented after tumor resection, there is no evidence that PCC patients profit from liberal fluid administration during laparoscopic adrenalectomy. To avoid volume overload, noninvasive techniques such as EDM should be routinely used to visualize the variable intraoperative course., Trial Registration: ClinicalTrials.gov, Identifier: NCT01425710.

A 53-year-old man with a history of primary hypertension for over 8 years underwent Tc-DTPA renal dynamic scintigraphy to evaluate the renal function. The images revealed an unexpected focus of abnormally increased DTPA activity in the region superior to the upper pole of the right kidney. Subsequent MRIs confirmed an adrenal mass. The results of pathological examination and immunohistochemistry after the resection of the lesion were consistent with adrenal pheochromocytoma.

Introduction: Excess catecholamine stimulates heat production in brown adipose tissue (BAT). Activation of BAT can be detected in patients presenting pheochromocytoma., Case Study: A 58-year-old female patient sought medical advice due to 13 kg weight loss over 2 years accompanied by sweating and high blood pressure. Thoracic-abdominal-pelvic CT-scan revealed a solid 40 mm mass in the left adrenal compartment with peri-adrenal nodules and a solid 80 mm mass at the lower end of the right kidney. 18 FDG-PET scan exhibited intense uptake in the supraclavicular, intercostal, mediastinal, peri-renal, mesenteric, iliac and inguinal spaces. Renal tumor with locoregional infiltration and remote metastases was initially considered. Diagnosis of pheochromocytoma was subsequently confirmed by a 10-fold increase in urinary catecholamine, metanephrine and normetanephrine levels. Left adrenalectomy confirmed the diagnosis of pheochromocytoma, with 3 lymph-node metastases in the adjacent adipose tissue surrounded by brown fat. The patient was clinically asymptomatic with normal blood pressure at 3 months post-surgery. A weight gain of 6 kg was recorded, with normalisation of catecholamines/metanephrine/normetanephrine levels. Bilateral peri-renal infiltration (including the right renal mass) disappeared on CT-scan, and TEP-18-FDG no longer showed hypermetabolism. Recurrent mediastinal metastases were diagnosed 6 months after surgery., Conclusion: Brown fat activation may mislead diagnosis of pheochromocytoma, suggesting multi-metastatic extra-adrenal tumor, if clinicians are not aware of it., (Copyright © 2019. Published by Elsevier Masson SAS.)

Context: Impaired diurnal blood pressure (BP) variability is related to higher cardiovascular risk., Objective: To assess diurnal variability of BP and its relation to target organ damage (TOD) and catecholamine phenotype in a consecutive sample of pheochromocytoma/paraganglioma (PPGL)., Design: We included 179 patients with PPGL All patients underwent 24 hours of ambulatory BP monitoring to determine dipping status. Differences in plasma metanephrine or urine adrenaline were used to distinguish catecholamine biochemical phenotype. To evaluate TOD, renal functions, presence of left ventricle hypertrophy (LVH), and the subgroup (n = 111) carotid-femoral pulse wave velocity (PWV) were assessed. Structural equation modeling was used to find the relationship among nocturnal dipping, catecholamine phenotype, and TOD parameters., Results: According to the nocturnal dipping, patients were divided into the three groups: dippers (28%), nondippers (40%), and reverse dippers (32%). Reverse dippers were older (P < 0.05), with a higher proportion of noradrenergic (NA) phenotype (P < 0.05), a higher prevalence of diabetes mellitus (P < 0.05), and sustained arterial hypertension (P < 0.01) and its duration (P < 0.05), as opposed to the other groups. All parameters of TOD were more pronounced only in reverse dippers compared with nondippers and dippers. The presence of NA phenotype (=absence of adrenaline production) was associated with reverse dipping and TOD (LVH and PWV)., Conclusions: Patients with reverse dipping had more substantial TOD compared with other groups. The NA phenotype plays an important role, not only in impaired diurnal BP variability but also independently from dipping status in more pronounced TOD of heart and vessels., (Copyright © 2019 Endocrine Society.)

Purpose of Review: The present paper will review the results of experimental and clinical studies aimed at defining the functional behavior of the central and peripheral nervous system in adrenal pheochromocytoma., Recent Findings: The contribution of sympathetic neural influences to the development of high blood pressure values in pheochromocytoma is complex. Studies performed in experimental animal models have shown that hypertension and the concomitant high circulating levels of catecholamines can lead to inhibition of central sympathetic neural outflow by reflex mechanisms and direct stimulation of central adrenergic receptors, respectively. However, these studies have also shown that high circulating levels of catecholamines favor a downregulation of alpha- and beta-adrenergic receptors, lessening their response to endogenous and exogenous adrenergic stimulation. The present paper reviews results of human studies performed by our group and others on the behavior of the central and peripheral nervous system in human pheochromocytoma. We discuss data collected in patients with different levels of peripheral sympathetic drive, i.e., before and after surgical removal of the adrenal pheochromocytoma. In the presence of elevated plasma catecholamine level, such as that characterizing adrenal pheochromocytoma, microneurography shows that central sympathetic neural activity is normal or even inhibited. At the peripheral vascular level, pheochromocytoma is characterized by a reduced vascular reactivity to exogenous sympathetic stimulation but a normal response by the vessels to endogenous adrenergic stimulation.

Insulin-like growth factor 1 (IGF1) has a critical role in maintaining tumor phenotype and survival of already transformed murine pheochromocytoma (pheo) cells (MPC4/30) and it is required for the initial establishment of these tumors. However, the role of local IGF1/IGF1R system in tumor microenvironment has not been fully understood. In vivo, by subcutaneous injection of pheo cells in heterozygous IGF1R knockout mice (L/n), we found that the time of noticeable tumor appearance was delayed, and incidence was decreased in L/n group compared to control (L/L) mice. Once established, tumor proliferation, vascularization or growth rate did not differ between groups. In vitro, fibroblast from L/n and L/L mice were cultured to generate conditioned media (CM) and differential matrixes on which pheo cells were seeded. Proliferation rate was higher when pheo cells were cultured with CM, or in differential matrix generated by L/L murine fibroblasts. A diminished fibronectin (FN) expression and secretion from L/n fibroblast was associated with decreased expression of integrin subunits in tumor cells. Also, soluble factors as IGF1 and insulin-like growth factor binding protein 2 (IGFBP2) were reduced. Our data suggest that IGF1 signaling through IGF1R may contribute to tumor cells anchorage and survival by interaction with both matrix and soluble factors produced by tumor microenvironment fibroblasts., (Copyright © 2019 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Analyses using the largest Korean cohort of adrenal incidentaloma (AI) revealed that subtle cortisol excess in premenopausal women and reduced dehydroepiandrosterone-sulfate (DHEA-S) in postmenopausal women and men are associated with bone mineral density (BMD) reduction in Asian patients with subclinical hypercortisolism (SH)., Introduction: Few studies evaluated bone metabolism in Asians with SH. We investigated associations of cortisol and DHEA-S, an adrenal androgen, with BMD in Asians with AI, with or without SH., Methods: We used cross-sectional data of a prospective multicenter study from Korea. We measured BMD, bone turnover markers, cortisol levels after 1-mg dexamethasone suppression test (1-mg DST), DHEA-S, and baseline cortisol to DHEA-S ratio (cort/DHEA-S) in 109 AI patients with SH (18 premenopausal, 38 postmenopausal women, and 53 men) and 686 with non-functional AI (NFAI; 59 premenopausal, 199 postmenopausal women, and 428 men)., Results: Pre- and postmenopausal women, but not men, with SH had lower BMDs at lumbar spine (LS) than those with NFAI (P = 0.008~0.016). Premenopausal women with SH also had lower BMDs at the hip than those with NFAI (P = 0.009~0.012). After adjusting for confounders, cortisol levels after 1-mg DST demonstrated inverse associations with BMDs at all skeletal sites only in premenopausal women (β = - 0.042~- 0.033, P = 0.019~0.040). DHEA-S had positive associations with LS BMD in postmenopausal women (β = 0.096, P = 0.001) and men (β = 0.029, P = 0.038). The cort/DHEA-S had inverse associations with LS BMD in postmenopausal women (β = - 0.081, P = 0.004) and men (β = - 0.029, P = 0.011). These inverse associations of cort/DHEA-S remained significant after adjusting for cortisol levels after 1-mg DST (β = - 0.079~- 0.026, P = 0.006~0.029). In postmenopausal women, the odds ratios of lower BMD by DHEA-S and cort/DHEA-S was 0.26 (95% CI, 0.08-0.82) and 3.40 (95% CI, 1.12-10.33), respectively., Conclusion: Subtle cortisol excess in premenopausal women and reduced DHEA-S in postmenopausal women and men may contribute to BMD reduction in Asians with SH.

Background: Pheochromocytoma is a rare neuroendocrine tumor, clinically characterized by high blood pressure, palpitations, and headache. It is often associated with abnormalities of the ventricular repolarization phase; the dispersion of ventricular repolarization is the basis for ventricular arrhythmias (torsion de point, ventricular tachycardia or ventricular fibrillation)., Objectives: Analysis of abnormal ventricular repolarization focused on the presence and amount of U wave in patients affected by pheochromocytoma and its modification after surgery., Materials and Methods: We reviewed pathology records of 722 patients admitted for adrenal nodule or suspected chromaffin-cell tumor and identified 39 patients affected by pheochromocytoma. Metanephrine, normetanephrine, and 3-methoxytyramine have been assessed by determining concentrations in 24-hour urine collection. Standard 12-lead electrocardiogram records have been reviewed with analysis of heart rate, P wave, PR interval, QRS duration, QTc, and U wave. Then we selected and compared 22 patients of 39 affected by pheochromocytoma, with both clinical and electrocardiographic data before and after surgery., Results: In our cohort of 39 patients affected by pheochromocytoma, we found U wave in ECG, before treatment, in 82.8 percent of patients, while only 37.0 percent after treatment (p<0.001) and we observed a statistically significant correlation between this wave and the urinary metanephrine. After surgery, in the selected 22 patients, we observed a clear significant reduction in systemic blood pressure, fasting glucose, metanephrine, normetanephrine, and 3-methoxytyramine. We found a significant reduction of U wave presence and leads involved in these patients after surgery (90.9% versus 9%). We observed a linear correlation between the amount of U waves in 12-lead electrocardiogram and metanephrine (r 2 =0.333, p=0.015), 3-methoxytyramine levels (r 2 =0.458, p=0.006), and tumor size (r 2 =0.429, p=0.003)., Conclusions: In our retrospective analysis, patients affected by pheochromocytoma presented U wave in electrocardiogram. The presence and amount of U wave were associated with the metanephrine levels and the tumor size with significant reduction after surgical removal.

Standard management protocols for patients with pheochromocytoma (PHEO) have been described in current guidelines. However, the standard management approach for cardiac surgical patients with concurrent clinically silent PHEO has not been established yet. The effects of open heart surgery and cardiopulmonary bypass (CPB) on PHEO presentation are poorly documented. Here, we report in detail the anesthetic management and hemodynamic changes in a case of CPB-assisted pulmonary valve replacement surgery with an incidentally discovered normotensive PHEO. A 55-year-old male with normotensive PHEO underwent an open heart pulmonary valve replacement surgery. Blood pressure (BP) fluctuated with an inherent alternation rhythm during the whole process of the surgery with a peak at 230/130 mmHg and nadir at 40/30 mm Hg. Administration of fluids and vasoconstrictor/vasodilator was used for BP optimization. However, the BP changed intractably with delayed responses to the optimization management. The hemodynamic instability observed in this case indicated that the risk of occurrence and severity of the PHEO crisis did not decrease in cases with previously silent PHEO and may be triggered in any clinical scenario, not in tumor removal procedures alone. Careful preoperative evaluation and preparation with multidisciplinary cooperation are of paramount importance for such patients because open chest cardiac surgery and CPB could complicate the situation. In addition, there is little evidence about the benefits of a combined cardiac surgery with PHEO resection in such a clinical scenario, which validates further investigation.

Rationale: Primary adrenal non-Hodgkin lymphomas are predominant diffuse large B cell lymphoma with frequently bilateral adrenal involvement, but the occurrence of nasal type extranodal NK/T cell lymphoma is relatively rare., Patient Concerns: A 40-year-old woman complaining of left back pain for 2-month was admitted to our department., Diagnosis: Based on the feature of enhanced computed tomography (CT) images which showed huge bilateral well-defined adrenal masses with heterogeneous enhancement, she was tentatively diagnosed as having primary adrenal malignancy. Postoperative pathology revealed the diagnosis of primary adrenal Epstein-Barr virus-associated nasal type extranodal NK/T-cell lymphoma., Interventions: Then, she underwent F-fluoro-2-deoxy-D-glucose (F-FDG) positron emission tomography (PET)/CT examination for staging, which showed homogeneously increased FDG uptake in the right adrenal gland and left thigh subcutaneous lesion, as well as heterogeneous increased FDG uptake in the left adrenal gland region with no abnormal uptake in the nasal cavity. Subsequently, the patient has performed 7 cycles of gemcitabine, L-asparaginase, ifosfamide, dexamethasone, etoposide (GLIDE) regimen and autologous stem cell transplantation., Outcomes: Fortunately, the subsequent 2 follow-up FDG PET/CT scans within 1 year revealed complete resolution with no abnormal FDG uptake in the initially involved sites after 7 cycles of GLIDE chemotherapy and autologous stem cell transplantation., Lessons: The enhanced CT and FDG PET/CT features of primary adrenal extranasal NK/T cell lymphoma are huge bilateral well-defined adrenal masses with heterogeneous enhancement, high FDG uptake, especially with subcutaneous involvement. And the awareness of this entity may help clinicians to differentiate it from other primary adrenal tumors and make reasonable therapeutic strategies. Besides, FDG PET/CT scan is very useful for the treatment follow-up of the primary adrenal extranasal NK/T cell lymphoma.

Patients harboring adrenal tumors are characterized by higher prevalence of metabolic syndrome (MetS) components and a higher incidence of cardiovascular complications, especially in cases of subclinical or overt hormonal hypersecretion. Early detection and referral of those patients in tertiary centers could prevent unfavorable outcomes. In this cross-sectional, retrospective study, we evaluated 111 consecutive patients with adrenal incidentalomas and 14 patients with known hypersecretory adrenal lesions (autonomous cortisol secretion, primary aldosteronism, and pheochromocytoma), who were investigated in our clinic. Based on the different distribution of MetS components in patients with non-functional and functional adrenal lesions we introduced a predictive model of hormonal hypersecretion using those components. We performed multivariate discriminant analysis and compared predictive results with conventional multiple logistic regression analysis. Diabetes, impaired glucose tolerance, impaired fasting glucose, hypertension, body mass index, HDL-cholesterol levels, triglyceride levels, drug treatment for lipid disorder (statins, fenofibrate, and fish oils, alone or in combination), and maximal adrenal lesion diameter were used as discriminating covariates. Multivariate discriminant function exhibited a sensitivity of 77.27% and specificity of 73.08% in predicting adrenal hormonal hypersecretion. Receiver operating characteristic curve of discriminant predictive function had an area under the curve value of 0.785, S.E. 0.04. Logistic function delivered comparable results. MetS components exhibit a good predictive feature of hormonal hypersecretion in patients with adrenal tumors. Predictive functions may help in the search for an easy and generally available algorithm to validly predict the functional activity of adrenal masses., Competing Interests: The authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Patients with cortisol secreting adrenal adenomas present with Cushing's syndrome (CS), while 5-15% of subjects with adrenal incidentalomas have subclinical hypercortisolism (SH) as they have biochemical abnormalities suggesting autonomous cortisol secretion without associated clinical features of CS., Goals: Examine HPA function immediately after resection of either of these adenomas and utilize the data to decide on initiating glucocorticoid replacement., Methods: ACTH, cortisol, and DHEA-S levels were measured frequently for 8 h after adrenalectomy in 14 patients with CS and 19 others with incidentalomas + SH. Glucocorticoids were withheld before/during surgery and administered 6-8 h postoperatively to those who had cortisol levels of <3 ug/dL (83 nmol/L)., Results: Preoperatively, incidentalomas + SH patients had larger tumors, higher ACTH, and DHEA-S but lower dexamethasone-suppressed serum cortisol levels than those with CS. Postoperatively, ACTH levels increased in both groups: (90.1 ± 31.6; 24.1 ± 14.4 ng/L, respectively; P < 0.001). Postoperative ACTH levels correlated negatively with preoperative Dexamethasone-suppressed cortisol concentrations in both groups. Patients with CS had steeper decline in cortisol concentrations than those with incidentalomas + SH. All patients with CS had hypocortisolemia requiring glucocorticoid therapy for several months, while only 5/19 with incidentalomas + SH had cortisol levels <3 ug/dL;(83 nmol/L) 6-8 h after adrenalectomy and received hydrocortisone replacement therapy for ≤4 weeks., Conclusions: Surgical stress stimulates HPA function even in patients with hypercortisolemia. Patients with incidentalomas + SH have incomplete HPA suppression that allows more robust response to surgical stress than that observed in patients with CS. HPA assessment immediately after surgical resection of adrenal incidentalomas identified those requiring glucocorticoid replacement before discharge.

A 45-year-old male suddenly experienced left-flank abdominal pain. Echocardiography revealed akinesis of the 'takotsubo cardiomyopathy' type. He experienced a sudden haemodynamic collapse (blood pressure, 324/154 mmHg; pulse rate, 180 beats/min) during emergency cardiac catheterisation. An abdominal computed tomography (CT) revealed expansion of a soft tissue mass 64 × 33 mm in dimension in the left adrenal region, with accumulation of fluid surrounding the left pararenal space. Three days after the attack, his urinary catecholamine concentrations were slightly elevated. We suspected the patient as having a pheochromocytoma followed by acute haemorrhagic rupture, based on signatures of adrenal mass, 'takotsubo cardiomyopathy', and the hypertensive crisis. Over the next few weeks, he recovered well as an outpatient, and his blood pressure remained around 110/60 mmHg without medication. Three weeks after the attack, an abdominal CT showed shrinkage of the ruptured adrenal mass (to a diameter of 30 mm) and absorption of the retroperitoneal hematoma. On day 190 after the attack, abdominal CT did not detect any left adrenal mass. This is the first report of the case showing a complete vanishing of ruptured adrenal mass with takotsubo cardiomyopathy. Although surgical approaches for ruptured adrenal mass involve either emergency or elective surgery, the patients did not need even the elective surgery. Accumulation of the similar cases may unravel clinical factors predicting self-limiting of the ruptured adrenal mass to avoid unnecessary risky surgery.

Pheochromocytoma is a rare catecholamine-secreting tumour that is typically located in the adrenal medulla or along the sympathetic ganglia. The typical symptoms are episodic in nature and include tachycardia, sweating and headache. These tumours can present as transient, reversible cardiomyopathy similar to takotsubo cardiomyopathy (TCM). TCM is characterised by transient hypokinesis of the left ventricular apex and is typically induced by emotional stress. We describe the case of a 26-year-old woman with a medical history significant for headaches who presented initially to her family physician with nausea, vomiting, headache and hypertension. She was started on lisinopril 10 mg daily. One week later, she presented to the emergency department with substernal severe chest pressure. Her troponin level was elevated. Coronary angiogram showed normal coronary arteries and left ventriculogram showed inverse TCM pattern. Serum catecholamines were very elevated confirming pheochromocytoma. She was successfully treated with alpha-blockers followed by surgical resection., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2018. No commercial re-use. See rights and permissions. Published by BMJ.)