Citations

Objective Several small studies reported increased prevalence and incidence of asymptomatic vertebral fractures in patients with non-functioning adrenal adenomas and adenomas with mild autonomous cortisol secretion. However, the risk of symptomatic fractures at vertebrae, and at other sites remains unknown. Our objective was to determine the prevalence and incidence of symptomatic site-specific fractures in patients with adrenal adenomas. Design Population-based cohort study, Olmsted County, Minnesota, USA, 1995–2017. Methods Participants were the patients with adrenal adenoma and age/sex-matched referent subjects. Patients with overt hormone excess were excluded. Main outcomes measures were prevalence and incidence of bone fractures. Results Of 1004 patients with adrenal adenomas, 582 (58%) were women, and median age at diagnosis was 63 years (20–96). At the time of diagnosis, patients had a higher prevalence of previous fractures than referent subjects (any fracture: 47.9% vs 41.3%, P = 0.003, vertebral fracture: 6.4% vs 3.6%, P = 0.004, combined osteoporotic sites: 16.6% vs 13.3%, P = 0.04). Median duration of follow-up was 6.8 years (range: 0–21.9 years). After adjusting for age, sex, BMI, tobacco use, prior history of fracture, and common causes of secondary osteoporosis, patients with adenoma had hazard ratio of 1.27 (95% CI: 1.07–1.52) for developing a new fracture during follow up when compared to referent subjects. Conclusions Patients with adrenal adenomas have higher prevalence of fractures at the time of diagnosis and increased risk to develop new fractures when compared to referent subjects.

Abstract Background: Benign adrenal tumors are frequently diagnosed on imaging and may pose health risks to patients regardless of functional status. Both non-functioning adrenal tumors (NFAT) and tumors with mild autonomous cortisol secretion (MACS) have been associated with increased cardiovascular events and risk factors. However, limited data exist on the association of adrenal adenomas with cardiometabolic outcomes in the population-based setting. Aim: 1) To determine the prevalence of cardiovascular co-morbidities and events and 2) to assess mortality in a population-based cohort of patients with adrenal adenomas. Methods: We identified adult patients living in the community diagnosed with an adrenal tumor from 1995-2017 using a medical records linkage system. Adrenal tumors were classified as MACS if cortisol was ≥1.8mcg/dL after 1 mg dexamethasone suppression test, NFAT if cortisol was <1.8 mcg/dL, and adenoma with unknown cortisol secretion (AUCS) if dexamethasone suppression test was not performed. Cardiovascular co-morbidities and events were assessed at baseline. Patients were then followed until death, migration out of the community, or through December 31, 2018. Results were compared to age and sex matched reference subjects without adrenal tumors and adjusted for tobacco use and BMI. Results: A total of 1,003 patients had adrenal adenomas with 136 (14%) NFAT, 86 (9%) MACS, and 781 (78%) AUCS. The median age of diagnosis was 63 years (range, 20-96) and 581 (58%) were women. At baseline, patients with adrenal adenomas were more likely to have hypertension (92% vs 81%, p<0.001), overweight/obesity (89% vs 82%, p<0.001), pre-diabetes/diabetes (82% vs 70%, p<0.001), dyslipidemia (89% vs 82%, p<0.001), and chronic kidney disease (11% vs 7%, p=0.004) than age and sex matched reference subjects. Myocardial infarctions (13% vs 8%, p <0.001), coronary intervention (9% vs 6%, p= 0.007), heart failure (12% vs 6%, p<0.001), peripheral vascular disease (26% vs 15%, p<0.001), and thromboembolic disease (7% vs 3%, p<0.001) were more prevalent in patients with adrenal adenomas, whereas overall survival was lower compared to reference subjects (60% vs 65%, p value = 0.013). Subgroup analysis (adjusted for age, sex, BMI, and smoking) demonstrated prevalence of cardiovascular events including peripheral vascular disease was highest in those with MACS (44.7%), followed by AUCS (40.1%), and then NFAT (36.6%), although differences between groups were not significant. Overall survival was lower in patients with MACS (62%) and AUCS (59%) compared to NFAT (71%), p<0.001. Conclusions: Adrenal adenomas are associated with significantly higher prevalence of cardiovascular risk factors and morbidity at the time of diagnosis and with increased morality during follow-up. Results are potentially related to abnormal cortisol secretion but are limited by suboptimal evaluation for hormone excess.

Abstract Background: Adrenal tumors are reported in 5% of adults, with malignancy rates in 1–12%, and rates of overt hormonal excess in 1–15 %. However, most estimates originate from convenience samples. Our objective was to determine the incidence, prevalence and clinical presentation of adrenal tumors in a population-based setting. Methods: We used a centralized epidemiologic database to identify patients diagnosed with adrenal tumors in a local community 1995 to 2017. The database is a unique medical records linkage system that allows access to hospital and community medical records for local residents (population 137,000). We calculated incidence rates (IR) as the number of new patients diagnosed while living in the study area, and prevalence as the number of patients living in the study area on Dec 31 2017. IR and prevalence were sex- and age-adjusted to the 2010 US Census population. Results: Of 1,287 patients diagnosed with adrenal tumor, the median age of diagnosis was 62 years (IQR 52–72), 713 (55%) were women, and 13 (1%) were younger than 18 years at diagnosis. IR was highest in patients >65 YO, followed by patients 40–64 YO, 18–39 YO and <18 YO (142 vs 66 vs 9 vs 2 per 100,000 persons years). IR per 100,000 increased from 4.4 (CI95% 0.3–8.6) in 1995 to 47.8 (CI95% 36.9–58.7) in 2017. Overall prevalence in the population was 0.53% in 2017, ranging from 0.01% among 0–17 YO to 1.9% among +65 YO. Malignant adrenal mass was diagnosed in 8.7% patients (4 patients with adrenal cortical carcinoma (0.3%) and 108 (8.4%) patients with other malignant mass). Pheochromocytoma was diagnosed in 11 (1.1%) patients and benign adrenal mass was diagnosed in 1,175 (90.2%) patients (1,076 (83.6%) with adrenal adenoma and 85 (6.6%) with other benign mass). Median tumor size was 15 mm (range 5–255), and 184 (14%) of patients had bilateral tumors. Only 255 (20%) patients had dexamethasone suppression test, 93 (36%) with cortisol>1.8 mcg/dl. Of 1,076 adrenal adenomas, 53 (4.9%) had overt hormone excess, 140 (13%) had nonfunctioning adrenal adenomas, and 88 (8.2%) had mild autonomous cortisol secretion. Hormonal work up for was incomplete in 795 (73.9%) adenomas. Patients discovered incidentally (1,050, 81.6%) had a lower rate of malignancy and hormone excess (5.3% vs 52% of patients with non-incidental discovery, p <0.001). Rate of malignancy was highest in children (67% vs 8% >18YO, p<0.001), bilateral tumors (16% vs 8% unilateral, p<0.001), tumors ≥4 cm (33% vs 7% in < 4 cm, p<0.001). Conclusion: IR of adrenal tumors increased 10-fold since 1995, and was highest in patients >65 YO. 8.7% of tumors were malignant, with a majority represented by malignant adrenal tumors other than adrenal cortical carcinoma. The risk of malignancy was highest in non-incidental discovery, children, and tumors > 4 cm. Overt hormone excess was diagnosed in 4.5% of patients. The majority of patients with adrenal adenomas had a suboptimal work up for hormone excess.

Abstract Background: Adrenal adenoma is reported in around 5% of adults undergoing cross-sectional imaging. Although most adenomas are considered non-functioning (NFAT), up to 48% present with mild autonomous cortisol secretion (MACS). Several studies reported increased prevalence and incidence of vertebral fractures in MACS; however conclusions are limited by small sample size, selection bias, inadequate reference population and length of follow up. Objective: To determine the prevalence and incidence of site-specific fragility fractures in a population-based cohort of patients with adrenal adenomas. Methods: Residents of local community with a radiographic diagnosis of adrenal adenoma between 1995 and 2017 were identified using a centralized epidemiologic database and matched with reference subjects for sex and age. All subjects were followed through 2017, until death or migration from the community. MACS was diagnosed based on cortisol level ≥1.8 mcg/dl after overnight 1mg dexamethasone suppression, NFAT based on cortisol level <1.8 mcg/dl, and patients not tested with dexamethasone were considered as adenoma with unknown cortisol secretion (AUCS). Results: Of 1003 patients with adrenal adenomas (581 women (58%), median age of diagnosis 63 years (20–96)), 136 (14%) were diagnosed with NFAT, 86 (9%) with MACS, and 781(78%) with AUCS. At the time of diagnosis, patients had higher BMI (median 30 vs 28 kg/m2, p<0.001), and higher prevalence of tobacco use (70% vs 54%, p<0.001) than reference subjects. Of 154 patients and 113 reference subjects with BMD available at baseline, patients had a higher median BMD at the total hips (0.93 vs 0.89, p=0.02) but similar median BMD at lumbar spine (1.05 vs 1.03, p=0.49) when compared to reference subjects. However, patients had a higher prevalence of fractures than reference subjects (any fracture: 50% vs 42%, p<0.001, vertebral fracture: 6.5% vs 3.7%, P=0.004). When adjusted for age, sex, and prior history of fracture, patients with adenoma had HR of 1.24 (CI 95% 1.04–1.48) for developing a new fracture and HR of 1.18 (CI 95% 0.97–1.44) when also adjusted for BMI and smoking. Subgroup analysis demonstrated that the prevalence of fractures at the time of diagnosis was higher in all 3 subgroups at any fragility fracture site when compared to reference subjects (NFAT: 44% vs 37%, MACS: 48% vs 43%, AUCS: 51% vs 43%); patients with MACS had the highest incidence of new fracture after 5 years of follow up when compared to AUCS and NFAT (cumulative incidence: MACS 25% vs NFAT 19% vs AUCS 16%), though the differences were not significant. Conclusions: Patients with adrenal adenomas have higher prevalence of fractures at the time of diagnosis. During follow up, patients with adenoma have a higher incidence of fractures even when adjusted for sex, age, and prior history of fracture, possibly due to underlying undiagnosed abnormal cortisol secretion.

Summary Carney complex (CNC) is a rare multiple neoplasia syndrome characterized by spotty pigmentation of the skin and mucosa in association with various non-endocrine and endocrine tumors, including primary pigmented nodular adrenocortical disease (PPNAD). A 20-year-old woman was referred for suspected Cushing syndrome. She had signs of cortisol excess as well as skin lentigines on physical examination. Biochemical investigation was suggestive of corticotropin (ACTH)-independent Cushing syndrome. Unenhanced computed tomography scan of the abdomen did not reveal an obvious adrenal mass. She subsequently underwent bilateral laparoscopic adrenalectomy, and histopathology was consistent with PPNAD. Genetic testing revealed a novel frameshift pathogenic variant c.488delC/p.Thr163MetfsX2 (ClinVar Variation ID: 424516) in the PRKAR1A gene, consistent with clinical suspicion for CNC. Evaluation for other clinical features of the complex was unrevealing. We present a case of PPNAD-associated Cushing syndrome leading to the diagnosis of CNC due to a novel PRKAR1A pathogenic variant. Learning points: PPNAD should be considered in the differential for ACTH-independent Cushing syndrome, especially when adrenal imaging appears normal. The diagnosis of PPNAD should prompt screening for CNC. CNC is a rare multiple neoplasia syndrome caused by inactivating pathogenic variants in the PRKAR1A gene. Timely diagnosis of CNC and careful surveillance can help prevent potentially fatal complications of the disease.