Publications by authors named "William F Young"

181 Publications

Concomitant Pheochromocytoma and Primary Aldosteronism: A Case Series and Literature Review.

J Endocr Soc 2021 Aug 16;5(8):bvab107. Epub 2021 Jun 16.

Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, MN, USA.

Context: The detection and management of concomitant pheochromocytoma (PHEO) and primary aldosteronism (PA) is not well understood.

Objective: To investigate varying presentations and outcomes of cases with coexisting PHEO and PA to provide an approach to its diagnosis and management.

Methods: We conducted a retrospective case series of adult patients with concomitant PHEO and PA at Mayo Clinic from 2000-2020 and an additional review of cases before 2000 and from the medical literature. Clinical, biochemical, radiologic, and histologic parameters were measured.

Results: Fifteen patients (53% men, median age 53 years) were diagnosed with concomitant PHEO and PA. The majority presented with hypertension (13, 87%) and hypokalemia (13, 87%), and 6 (40%) presented with symptoms suggestive of catecholamine excess. All patients who underwent preoperative workup for catecholamine excess (14, 93%) were found to have biochemical levels above the upper limits of normal. Adrenal vein sampling (AVS) was performed in 9 patients (60%), where 5 (56%) were diagnosed with bilateral PA, and 4 (44%) with unilateral PA. Patients underwent either unilateral (12, 80%) or bilateral (3, 20%) adrenalectomy. Biochemical improvement or resolution of catecholamine excess was confirmed in all cases with documented measurements. Recurrence of PHEO was not observed. Six patients (40%) displayed persistent PA postoperatively.

Conclusion: Concomitant PHEO and PA is a rare but likely underreported condition. Hypertension with or without hypokalemia should prompt evaluation for PA, while any indeterminate adrenal mass should be assessed for PHEO. Coexisting disease warrants consideration of AVS to determine the laterality of PA to ensure appropriate management.
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http://dx.doi.org/10.1210/jendso/bvab107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271195PMC
August 2021

Diagnostic Accuracy of Dehydroepiandrosterone Sulfate and Corticotropin in Autonomous Cortisol Secretion.

Biomedicines 2021 Jun 28;9(7). Epub 2021 Jun 28.

Division of Endocrinology, Mayo Clinic, Rochester, MN 55902, USA.

Autonomous cortisol secretion (ACS) affects up to 50% of patients with adrenal adenomas. Despite the limited evidence, clinical guidelines recommend measurement of serum concentrations of dehydroepiandrosterone-sulfate (DHEA-S) and corticotropin (ACTH) to aid in the diagnosis of ACS. Our objective was to determine the accuracy of serum concentrations of DHEA-S and ACTH in diagnosing ACS. We conducted a retrospective single center study of adults with adrenal adenoma evaluated between 2000-2020. Main outcome measure was diagnostic accuracy of DHEA-S and ACTH. ACS was defined as post-dexamethasone cortisol >1.8 mcg/dL. Of 468 patients, ACS was diagnosed in 256 (55%) patients with a median post-DST cortisol of 3.45 mcg/dL (range, 1.9-32.7). Patients with ACS demonstrated lower serum concentrations of DHEA-S (35 vs. 87.3 mcg/dL, < 0.0001) and ACTH (8.3 vs. 16 pg/mL, < 0.0001) compared to patients with non-functioning adrenal tumors (NFAT). Serum DHEA-S concentration <40 mcg/dL diagnosed ACS with 84% specificity and 81% PPV, while serum ACTH concentration <10 pg/mL diagnosed ACS with 75% specificity and 78% PPV. The combination of serum concentrations of DHEA-S <40 mcg/dL and ACTH <10 pg/mL diagnosed ACS with the highest accuracy with 92% specificity and 87% PPV. Serum concentrations of DHEA-S and ACTH provide additional value in diagnosing ACS.
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http://dx.doi.org/10.3390/biomedicines9070741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301396PMC
June 2021

Cardiometabolic Outcomes and Mortality in Patients with Adrenal Adenomas: A Population-Based Cohort Study.

J Clin Endocrinol Metab 2021 Jun 29. Epub 2021 Jun 29.

Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, Minnesota, USA.

Context: While adrenal adenomas have been linked with cardiovascular morbidity in convenience samples of patients from specialized referral centers, large-scale population-based data is 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.

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 1,004 patients (58% women, median age 63 years). At baseline, patients with adrenal adenomas were more likely to have hypertension (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(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 two groups.

Conclusion: Adrenal adenomas are associated with an increased prevalence and incidence of adverse cardiometabolic outcomes in a population-based cohort.
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http://dx.doi.org/10.1210/clinem/dgab468DOI Listing
June 2021

Multiple endocrine neoplasia type 1 in children and adolescents: Clinical features and treatment outcomes.

Surgery 2021 Jun 25. Epub 2021 Jun 25.

Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, United Kingdom. Electronic address:

Background: Clinical manifestations and treatment outcomes in children and adolescents with multiple endocrine neoplasia type 1 are not well characterized.

Methods: We conducted a retrospective cohort study of 80 patients with multiple endocrine neoplasia type 1 who commenced tumor surveillance at ≤18 years of age.

Results: Fifty-six patients (70%) developed an endocrine tumor by age ≤18 years (median age = 14 years, range = 6-18 years). Primary hyperparathyroidism occurred in >80% of patients, with >70% undergoing parathyroidectomy, in which less-than-subtotal (<3-gland) resection resulted in decreased disease-free outcomes versus subtotal (3-3.5-gland) or total (4-gland) parathyroidectomy (median 27 months versus not reached; P = .005). Pancreaticoduodenal neuroendocrine tumors developed in ∼35% of patients, of whom >70% had nonfunctioning tumors, >35% had insulinomas, and <5% had gastrinomas, with ∼15% having metastases and >55% undergoing surgery. Pituitary tumors developed in >30% of patients, and ∼35% were macroprolactinomas. Tumor occurrence in male patients and female patients was not significantly different. Genetic analyses revealed 38 germline MEN1 mutations, of which 3 were novel.

Conclusion: Seventy percent of children aged ≤18 years with multiple endocrine neoplasia type 1 develop endocrine tumors, which include parathyroid tumors for which less-than-subtotal parathyroidectomy should be avoided; pancreaticoduodenal neuroendocrine tumors that may metastasize; and pituitary macroprolactinomas.
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http://dx.doi.org/10.1016/j.surg.2021.04.041DOI Listing
June 2021

International consensus on initial screening and follow-up of asymptomatic SDHx mutation carriers.

Nat Rev Endocrinol 2021 Jul 21;17(7):435-444. Epub 2021 May 21.

INSERM, PARCC, Equipe Labellisée par la Ligue contre le Cancer, Paris, France.

Approximately 20% of patients diagnosed with a phaeochromocytoma or paraganglioma carry a germline mutation in one of the succinate dehydrogenase (SDHx) genes (SDHA, SDHB, SDHC and SDHD), which encode the four subunits of the SDH enzyme. When a pathogenic SDHx mutation is identified in an affected patient, genetic counselling is proposed for first-degree relatives. Optimal initial evaluation and follow-up of people who are asymptomatic but might carry SDHx mutations have not yet been agreed. Thus, we established an international consensus algorithm of clinical, biochemical and imaging screening at diagnosis and during surveillance for both adults and children. An international panel of 29 experts from 12 countries was assembled, and the Delphi method was used to reach a consensus on 41 statements. This Consensus Statement covers a range of topics, including age of first genetic testing, appropriate biochemical and imaging tests for initial tumour screening and follow-up, screening for rare SDHx-related tumours and management of elderly people who have an SDHx mutation. This Consensus Statement focuses on the management of asymptomatic SDHx mutation carriers and provides clinicians with much-needed guidance. The standardization of practice will enable prospective studies in the near future.
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http://dx.doi.org/10.1038/s41574-021-00492-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205850PMC
July 2021

Pheochromocytoma and Paraganglioma in Pregnancy: a New Era.

Curr Cardiol Rep 2021 05 7;23(6):60. Epub 2021 May 7.

Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.

Purpose Of Review: Pheochromocytoma and paraganglioma (PPGL) in pregnancy is a rare entity and management of these patients is fraught with uncertainty. Our objective is to review current literature and discuss diagnosis and management of these patients.

Recent Findings: Outcomes of PPGL in pregnancy have improved in recent years. The greatest risk for adverse maternal and fetal outcomes is the diagnosis of PPGL after delivery. Alpha- and beta-adrenergic blockade is well tolerated and is associated with less adverse outcomes. Antepartum surgery is not associated with improved maternal or fetal outcomes. Biochemical testing and cross-sectional imaging should be performed prior to conception for patients with a known germline variant associated with PPGL.

Conclusions: Medical therapy should be initiated when PPGL is diagnosed in pregnancy. Antepartum surgery should be reserved for special circumstances. Case detection testing in high-risk patients can identify PPGL before pregnancy.
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http://dx.doi.org/10.1007/s11886-021-01485-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251512PMC
May 2021

Presentation and outcomes of adrenal ganglioneuromas: A cohort study and a systematic review of literature.

Clin Endocrinol (Oxf) 2021 Jul 22;95(1):47-57. Epub 2021 Mar 22.

Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.

Objective: To describe the presentation and outcomes of patients with adrenal ganglioneuromas (AGNs).

Design: Single-centre retrospective cohort study (1 January 1995 to 31 December 2019) and systematic review of literature (1 January 1980 to 19 November 2019).

Patients: Diagnosed with histologically confirmed AGN.

Measurements: Baseline clinical, imaging and biochemical characteristics, recurrence rates and mortality. Subgroup analysis was performed on tumours with histologic elements of ganglioneuroma and pheochromocytoma (ie composite tumours).

Results: The cohort study included 45 patients with AGN, 20 (44%) of which had composite tumours. Compared to pure AGN, patients with composite tumour were older (median age, 62.5 vs. 35 years, p < .001), had smaller tumours (median size, 3.9 vs. 5.7 cm, p = .016) and were discovered incidentally less frequently (65% vs. 84%, p = .009). No recurrences or ganglioneuroma-specific mortality occurred during follow-up (range, 0-266 months). The systematic review included 14 additional studies and 421 patients. The mean age of diagnosis was 39 years, and 47% were women. AGNs were discovered incidentally in 72% of patients, were predominantly unilateral (99%) and had a mean diameter of 5.8 cm and an unenhanced computed tomography (CT) attenuation of -118 to 49 Hounsfield units (HU). On imaging, 69% of AGNs were homogenous, 41% demonstrated calcifications, and 40% were lobulated.

Conclusions: AGNs are rare benign tumours that present with variable imaging features including large size, unenhanced CT attenuation >20 HU, calcifications and lobulated shape. Imaging characteristics can assist in establishing a diagnosis and avoiding an unnecessary adrenalectomy. The association of pheochromocytomas with AGNs is frequent. Diagnosis should include biochemical testing.
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http://dx.doi.org/10.1111/cen.14460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178203PMC
July 2021

The Role for Metyrosine in the Treatment of Patients With Pheochromocytoma and Paraganglioma.

J Clin Endocrinol Metab 2021 May;106(6):e2393-e2401

Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.

Context: Treatment of pheochromocytoma and paraganglioma (PPGL) requires preintervention titration of alpha- and beta-adrenergic blockade, but patients may still be at risk for complications from catecholamine excess. Metyrosine decreases catecholamine production, making it an attractive therapeutic adjunct for select patients.

Evidence Acquisition: A systematic literature review was performed (Ovid Medline and Scopus databases) on December 17, 2019, including studies with humans and original data. Studies with 10 or more patients on metyrosine for PPGL were included. Studies were screened for overlapping populations, and the most comprehensive study was included. The references of included studies were reviewed for additional data. Patient data from our institution between 2000 and 2015 were also reviewed.

Evidence Synthesis: Metyrosine is well tolerated when used for a short course and can improve intraoperative outcomes in PPGL. Metyrosine should be considered when a difficult PPGL resection is expected (eg, pericardiac paraganglioma, abdominal paraganglioma with great vessel involvement), a large release of catecholamines is anticipated (eg, ablative therapy, chemotherapy), or when standard alpha- and beta-adrenergic blockade are not tolerated or cannot adequately control hypertension. Side effects are generally mild and self-limited, with sedation in a majority of patients. Extrapyramidal side effects are rare but can limit use of metyrosine. Because of its expense and limited availability, metyrosine use should be carefully planned and timed in relation to surgery.

Conclusions: Metyrosine is a safe addition to traditional alpha- and beta-adrenergic blockade and should be considered in those patients with PPGL at high risk for acute release of catecholamines.
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http://dx.doi.org/10.1210/clinem/dgab130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118583PMC
May 2021

Hormonal and Metabolic Changes of Aging and the Influence of Lifestyle Modifications.

Mayo Clin Proc 2021 03;96(3):788-814

Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, MN. Electronic address:

Increased life expectancy combined with the aging baby boomer generation has resulted in an unprecedented global expansion of the elderly population. The growing population of older adults and increased rate of age-related chronic illness has caused a substantial socioeconomic burden. The gradual and progressive age-related decline in hormone production and action has a detrimental impact on human health by increasing risk for chronic disease and reducing life span. This article reviews the age-related decline in hormone production, as well as age-related biochemical and body composition changes that reduce the bioavailability and actions of some hormones. The impact of hormonal changes on various chronic conditions including frailty, diabetes, cardiovascular disease, and dementia are also discussed. Hormone replacement therapy has been attempted in many clinical trials to reverse and/or prevent the hormonal decline in aging to combat the progression of age-related diseases. Unfortunately, hormone replacement therapy is not a panacea, as it often results in various adverse events that outweigh its potential health benefits. Therefore, except in some specific individual cases, hormone replacement is not recommended. Rather, positive lifestyle modifications such as regular aerobic and resistance exercise programs and/or healthy calorically restricted diet can favorably affect endocrine and metabolic functions and act as countermeasures to various age-related diseases. We provide a critical review of the available data and offer recommendations that hopefully will form the groundwork for physicians/scientists to develop and optimize new endocrine-targeted therapies and lifestyle modifications that can better address age-related decline in heath.
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http://dx.doi.org/10.1016/j.mayocp.2020.07.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020896PMC
March 2021

Collision of Craniopharyngioma and Pituitary Adenoma: Comprehensive Review of an Extremely Rare Sellar Condition.

World Neurosurg 2021 05 26;149:e51-e62. Epub 2021 Feb 26.

Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota, USA. Electronic address:

Objective: The collision of pituitary adenoma and craniopharyngioma is extremely rare and thus there remains a paucity of data.

Methods: We described a patient from our institution. We also performed a systematic review and subsequent quantitative synthesis of the literature (n = 21) and our institutional case to yield an integrated cohort, and a descriptive analysis was carried out.

Results: Twenty-two patients (15 males and 7 females) were included in the integrated cohort. The median age was 47.0 years (range, 8-75 years). The tumor subtypes were 5 somatotropic, 5 lactotropic, 4 nonfunctioning, 3 gonadotropic, 2 corticotropic, 1 plurihormonal, and 1 silent subtype 3 for pituitary adenomas, and 19 adamantinomatous, 2 papillary, and 1 unknown subtype for craniopharyngiomas. Three different radiographic patterns were observed: solid mass with cystic component (n = 5), coexistence of two distinct solid components (n = 3), and a mixed-intensity solid mass (n = 5). The first 2 were consistent with histologically separate collision, whereas the third was consistent with histologically admixed collision. Among 19 patients in whom the postoperative course was recorded, a secondary intervention was required in 14 (73.7%) because of tumor progression or residual. The recurrence rate after gross total resection was 33.3%. Postoperative hormone replacement was required in 33.3%. The 10-year cumulative overall survival was 73.1%.

Conclusions: Most craniopharyngiomas were adamantinomatous. There are 2 types of collisions: separated and admixed. Tumor control, overall survival, and endocrinologic remission are more challenging to achieve than for solitary tumors, but gross total resection of both tumors is important for satisfactory tumor control.
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http://dx.doi.org/10.1016/j.wneu.2021.02.091DOI Listing
May 2021

Biological Effective Dose as a Predictor of Hypopituitarism After Single-Fraction Pituitary Adenoma Radiosurgery: Dosimetric Analysis and Cohort Study of Patients Treated Using Contemporary Techniques.

Neurosurgery 2021 03;88(4):E330-E335

Departments of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota.

Background: Hypopituitarism is the most frequent complication after pituitary adenoma stereotactic radiosurgery (SRS) and is correlated with increasing radiation to the pituitary gland. Biological effective dose (BED) is a dosimetric parameter that incorporates a time component to adjust for mechanisms of deoxyribonucleic acid repair activated during treatment.

Objective: To assess mean gland BED as a predictor of post-SRS hypopituitarism, as compared to mean gland dose, in a contemporary cohort study of patients undergoing single-fraction SRS for pituitary adenoma.

Methods: Cohort study of 97 patients undergoing single-fraction SRS from 2007 to 2014. Eligible patients had no prior pituitary irradiation, normal pre-SRS endocrine function, and >24 mo of endocrine follow-up. Cox proportional hazards analysis was used to assess mean gland dose and BED as predictors of new post-SRS hypopituitarism.

Results: Median post-SRS follow-up was 48 mo (interquartile range [IQR], 34-68). A total of 27 patients (28%) developed new hypopituitarism at a median 22 mo (IQR, 12-36). Actuarial rates of new endocrinopathy were 17% at 2 yr (95% CI 10%-25%) and 31% at 5 yr (95% CI 20%-42%). On univariate analysis, sex (P = .02), gland volume (P = .03), mean gland dose (P < .0001), and BED significantly predicted new hypopituitarism (P < .0001). After adjusting for sex and gland volume, BED > 45 Gy2.47 and mean gland dose > 10 Gy were significantly associated increased risk of hypopituitarism (hazard ratio [HR] = 14.32, 95% CI = 4.26-89.0, P < .0001; HR = 11.91, 95% CI = 3.54-74.0, P < .0001).

Conclusion: BED predicted hypopituitarism more reliably than mean gland dose after pituitary adenoma SRS, but additional studies are needed to confirm these results.
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http://dx.doi.org/10.1093/neuros/nyaa555DOI Listing
March 2021

Maternal and fetal outcomes in phaeochromocytoma and pregnancy: a multicentre retrospective cohort study and systematic review of literature.

Lancet Diabetes Endocrinol 2021 01 26;9(1):13-21. Epub 2020 Nov 26.

Section for Preventive Medicine, Faculty of Medicine, Albert-Ludwigs-University, Freiburg, Germany.

Background: Phaeochromocytoma or paraganglioma (collectively known as PPGL) in pregnant women can lead to severe complications and death due to associated catecholamine excess. We aimed to identify factors associated with maternal and fetal outcomes in women with PPGL during pregnancy.

Methods: We did a multicentre, retrospective study of patients with PPGL and pregnancy between Jan 1, 1980, and Dec 31, 2019, in the International Pheochromocytoma and Pregnancy Registry and a systematic review of studies published between Jan 1, 2005, and Dec 27, 2019 reporting on at least five cases. The inclusion criteria were pregnancy after 1980 and PPGL before or during pregnancy or within 12 months post partum. Eligible patients from the retrospective study and systematic review were included in the analysis. Outcomes of interest were maternal or fetal death and maternal severe cardiovascular complications of catecholamine excess. Potential variables associated with these outcomes were evaluated by logistic regression.

Findings: The systematic review identified seven studies (reporting on 63 pregnancies in 55 patients) that met the eligibility criteria and were of adequate quality. A further 197 pregnancies in 186 patients were identified in the International Pheochromocytoma and Pregnancy Registry. After excluding 11 pregnancies due to potential overlap, the final cohort included 249 pregnancies in 232 patients with PPGL. The diagnosis of PPGL was made before pregnancy in 37 (15%) pregnancies, during pregnancy in 134 (54%), and after delivery in 78 (31%). Of 144 patients evaluated for genetic predisposition for phaeochromocytoma, 95 (66%) were positive. Unrecognised PPGL during pregnancy (odds ratio 27·0; 95% CI 3·5-3473·1), abdominal or pelvic tumour location (11·3; 1·5-1440·5), and catecholamine excess at least ten-times the upper limit of the normal range (4·7; 1·8-13·8) were associated with adverse outcomes. For patients diagnosed during pregnancy, α-adrenergic blockade therapy was associated with fewer adverse outcomes (3·6; 1·1-13·2 for no α-adrenergic blockade vs α-adrenergic blockade), whereas surgery during pregnancy was not associated with better outcomes (0·9; 0·3-3·9 for no surgery vs surgery).

Interpretation: Unrecognised and untreated PPGL was associated with a substantially higher risk of either maternal or fetal complications. Appropriate case detection and counselling for premenopausal women at risk for PPGL could prevent adverse pregnancy-related outcomes.

Funding: US National Institutes of Health.
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http://dx.doi.org/10.1016/S2213-8587(20)30363-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758862PMC
January 2021

Epidemiology of adrenal tumours in Olmsted County, Minnesota, USA: a population-based cohort study.

Lancet Diabetes Endocrinol 2020 11;8(11):894-902

Division of Endocrinology, Diabetes, Metabolism and Nutrition, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA. Electronic address:

Background: Adrenal tumours are commonly encountered in clinical practice, but epidemiological data mainly originate from referral centres. We aimed to determine incidence, prevalence, and rates of malignancy and hormone excess in patients with adrenal tumours in a standardised geographically well defined population.

Methods: In this retrospective population-based cohort study we assessed the standardised incidence rate of adrenal tumours in all patients with tumours who lived in Olmsted County, MN, USA, from Jan 1, 1995, to Dec 31, 2017. The Rochester Epidemiology Project infrastructure, which links medical records across all health-care providers for the entire population of Olmsted County since 1966, was used to allow researchers to identify individuals with specific diagnoses, surgical interventions, and other procedures, and to locate their medical records, which were then used in the analysis. Incidence rates and prevalence were standardised for age and sex according to the 2010 US Population.

Findings: An adrenal tumour was diagnosed in 1287 patients (median age 62 years; 713 (55·4%) were women; and 13 (1·0%) were children). Standardised incidence rates increased from 4·4 (95% CI 0·3-8·6) per 100 000 person-years in 1995 to 47·8 (36·9-58·7) in 2017, mainly because of the incidental discovery of adenomas less than 40 mm in diameter in patients older than 40 years. Prevalence of adrenal tumours in 2017 was 532 per 100 000 inhabitants, ranging from 13 per 100 000 in children (aged <18 years) to 1900 per 100 000 in patients older than 65 years. 111 (8·6%) of 1287 patients were diagnosed with malignancy (96 [7·5%] of whom has metastases), 14 (1·1%) with phaeochromocytoma, and 53 (4·1%) with overt steroid hormone excess. Malignancy was more common in children (62%) versus those older than 18 years (8%; p<0·0001), tumours discovered during cancer-staging or follow-up (43% vs 3% for incidentalomas; p<0·0001), tumours more than 40 mm in diameter (34% vs 6% for tumours <20 mm; p<0·0001), tumours with unenhanced CT attenuation of 30 Hounsfield units or more (20% vs 1% for <20 Hounsfield units; p<·0001), and bilateral masses (16% vs 7% for unilateral, p=0·0004).

Interpretation: Adrenal tumour standardised incidence rates increased 10 times from 1995 to 2017. Population-based data revealed lower rates of malignancy, phaeochromocytoma, and overt steroid hormone excess than previously reported.

Funding: National Institutes of Health.
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http://dx.doi.org/10.1016/S2213-8587(20)30314-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601441PMC
November 2020

Differences in outcomes of bilateral adrenalectomy in patients with ectopic ACTH producing tumor of known and unknown origin.

Am J Surg 2021 02 5;221(2):460-464. Epub 2020 Sep 5.

Mayo Clinic, Department of Surgery, 200 1st Street, 55905, Rochester, MN, USA. Electronic address:

Background: Endogenous Cushing syndrome (CS) can be caused by ectopic corticotropin-producing tumors of known (EK) and unknown origin (EU). Bilateral adrenalectomy (BA) can be used as definite treatment of hypercortisolism in such cases. This study compared patients undergoing BA for CS secondary to EK vs EU.

Methods: Retrospective review (1995-2017) of patients undergoing BA due to EK or EU. We analyzed demographic characteristics, laboratory values, intraoperative variables, surgical outcomes, and survival.

Results: 48 patients (26 EU, 22 EK) were identified. Serum cortisol and ACTH concentrations were similar. 92% of BA for EU were performed minimally invasively vs 77% for EK, P = 0.22. Complications occurred in 19% of EU and 4.5% EK, P = 0.2. Mean survival was 4.3 years for EU and 4.0 years for EK without difference in all-cause mortality P = 0.63.

Conclusion: BA cure rate was 100% for CS in EU and EK. Morbidity, long term and all-cause mortality differences were not statistically significant between EK and EU.
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http://dx.doi.org/10.1016/j.amjsurg.2020.08.047DOI Listing
February 2021

Urine steroid metabolomics for the differential diagnosis of adrenal incidentalomas in the EURINE-ACT study: a prospective test validation study.

Lancet Diabetes Endocrinol 2020 09 23;8(9):773-781. Epub 2020 Jul 23.

Medizinische Klinik and Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, Munich, Germany.

Background: Cross-sectional imaging regularly results in incidental discovery of adrenal tumours, requiring exclusion of adrenocortical carcinoma (ACC). However, differentiation is hampered by poor specificity of imaging characteristics. We aimed to validate a urine steroid metabolomics approach, using steroid profiling as the diagnostic basis for ACC.

Methods: We did a prospective multicentre study in adult participants (age ≥18 years) with newly diagnosed adrenal masses. We assessed the accuracy of diagnostic imaging strategies based on maximum tumour diameter (≥4 cm vs <4 cm), imaging characteristics (positive vs negative), and urine steroid metabolomics (low, medium, or high risk of ACC), separately and in combination, using a reference standard of histopathology and follow-up investigations. With respect to imaging characteristics, we also assessed the diagnostic utility of increasing the unenhanced CT tumour attenuation threshold from the recommended 10 Hounsfield units (HU) to 20 HU.

Findings: Of 2169 participants recruited between Jan 17, 2011, and July 15, 2016, we included 2017 from 14 specialist centres in 11 countries in the final analysis. 98 (4·9%) had histopathologically or clinically and biochemically confirmed ACC. Tumours with diameters of 4 cm or larger were identified in 488 participants (24·2%), including 96 of the 98 with ACC (positive predictive value [PPV] 19·7%, 95% CI 16·2-23·5). For imaging characteristics, increasing the unenhanced CT tumour attenuation threshold to 20 HU from the recommended 10 HU increased specificity for ACC (80·0% [95% CI 77·9-82·0] vs 64·0% [61·4-66.4]) while maintaining sensitivity (99·0% [94·4-100·0] vs 100·0% [96·3-100·0]; PPV 19·7%, 16·3-23·5). A urine steroid metabolomics result indicating high risk of ACC had a PPV of 34·6% (95% CI 28·6-41·0). When the three tests were combined, in the order of tumour diameter, positive imaging characteristics, and urine steroid metabolomics, 106 (5·3%) participants had the result maximum tumour diameter of 4 cm or larger, positive imaging characteristics (with the 20 HU cutoff), and urine steroid metabolomics indicating high risk of ACC, for which the PPV was 76·4% (95% CI 67·2-84·1). 70 (3·5%) were classified as being at moderate risk of ACC and 1841 (91·3%) at low risk (negative predictive value 99·7%, 99·4-100·0).

Interpretation: An unenhanced CT tumour attenuation cutoff of 20 HU should replace that of 10 HU for exclusion of ACC. A triple test strategy of tumour diameter, imaging characteristics, and urine steroid metabolomics improves detection of ACC, which could shorten time to surgery for patients with ACC and help to avoid unnecessary surgery in patients with benign tumours.

Funding: European Commission, UK Medical Research Council, Wellcome Trust, and UK National Institute for Health Research, US National Institutes of Health, the Claire Khan Trust Fund at University Hospitals Birmingham Charities, and the Mayo Clinic Foundation for Medical Education and Research.
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http://dx.doi.org/10.1016/S2213-8587(20)30218-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447976PMC
September 2020

Not all adrenal incidentalomas require biochemical testing to exclude pheochromocytoma: Mayo clinic experience and a meta-analysis.

Gland Surg 2020 Apr;9(2):362-371

Department of Surgery, Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN, USA.

Background: Excluding a pheochromocytoma is important when a patient presents with an incidentally discovered adrenal mass. However, biochemical testing for pheochromocytoma can be cumbersome, time consuming, or falsely positive. Our objective was to determine if unenhanced computed tomography (CT) imaging alone can be used to rule out pheochromocytoma.

Methods: We performed a retrospective study of all patients with a pathologically confirmed pheochromocytoma and unenhanced CT imaging who were treated at the Mayo Clinic between 1998 and 2016. Additionally, we performed a systematic review and meta-analysis of original studies published after 2005 with patients who had adrenal masses, more than 10 patients with pheochromocytomas, and reported attenuation on unenhanced CT imaging in Hounsfield units (HU).

Results: In the Mayo cohort, we identified 186 patients and 199 pheochromocytomas with unenhanced CT imaging. The mean unenhanced CT attenuation was 35±9 HU (range, 15-62), and only 15 tumors had attenuation ≤20 HU. The systematic review identified 26 studies (1,217 tumors), and 23 studies provided a mean unenhanced CT attenuation. The overall mean unenhanced CT attenuation across the studies was 35.6 HU (95% CI, 22.0-49.1 HU). A cutoff of >10 HU had a 100% sensitivity (95% CI, 1.00-1.00) for pheochromocytoma with low heterogeneity between the 21 qualified studies (I=0%). Sensitivity for pheochromocytoma was 100% and 99% for an unenhanced CT attenuation cutoff of >15 and >20 HU.

Conclusions: Biochemical testing may not be required to exclude pheochromocytoma if an incidental adrenal mass has low attenuation (<10 HU) on unenhanced CT images.
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http://dx.doi.org/10.21037/gs.2020.03.04DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225448PMC
April 2020

Bilateral pheochromocytoma: Clinical characteristics, treatment and longitudinal follow-up.

Clin Endocrinol (Oxf) 2020 09 22;93(3):288-295. Epub 2020 Jun 22.

Division of Endocrinology, Diabetes, and Nutrition, Mayo Clinic, Rochester, MN, USA.

Objective: Comprehensive data about patients with bilateral pheochromocytoma are limited. We aimed to describe the clinical presentation, genetic analysis, treatment and outcomes of patients with bilateral pheochromocytoma.

Design: A retrospective study at a tertiary care centre.

Patients: All patients with bilateral pheochromocytoma evaluated at Mayo Clinic in Rochester, Minnesota between January 1951 and December 2015.

Measurements: Tumour size, genetic testing, plasma/urine metanephrines and catecholamines.

Results: A total of 94 patients (51% women) were diagnosed with bilateral pheochromocytoma at a median age at first presentation of 31 years (range, 4-70). Bilateral disease was noted in 8.0% of pheochromocytoma patient overall and 37.5% of patients 18 years of younger. Most patients presented with synchronous tumours (80%). Median time to metachronous tumours was 4.5 years (range, 1-38). Genetic disease was identified in 75 (80%) patients, including MEN 2A (42.6%), VHL (19.1%), MEN 2B (9.6%) and NF1 (8.5%). Excess catecholamines were present in 97% of patients. Patients with synchronous pheochromocytoma commonly underwent simultaneous bilateral adrenalectomy (99%), and 18 (24%) had cortical-sparing surgery. Multicentric tumours were reported in 23 of 77 (30%) patients with available data. Recurrent disease was found in 9.6% of patients, and 8.5% developed metastatic disease. Median follow-up was 8.5 years. At the study conclusion, 4 patients had died due to pheochromocytoma or adrenalectomy.

Conclusions: Bilateral pheochromocytoma occurred in 7.0% of adults with pheochromocytoma and 37.5% of paediatric patients. Genetic disease was identified in 80% of patients, predominantly MEN2A. Multicentric tumours were common, but most were still cured following adrenalectomy.
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http://dx.doi.org/10.1111/cen.14222DOI Listing
September 2020

Bilateral Adrenalectomy: Differences between Cushing Disease and Ectopic ACTH-Producing Tumors.

Ann Surg Oncol 2020 Oct 9;27(10):3851-3857. Epub 2020 May 9.

Department of Surgery, Mayo Clinic, Rochester, MN, USA.

Background: Bilateral adrenalectomy (BA) is a curative treatment for hypercortisolism in patients with corticotropin (ACTH)-dependent Cushing syndrome. Indications include refractory Cushing's disease (CD) following failed pituitary surgery, and occult or unresectable ectopic ACTH-producing neoplasms (EA).

Methods: This was a single-center, retrospective review (1995-2017) of patients undergoing BA for CD or EA. Demographics, laboratory findings, and intraoperative and postoperative variables were analyzed.

Results: Of 137 patients, 83 (61%) had CD and 54 (39%) had EA; 87% of CD patients were female versus 46% of EA patients (p < 0.0001). Mean age at diagnosis was 40 ± 15 years for CD and 49 ± 18 years for EA (p = 0.004). Preoperative serum cortisol concentrations were higher in the EA cohort (63 ± 40 μg/dL) versus the CD cohort (33 ± 19 μg/dL) [p < 0.001], with no significant differences in serum ACTH. Time from diagnosis until adrenalectomy was 54 ± 69 months for CD versus 4 ± 13 for EA (p = 0.002). Most patients underwent minimally invasive surgery (MIS; 86% CD vs. 75% EA; p = 0.19). There was no difference between the rates of conversion to an open approach, intraoperative blood loss, or operative time between groups, and no difference between complications in CD versus EA (p = 1.0). Five-year survival was significantly shorter among the EA cohort (30% for EA vs. 80% for CD; p < 0.001).

Conclusion: Patients with EA presented with higher serum cortisol levels compared with patients with CD. EA patients were more likely to require intraoperative transfusion and postoperative intensive care. BA in patients with CD and EA can be performed safely in an MIS fashion, with similar morbidity; however, survival at 5 years was significantly less in the EA cohort.
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http://dx.doi.org/10.1245/s10434-020-08451-4DOI Listing
October 2020

Clinical course of adrenal myelolipoma: A long-term longitudinal follow-up study.

Clin Endocrinol (Oxf) 2020 07 23;93(1):11-18. Epub 2020 Apr 23.

Division of Endocrinology, Diabetes, and Nutrition, Mayo Clinic, Rochester, MN, USA.

Objective: We aimed to describe clinical course of myelolipoma and to identify predictors of tumour growth and need for surgery.

Design: A retrospective study.

Patients: Consecutive patients with myelolipoma.

Results: A total of 321 myelolipomas (median size, 2.3 cm) were diagnosed in 305 patients at median age of 63 years (range, 25-87). Median follow-up was 54 months. Most myelolipomas were incidentally detected (86%), whereas 9% were discovered during cancer staging and 5% during workup of mass effect symptoms. Thirty-seven (12%) patients underwent adrenalectomy. Compared to myelolipomas <6 cm, tumours ≥6 cm were more likely to be bilateral (21% vs 3%, P < .0001), cause mass effect symptoms (32% vs 0%, P < .0001), have haemorrhagic changes (14% vs 1%, P < .0001) and undergo adrenalectomy (52% vs 5%, P < .0001). Among patients with ≥6 months of imaging follow-up, median size change was 0 mm (-10, 115) and median growth rate was 0 mm/y (-6, 14). Compared to <1 cm growth, ≥1 cm growth correlated with larger initial size (3.6 vs 2.3 cm, P = .02), haemorrhagic changes (12% vs 2%, P = .007) and adrenalectomy (35% vs 8%, P < .0001).

Conclusions: Most myelolipomas are incidentally discovered on cross-sectional imaging. Myelolipomas ≥6 are more likely to cause mass effect symptoms, have haemorrhagic changes and undergo resection. Tumour growth ≥1 cm is associated with larger myelolipoma and haemorrhagic changes. Adrenalectomy should be considered in symptomatic patients with large tumours and when there is evidence of haemorrhage or tumour growth.
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http://dx.doi.org/10.1111/cen.14188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292791PMC
July 2020

The Impact of Insulin-Like Growth Factor Index and Biologically Effective Dose on Outcomes After Stereotactic Radiosurgery for Acromegaly: Cohort Study.

Neurosurgery 2020 09;87(3):538-546

Department of Neurological Surgery, Mayo Clinic, Rochester, Minnesota.

Background: Stereotactic radiosurgery (SRS) is a safe and effective treatment for acromegaly.

Objective: To improve understanding of clinical and dosimetric factors predicting biochemical remission.

Methods: A single-institution cohort study of nonsyndromic, radiation-naïve patients with growth hormone-producing pituitary adenomas (GHA) having single-fraction SRS between 1990 and 2017. Exclusions were treatment with pituitary suppressive medications at the time of SRS, or <24 mo of follow-up. The primary outcome was biochemical remission-defined as normalization of insulin-like growth factor-1 index (IGF-1i) off suppression. Biochemical remission was assessed using Cox proportional hazards. Prior studies reporting IGF-1i were assessed via systematic literature review and meta-analysis using random-effect modeling.

Results: A total of 102 patients met study criteria. Of these, 46 patients (45%) were female. The median age was 49 yr (interquartile range [IQR] = 37-59), and the median follow-up was 63 mo (IQR = 29-100). The median pre-SRS IGF-1i was 1.66 (IQR = 1.37-3.22). The median margin dose was 25 Gy (IQR = 21-25); the median estimated biologically effective dose (BED) was 169.49 Gy (IQR = 124.95-196.00). Biochemical remission was achieved in 58 patients (57%), whereas 22 patients (22%) had medication-controlled disease. Pre-SRS IGF-1i ≥ 2.25 was the strongest predictor of treatment failure, with an unadjusted hazard ratio (HR) of 0.51 (95% CI = 0.26-0.91, P = .02). Number of isocenters, margin dose, and BED predicted remission on univariate analysis, but after adjusting for sex and baseline IGF-1i, only BED remained significant-and was independently associated with outcome in continuous (HR = 1.01, 95% CI = 1.00-1.01, P = .02) and binary models (HR = 2.27, 95% CI = 1.39-5.22, P = .002). A total of 24 patients (29%) developed new post-SRS hypopituitarism. Pooled HR for biochemical remission given subthreshold IGF-1i was 2.25 (95% CI = 1.33-3.16, P < .0001).

Conclusion: IGF-1i is a reliable predictor of biochemical remission after SRS. BED appears to predict biochemical outcome more reliably than radiation dose, but confirmatory study is needed.
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http://dx.doi.org/10.1093/neuros/nyaa054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426191PMC
September 2020

Pituitary adenomas in the setting of multiple endocrine neoplasia type 1: a single-institution experience.

J Neurosurg 2020 Apr 3;134(3):1132-1138. Epub 2020 Apr 3.

Departments of1Neurological Surgery.

Objective: Multiple endocrine neoplasia type 1 (MEN1) is a rare, autosomal-dominant tumor disorder characterized by the development of pituitary tumors and other endocrine neoplasms. Diagnosis is made clinically based on the development of 2 or more canonical lesions (parathyroid gland, anterior pituitary, and enteropancreatic tumors) or in family members of a patient with a clinical diagnosis of MEN1 and the occurrence of one of the MEN1-associated tumors. The goal of this study was to characterize pituitary tumors arising in the setting of MEN1 at a single institution. The probability of tumor progression and the likelihood of surgical intervention in patients with asymptomatic nonfunctional pituitary adenomas were also analyzed.

Methods: A retrospective review of a prospectively maintained institutional database was performed for patients with MEN1 diagnosed from 1970 to 2017. Data included patient demographics, tumor characteristics, treatment strategies, and outcomes.

Results: A review of the database identified 268 patients diagnosed with MEN1, of whom 158 (59%) were female. Among the 268 patients, 139 (51.8%) had pituitary adenomas. There was a higher prevalence in women than in men (65% vs 35%, p < 0.005). Functional adenomas (57%) were more common. Prolactin-secreting adenomas were the most common functional tumors. Macroadenomas were seen in 27% of patients and were more likely to be symptomatic and locally aggressive (p < 0.001). Forty-nine patients (35%) underwent transsphenoidal resection at some point during their disease course. In 52 patients who were initially observed with MEN1 asymptomatic nonfunctional adenomas, only 5 (10%) progressed to need surgery. In MEN1 patients, an initial parathyroid lesion is most likely followed in order by pituitary, pancreatic, adrenal, and, finally, rare carcinoid tumors.

Conclusions: Asymptomatic nonfunctional pituitary adenomas in patients with MEN1 may be followed safely with MRI. In this series, parathyroid tumors developed at the lowest median age of all cardinal tumors, and development of additional cardinal MEN1 lesions followed a predictable pattern. This pattern of disease progression could have significant implications for disease surveillance in clinical practice and may help to target clinical resources to the lesions most likely to develop next. This may aid with early detection and treatment and warrants further study.
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http://dx.doi.org/10.3171/2020.1.JNS193538DOI Listing
April 2020

The Impact of Mild Autonomous Cortisol Secretion on Bone Turnover Markers.

J Clin Endocrinol Metab 2020 05;105(5)

Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota.

Context: Several studies have reported increased risk of fragility fractures in patients with mild autonomous cortisol secretion (MACS), discordant to the degree of bone density deterioration.

Objective: To evaluate the effect of MACS on bone metabolism in patients with adrenal adenomas.

Design: Cross-sectional study with prospective enrollment, 2014-2019.

Setting: Referral center.

Patients: 213 patients with adrenal adenomas: 22 Cushing syndrome (CS), 92 MACS and 99 nonfunctioning adrenal tumors (NFAT).

Main Outcome Measures: Osteocalcin, procollagen I intact N-terminal (PINP), C-terminal telopeptide (CTX), sclerostin.

Results: Patients with CS demonstrated lower markers of bone formation compared with patients with MACS and NFAT (CS vs MACS vs NFAT: mean osteocalcin 14.8 vs 20.1 vs 21.3 ng/mL [P < 0.0001]; mean PINP 34.8 vs 48.7 vs 48.5 µg/L [P = 0.003]). Severity of cortisol excess was inversely associated with sclerostin (CS vs MACS vs NFAT: mean sclerostin 419 vs 538 vs 624 ng/L, [P < 0.0001]). In a multivariable model of age, sex, body mass index, cortisol, and bone turnover markers, sclerostin was a significant predictor of low bone mass in patients with MACS (OR 0.63 [CI 95%, 0.40-0.98] for each 100 ng/L of sclerostin increase).After adrenalectomy, osteocalcin, CTX, and sclerostin increased by a mean difference of 6.3 ng/mL, 0.12 ng/mL, and 171 pg/mL (P = 0.02 for all), respectively.

Conclusions: Lower sclerostin level in patients with MACS reflects a reduction in osteocyte function or number associated with exposure to chronic cortisol excess. Increase in bone turnover markers after adrenalectomy suggests restoration of favorable bone metabolism.
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http://dx.doi.org/10.1210/clinem/dgaa120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108681PMC
May 2020

Metastatic Pheochromocytoma: In Search of a Cure.

Authors:
William F Young

Endocrinology 2020 03;161(3)

Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.

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http://dx.doi.org/10.1210/endocr/bqz019DOI Listing
March 2020

Tumor-specific prognosis of mutation-positive patients with head and neck paragangliomas.

J Vasc Surg 2020 05 5;71(5):1602-1612.e2. Epub 2020 Feb 5.

Department of Vascular Surgery, Mayo Clinic, Rochester, Minn.

Background: Genetic testing to identify succinate dehydrogenase (SDH) mutations in patients with head and neck paraganglioma (HNP) has been in clinical practice for more than a decade. However, the recurrence and metachronous tumor occurrence risks in surgically treated mutation-positive patients are not well studied.

Methods: Clinical and procedural details of consecutive patients who underwent excision for HNP from January 1996 to October 2016 were retrospectively reviewed. End points included recurrence, metachronous tumor detection, and mortality. Germline DNA was tested to identify mutations in SDHx genes. Patients were divided into three groups on the basis of genetic testing: group I, positive; group II, negative; and group III, unknown or offered but not tested.

Results: HNP was diagnosed in 268 patients, 214 (147 female; mean age, 47 years) included in this study. Directed genetic testing was performed in 68; mutations were detected in SDH in 47 (69%), a majority SDHD. In group I, 47 patients had 64 procedures for 81 tumors (52 carotid body tumors [CBTs]); 17 (36%) were bilateral, 7 (15%) multiple, 3 (6%) functional, and 7 (15%) malignant. Residual tumor in 10 was significant in 2, managed by radiation therapy and reoperation. Local recurrence was detected in 12 patients (25%) at a median of 8 years; 11 metachronous mediastinal and retroperitoneal paragangliomas were detected in 8 (17%) at a median of 13 years. Systemic metastases occurred in five (10%). Six patients (13%) had more than one recurrence. In group II, 21 patients had 22 procedures for 23 tumors, 17 CBTs. Two (9%) were bilateral and two (9%) malignant. Excision was complete in all with no recurrence or systemic metastasis at last follow-up. For group III, 146 patients underwent 153 procedures for 156 tumors, 95 CBTs; 7 (5%) were bilateral, 2 (1%) multiple, 8 (5%) functional, and 1 (0.6%) malignant. Local recurrence was detected in nine (6%) at a median of 9 years and metachronous HNP in three (2%) at a median of 5 years. Systemic metastases occurred in two (1%). Mortality was 4% in group I and 3% in group III, none procedure or tumor related. Group I (mutation positive) had 10-year overall, recurrence-free, and metachronous tumor-free survival rates of 93%, 69.4%, and 73%, respectively, lower than the other groups (P < .001).

Conclusions: Bilateral, functional, malignant, recurrent, and metachronous tumors are more common in SDH mutation-positive patients with HNP. Overall survival in patients with HNP is high. Metachronous tumors or local recurrences occur late, and long-term follow-up is necessary.
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http://dx.doi.org/10.1016/j.jvs.2019.08.232DOI Listing
May 2020

Pheochromocytoma and Paraganglioma. Reply.

N Engl J Med 2019 11;381(19):1883

Cleveland Clinic, Cleveland, OH.

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http://dx.doi.org/10.1056/NEJMc1912022DOI Listing
November 2019

Response to Letter to the Editor: "Pheochromocytoma Characteristics and Behavior Differ Depending on Method of Discovery".

J Clin Endocrinol Metab 2020 02;105(2)

Division of Endocrinology, Diabetes, and Nutrition, Mayo Clinic, Rochester, MN.

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http://dx.doi.org/10.1210/clinem/dgz084DOI Listing
February 2020

Comparison between functional and non-functional adrenocortical carcinoma.

Surgery 2020 01 19;167(1):216-223. Epub 2019 Sep 19.

Department of Surgery, Mayo Clinic, Rochester, MN. Electronic address:

Background: While roughly half of adrenocortical carcinomas are functional, whether functional status impacts outcomes remains controversial. We compared presentation and survival for functional and nonfunctional neoplasms.

Methods: Adult patients presented with adrenocortical carcinomas at the Mayo Clinic were included. Tumor characteristics and outcomes were analyzed.

Results: The 266 identified patients presented with stage I (6%), II (33%), III (26%), and IV disease (32%); stage was unknown in 3%. Fifty-three percent of tumors were functional; patients with functional adrenocortical carcinomas were younger, more likely to be female, and more likely to present with metastatic disease. Surgical resection was undertaken in 84% of patients with 69% having R0 resection. While 30-day morbidity was similar between functional and nonfunctional adrenocortical carcinomas, median overall survival was better for nonfunctional adrenocortical carcinomas (median 66 vs 22 months, P = .01). Functional adrenocortical carcinomas was independently associated with shorter survival after adjusting for age, sex, grade, stage, and resection attempt: hazard ratio = 1.5 (95% confidence interval, 1.04-2.14, P = .03).

Conclusion: In our cohort, long term survival was worse for all patients with functional tumors. However, when analyzing patients with R0 resection, there was no survival difference between functional and nonfunctional adrenocortical carcinomas, signaling need for better understanding of adrenocortical carcinomas behavior to individualize and optimize treatment strategies.
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http://dx.doi.org/10.1016/j.surg.2019.04.066DOI Listing
January 2020

Comparison of Pheochromocytoma-Specific Morbidity and Mortality Among Adults With Bilateral Pheochromocytomas Undergoing Total Adrenalectomy vs Cortical-Sparing Adrenalectomy.

JAMA Netw Open 2019 08 2;2(8):e198898. Epub 2019 Aug 2.

Department of Biochemistry and Molecular Biology, School of Life Sciences, Central South University, Changsha, China.

Importance: Large studies investigating long-term outcomes of patients with bilateral pheochromocytomas treated with either total or cortical-sparing adrenalectomies are needed to inform clinical management.

Objective: To determine the association of total vs cortical-sparing adrenalectomy with pheochromocytoma-specific mortality, the burden of primary adrenal insufficiency after bilateral adrenalectomy, and the risk of pheochromocytoma recurrence.

Design, Setting, And Participants: This cohort study used data from a multicenter consortium-based registry for 625 patients treated for bilateral pheochromocytomas between 1950 and 2018. Data were analyzed from September 1, 2018, to June 1, 2019.

Exposures: Total or cortical-sparing adrenalectomy.

Main Outcomes And Measures: Primary adrenal insufficiency, recurrent pheochromocytoma, and mortality.

Results: Of 625 patients (300 [48%] female) with a median (interquartile range [IQR]) age of 30 (22-40) years at diagnosis, 401 (64%) were diagnosed with synchronous bilateral pheochromocytomas and 224 (36%) were diagnosed with metachronous pheochromocytomas (median [IQR] interval to second adrenalectomy, 6 [1-13] years). In 505 of 526 tested patients (96%), germline mutations were detected in the genes RET (282 patients [54%]), VHL (184 patients [35%]), and other genes (39 patients [7%]). Of 849 adrenalectomies performed in 625 patients, 324 (52%) were planned as cortical sparing and were successful in 248 of 324 patients (76.5%). Primary adrenal insufficiency occurred in all patients treated with total adrenalectomy but only in 23.5% of patients treated with attempted cortical-sparing adrenalectomy. A third of patients with adrenal insufficiency developed complications, such as adrenal crisis or iatrogenic Cushing syndrome. Of 377 patients who became steroid dependent, 67 (18%) developed at least 1 adrenal crisis and 50 (13%) developed iatrogenic Cushing syndrome during median (IQR) follow-up of 8 (3-25) years. Two patients developed recurrent pheochromocytoma in the adrenal bed despite total adrenalectomy. In contrast, 33 patients (13%) treated with successful cortical-sparing adrenalectomy developed another pheochromocytoma within the remnant adrenal after a median (IQR) of 8 (4-13) years, all of which were successfully treated with another surgery. Cortical-sparing surgery was not associated with survival. Overall survival was associated with comorbidities unrelated to pheochromocytoma: of 63 patients who died, only 3 (5%) died of metastatic pheochromocytoma.

Conclusions And Relevance: Patients undergoing cortical-sparing adrenalectomy did not demonstrate decreased survival, despite development of recurrent pheochromocytoma in 13%. Cortical-sparing adrenalectomy should be considered in all patients with hereditary pheochromocytoma.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.8898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692838PMC
August 2019

Pheochromocytoma and Paraganglioma.

N Engl J Med 2019 08;381(6):552-565

From the Section for Preventive Medicine, Medical Center-University of Freiburg, Faculty of Medicine, Albert-Ludwigs-University, Freiburg, Germany (H.P.H.N.); the Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Department of Internal Medicine, Mayo Clinic, Rochester, MN (W.F.Y.); and the Genomic Medicine Institute, Lerner Research Institute, and Taussig Cancer Institute, Cleveland Clinic, Cleveland (C.E.).

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http://dx.doi.org/10.1056/NEJMra1806651DOI Listing
August 2019
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