CoChat
Sign Up
Cited by 347Adrenal and Paraganglionic TumorsAdrenal Hormones and DisordersPituitary Gland Disorders and Treatments

Adrenal incidentaloma

Open access
Sherlock, Mark, Scarsbrook, Andrew, Abbas, Afroze, Fraser, Sheila, Limumpornpetch, Padiporn, Dineen, Rosemary, Stewart, Paul M·2020·Endocrine Reviews
DOI 10.1210/endrev/bnaa008PMC PMC7431180
Open this paper in CoChat — free account

Abstract

An adrenal incidentaloma is now established as a common endocrine diagnosis that requires a multidisciplinary approach for effective management. The majority of patients can be reassured and discharged, but a personalized approach based upon image analysis, endocrine workup, and clinical symptoms and signs are required in every case. Adrenocortical carcinoma remains a real concern but is restricted to <2% of all cases. Functional adrenal incidentaloma lesions are commoner (but still probably <10% of total) and the greatest challenge remains the diagnosis and optimum management of autonomous cortisol secretion. Modern-day surgery has improved outcomes and novel radiological and urinary biomarkers will improve early detection and patient stratification in future years to come.

AI snapshot

Written from the paper’s full text.

TL;DR

Adrenal incidentaloma is a common endocrine diagnosis requiring multidisciplinary, personalized assessment; most patients can be reassured and discharged once malignancy and hormone hypersecretion are excluded. Adrenocortical carcinoma remains a concern but is <2% of cases, while functional lesions are commoner and autonomous cortisol secretion is the greatest diagnostic and management challenge.

Key findings

  • AI affects ~2% of the general population and over 7% of those over 70 years; it is rare below 40 years. About 2% of patients with AI have adrenocortical cancer, and up to 10% have autonomous secretion of adrenal hormones.
  • The initial investigation of choice is an unenhanced CT of both adrenal glands. An unenhanced CT attenuation of ≤10 HU is consistent with a lipid-rich benign adenoma; pheochromocytomas have mean HU scores of 30 to 35, and only 0.5% have an unenhanced CT attenuation of ≤10 HU.
  • Pheochromocytoma and autonomous cortisol secretion should be excluded in every case, and aldosteronism in patients with underlying hypertension and/or hypokalemia. For ACS screening, a post-dexamethasone cortisol ≤1.8 µg/dL is normal, 1.9–5.0 µg/dL may indicate possible ACS, and >5.0 µg/dL suggests ACS; sensitivity rises from 80% at a 140 nmol/L cutoff to 95% at 50 nmol/L, with lower specificity.
  • Most patients with AI can be discharged once malignancy and hormone hypersecretion have been excluded. A causative link between cortisol hypersecretion and age-related comorbidities should be firmly established before recommending surgical excision.

Methods

  • Narrative review synthesizing epidemiology, anatomy and physiology, etiology, endocrine workup, imaging, surgical management, and future biomarkers for adrenal incidentaloma.
  • Data are drawn from published autopsy, CT, clinical series, guidelines, systematic reviews, and meta-analyses; no primary patient cohort or new experimental data are presented.
  • Main analysis is qualitative synthesis and tabulation of published literature, including tables of prevalence, diagnostic tests, and surgical outcomes; no formal systematic review or meta-analysis methods are stated.

Limitations

  • The paper states that many included studies are limited by retrospective nature, specialized center bias, patient selection bias, recall bias, and small sample size; source data are highly variable in autopsy, surgery, or radiological origin, patient selection, and AI definition.
  • The paper states there is no gold standard test for diagnosing ACS, false positives are common, and age-related comorbidities can themselves cause physiological hypercortisolism; robust evidence for surgical treatment of ACS is lacking, with most studies small, retrospective, uncontrolled, and nonrandomized.
  • Evident from the text: as a narrative review, it does not describe a systematic search strategy or formal quality assessment, so recommendations rest on heterogeneous observational data and expert synthesis.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1210/endrev/bnaa008

Cites

392 of 392 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 382 cited sources checked · 0 supported · 0 flagged

  • Interpretationcitation

    The higher prevalence in Song et al. may be because the study protocol included a dedicated radiological review of adrenal imaging in a significant percentage of cases, possibly resulting in diagnosis of more AI than in routine practice.

    “However, the study protocol included a dedicated radiological review of adrenal imaging in a significant percentage of cases, thereby possibly resulting in the diagnosis of more AI than would have been encountered in routine radiological clinical practice (44,45).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [44] Davenport, 2011, The prevalence of adrenal incidentaloma in routine clinical practice, Endocrine. source

      Not checked in the free run.

    • cites [45] Cawood, 2009, Recommended evaluation of adrenal incidentalomas is costly, has high false-positive rates and confers a risk of fatal cancer that is similar to the risk of the adrenal lesion becoming malignant; time for a rethink?, Eur J Endocrinol. source

      Not checked in the free run.

  • Premisecitation

    In autopsy series with greater than 1000 patients, the reported prevalence of AI ranges from 1.05% to 8.7%.

    “In the autopsy series with large patient numbers (series with greater than 1000 patients) (9-16), the reported prevalence of AI ranges from 1.05% (9) to 8.7% (10) (Table 1 (9-31)).”
    Quote in the paperNot a substantial claim0 of 8 sources checked
    • cites [9] Kokko, 1967, Adrenal adenoma and hypertension, Lancet. source

      Not checked in the free run.

    • cites [10] Hedeland, 1968, On the prevalence of adrenocortical adenomas in an autopsy material in relation to hypertension and diabetes, Acta Med Scand. source

      Not checked in the free run.

    • cites [11] Russi, 1945, Small adenomas of the adrenal cortex in hypertension and diabetes, Arch Intern Med (Chic). source

      Not checked in the free run.

    • cites [12] Commons, 1948, Adenomas of the adrenal cortex, Arch Intern Med (Chic). source

      Not checked in the free run.

    • cites [13] Schroeder, 1954, Studies on “essential” hypertension. V. An endocrine hypertensive syndrome, Ann Intern Med. source

      Not checked in the free run.

    • cites [14] Dévényi, 1967, Possibility of normokalaemic primary aldosteronism as reflected in the frequency of adrenal cortical adenomas, J Clin Pathol. source

      Not checked in the free run.

    • cites [15] Russell, 1972, Adrenal cortical adenomas and hypertension. A clinical pathologic analysis of 690 cases with matched controls and a review of the literature, Medicine (Baltimore). source

      Not checked in the free run.

    • cites [16] Kawano, 1989, Adrenal incidentaloma–report of 14 operated cases and analysis of 4-year autopsy series of Japan, Nihon Geka Gakkai Zasshi.

      Not checked in the free run.

  • Interpretationcitation

    Among autopsy and radiology series, the prevalence of AIs increases with age, showing a peak incidence in the fifth to seventh decades.

    “Among autopsy and radiology series, the prevalence of AIs increases with age, showing a peak incidence in the fifth to seventh decades (Table 3 (39,40,42,46-84)).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites 39,40,42,46-84

      Not checked in the free run.

  • Premisecitation

    Fewer AIs underwent surgical resection in the Korean COAR study than in the Italian cohort.

    “Also, fewer AIs underwent surgical resection in the Korean study.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [81] Ahn, 2018, Characteristics of adrenal incidentalomas in a large, prospective computed tomography-based multicenter study: the COAR study in Korea, Yonsei Med J. source

      Not checked in the free run.

    • cites [66] Mantero, 2000, A survey on adrenal incidentaloma in Italy. Study Group on Adrenal Tumors of the Italian Society of Endocrinology, J Clin Endocrinol Metab.

      Not checked in the free run.

  • Premisecitation

    The prevalence of any disease increases with the observer's ability to detect the abnormalities associated with the disease.

    “The prevalence of any disease increases with the observer’s ability to detect the abnormalities associated with the disease (32).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Black, 1993, Advances in diagnostic imaging and overestimations of disease prevalence and the benefits of therapy, N Engl J Med. source

      Not checked in the free run.

  • Classified as probably not a substantial claim. 50
  • May combine two claims. 103

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Findingnone given

    Up to 10% of patients with AI have autonomous secretion of adrenal hormones.

    “Up to 10% of patients with AI have autonomous secretion of adrenal hormones”
    • Also stated in: § Abstract · hedged
      “Functional adrenal incidentaloma lesions are commoner (but still probably <10% of total)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    The mean diameter of AI discovered by CT scan is 30 mm, ranging from 8 to 230 mm.

    “The mean diameter of AI discovered by CT scan is 30 mm, ranging from 8 to 230 mm (Table 3 (39,40,42,46-84))”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites 39,40,42,46-84

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Findingnone given

    Adrenal incidentaloma (AI) is a common endocrine diagnosis affecting approximately 2% of the general population.

    “Adrenal incidentaloma (AI) is a common endocrine diagnosis affecting ~2% of the general population, but over 7% of those over 70 years.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Findingnone given

    Approximately 2% of patients with AI have adrenocortical cancer.

    “~2% of patients with AI have adrenocortical cancer”
    • Also stated in: § Abstract · plain
      “Adrenocortical carcinoma remains a real concern but is restricted to <2% of all cases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The prevalence of AIs varies depending on the source of data (autopsy, surgery, or radiology series) and patient selection (from general or specialized units).

    “The prevalence of AIs varies depending on the source of data (autopsy, surgery, or radiology series) and patient selection (from general or specialized units).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In the COAR study of 1005 Korean patients with AIs, AIs were more frequent in men (57%) and the population was younger (median 55 years) than the Italian patient cohort.

    “AIs in Korean patients were more frequent in men (57%) and the population was younger (median 55 years) than the Italian patient cohort.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [81] Ahn, 2018, Characteristics of adrenal incidentalomas in a large, prospective computed tomography-based multicenter study: the COAR study in Korea, Yonsei Med J. source

      Not checked in the free run.

    • cites [66] Mantero, 2000, A survey on adrenal incidentaloma in Italy. Study Group on Adrenal Tumors of the Italian Society of Endocrinology, J Clin Endocrinol Metab.

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Previous imaging studies have reported that AIs are more common in females; however, this has not been observed in autopsy studies.

    “Previous imaging studies have reported that AIs are more common in females (66,71,73); however, this has not been observed in autopsy studies (11,85).”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [66] Mantero, 2000, A survey on adrenal incidentaloma in Italy. Study Group on Adrenal Tumors of the Italian Society of Endocrinology, J Clin Endocrinol Metab.

      Not checked in the free run.

    • cites [71] Kasperlik-Załuska, 2008, Incidentally discovered adrenal tumors: a lesson from observation of 1,444 patients, Horm Metab Res. source

      Not checked in the free run.

    • cites [73] Comlekci, 2010, Adrenal incidentaloma, clinical, metabolic, follow-up aspects: single centre experience, Endocrine. source

      Not checked in the free run.

    • cites [11] Russi, 1945, Small adenomas of the adrenal cortex in hypertension and diabetes, Arch Intern Med (Chic). source

      Not checked in the free run.

    • cites [85] Kloos, 1995, Incidentally discovered adrenal masses, Endocr Rev.

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Over the last 2 decades, there has been a dramatic increase in the detection of AIs; series with contemporary high-resolution CT techniques report a prevalence close to that observed at autopsy.

    “Over the last 2 decades, there has been a dramatic increase in the detection of AIs; series with contemporary high-resolution CT techniques report a prevalence close to that observed at autopsy (Table 2 (36-44)).”
    Quote in the paperNot a substantial claim0 of 9 sources checked
    • cites [36] Davenport, 2014, Adrenal incidentalomas: management in British district general hospitals, Postgrad Med J. source

      Not checked in the free run.

    • cites [37] Maher, 2018, Adrenal incidentaloma follow-up is influenced by patient, radiologic, and medical provider factors: a review of 804 cases, Surgery. source

      Not checked in the free run.

    • cites [38] Taya, 2019, The relationship between adrenal incidentalomas and mortality risk, Eur Radiol. source

      Not checked in the free run.

    • cites [39] Herrera, 1991, Incidentally discovered adrenal tumors: an institutional perspective, Surgery.

      Not checked in the free run.

    • cites [40] Caplan, 1994, Subclinical hormone secretion by incidentally discovered adrenal masses, Arch Surg. source

      Not checked in the free run.

    • cites [41] Bovio, 2006, Prevalence of adrenal incidentaloma in a contemporary computerized tomography series, J Endocrinol Invest. source

      Not checked in the free run.

    • cites [42] Song, 2008, The incidental adrenal mass on CT: prevalence of adrenal disease in 1,049 consecutive adrenal masses in patients with no known malignancy, AJR Am J Roentgenol. source

      Not checked in the free run.

    • cites [43] Hammarstedt, 2010, Adrenal lesion frequency: a prospective, cross-sectional CT study in a defined region, including systematic re-evaluation, Acta Radiol. source

      Not checked in the free run.

    • cites [44] Davenport, 2011, The prevalence of adrenal incidentaloma in routine clinical practice, Endocrine. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Russell et al. reported an overall prevalence of adrenal cortical adenomas (all sizes) of 1.73%, increasing to 3.03% in patients older than 20 years.

    “They reported an overall prevalence of adrenal cortical adenomas (of all sizes) of 1.73%, increasing to 3.03% in patients older than 20 years (15).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Russell, 1972, Adrenal cortical adenomas and hypertension. A clinical pathologic analysis of 690 cases with matched controls and a review of the literature, Medicine (Baltimore). source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    The first CT scan series regarding AIs, published between 1982 and 1986, reported a prevalence of 0.6% to 1.3%, which likely represents an underestimation due to low-resolution technology and failure to detect smaller lesions.

    “The first CT scan series regarding AIs, published between 1982 and 1986, reported a prevalence of 0.6% to 1.3% (33-35), which likely represents an underestimation due to the low-resolution technology available at the time and failure to detect smaller lesions.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [33] Glazer, 1982, Nonfunctioning adrenal masses: incidental discovery on computed tomography, AJR Am J Roentgenol. source

      Not checked in the free run.

    • cites [34] Prinz, 1982, Incidental asymptomatic adrenal masses detected by computed tomographic scanning. Is operation required?, JAMA. source

      Not checked in the free run.

    • cites [35] Belldegrun, 1986, Incidentally discovered mass of the adrenal gland, Surg Gynecol Obstet.

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The higher frequency of AIs in Bovio et al. may reflect improved modern scanning technology, but the study included only patients older than 55 years, thereby only capturing patients at an age at which there is a greater prevalence of adrenal masses.

    “While this increase may reflect improved modern scanning technology, the study included only patients older than 55 years of age, thereby only capturing patients at an age at which there is a greater prevalence of adrenal masses.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Of the total identified adenomas in the Japanese autopsy series (n=101), 25 were in patients <50 years, while 75% were in patients older than 50 years.

    “Of the total number of identified adenomas in this autopsy series (n = 101), only 25 were identified in patients <50 years, while the remaining 75% were identified in patients older than 50 years.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Kobayashi, 1991, Primary adrenocortical tumors in autopsy records--a survey of “Cumulative Reports in Japan” from 1973 to 1984, Jpn J Surg source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    The fact that fewer patients in the COAR study underwent adrenalectomy may be due to smaller adenoma size at discovery, an increase in detailed characterization of AIs using improved imaging techniques, and endocrinological assessment leading to more reassurance regarding their benign nature.

    “The fact that fewer patients in the COAR study underwent adrenalectomy may be due to smaller adenoma size at discovery, an increase in the detailed characterization of AIs using improved imaging techniques (discussed in “Imaging Evaluation of an AI”), and endocrinological assessment (discussed in “Endocrine Work-up of AI”) leading to more reassurance regarding their benign nature.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In 2006, Bovio et al. reported a frequency of AIs of 4.4% in a prospective study of 520 patients, significantly higher than previous imaging series.

    “In 2006, Bovio et al. (41) reported a frequency of AIs of 4.4% in a prospective study of 520 patients. This was significantly higher than the previous imaging series.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Bovio, 2006, Prevalence of adrenal incidentaloma in a contemporary computerized tomography series, J Endocrinol Invest. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Many studies of AI characteristics are limited by retrospective nature, specialized center bias, patient selection bias, recall bias, and small sample size.

    “Many studies are limited by their retrospective nature, specialized center bias, patient selection bias, recall bias, and small sample size.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    There has been an increase in knowledge concerning the natural history of untreated adrenal lesions, and recent development of international evidence-based management guidelines reflect this.

    “There has also been an increase in our knowledge concerning the natural history of untreated adrenal lesions and the recent development of international evidence-based management guidelines reflect this (4,6).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [4] Fassnacht, 2016, Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors, Eur J Endocrinol. source

      Not checked in the free run.

    • cites [6] Zeiger, 2009, The American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons medical guidelines for the management of adrenal incidentalomas, Endocr Pract. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Reinhard et al. reported a prevalence of 5% for adrenal adenomas in an autopsy series of 498 cases.

    “In a further autopsy series of 498 cases, Reinhard et al. (30) reported a higher prevalence of 5% for adrenal adenomas.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Reinhard, 1996, Adrenocortical nodules in post-mortem series. Development, functional significance, and differentiation from adenomas, Gen Diagn Pathol.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In 2002, Thompson described the PASS tool, based on 12 histological features, to distinguish benign and malignant pheochromocytomas.

    “In 2002 Thompson described a tool, Pheochromocytoma of the Adrenal gland Scaled Score (PASS), based on the presence or absence of 12 specific histological features to allow better distinction between benign and malignant tumors (119).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [119] Thompson, 2002, Pheochromocytoma of the Adrenal gland Scaled Score (PASS) to separate benign from malignant neoplasms: a clinicopathologic and immunophenotypic study of 100 cases, Am J Surg Pathol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Adrenocortical carcinomas are retroperitoneal and may present late, often having reached a large size.

    “As ACCs are retroperitoneal they may present late and have often reached a large size (131).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [131] Schteingart, 2001, Overexpression of CXC chemokines by an adrenocortical carcinoma: a novel clinical syndrome, J Clin Endocrinol Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    S100 protein usually highlights sustentacular cells in pheochromocytomas and is negative in adrenocortical tumors.

    “S100 protein usually highlights sustentacular cells in pheochromocytomas and is negative in adrenocortical tumors.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [109] Erickson, 2018, Challenges in surgical pathology of adrenocortical tumours, Histopathology. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Subsequent validation by a panel of experienced pathologists concluded that due to significant inter- and intraobserver variation, PASS was not recommended for clinical prognostication.

    “Subsequent validation by a panel of experienced pathologists concluded that due to significant inter- and intraobserver variation PASS was not recommended for clinical prognostication (120).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [120] Wu, 2009, Observer variation in the application of the Pheochromocytoma of the Adrenal Gland Scaled Score, Am J Surg Pathol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The cutoff at which a Ki67 labeling index confirms the diagnosis of ACC and predicts aggressive disease is debated and ranges from >2.5% to >7%.

    “The cutoff at which a Ki67 labeling index confirms the diagnosis of ACC and predicts aggressive disease is debated and ranges from >2.5% to >7% (113,115-117).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [113] Nakamura, 2015, Adrenocortical carcinoma: review of the pathologic features, production of adrenal steroids, and molecular pathogenesis, Endocrinol Metab Clin North Am. source

      Not checked in the free run.

    • cites [115] McNicol, 2008, Lesions of the adrenal cortex, Arch Pathol Lab Med. source

      Not checked in the free run.

    • cites [116] Morimoto, 2008, Immunohistochemistry of a proliferation marker Ki67/MIB1 in adrenocortical carcinomas: Ki67/MIB1 labeling index is a predictor for recurrence of adrenocortical carcinomas, Endocr J. source

      Not checked in the free run.

    • cites [117] Schmitt, 2006, IGFII and MIB1 immunohistochemistry is helpful for the differentiation of benign from malignant adrenocortical tumours, Histopathology. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    GAPP scoring was independently validated by Koh et al. and is considered a useful risk stratification tool for the prediction of metastatic potential.

    “GAPP scoring was independently validated by Koh et al. and is considered a useful risk stratification tool for the prediction of metastatic potential (122).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [122] Koh, 2017, Validation of pathological grading systems for predicting metastatic potential in pheochromocytoma and paraganglioma, PLoS One. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Feminization and hyperaldosteronism are rare in adrenocortical carcinoma, occurring in less than 10% of cases.

    “Feminization and hyperaldosteronism are rare occurring in <10% of cases (127,130).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [127] Ng, 2003, Adrenocortical carcinoma: diagnosis, evaluation and treatment, J Urol. source

      Not checked in the free run.

    • cites [130] Wajchenberg, 2000, Adrenocortical carcinoma: clinical and laboratory observations, Cancer. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Tumors with a PASS score >4 were defined as having malignant potential, whereas those with a lower score were considered benign.

    “Tumors with a PASS score >4 were defined as having malignant potential, whereas those with a lower score were considered benign.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [119] Thompson, 2002, Pheochromocytoma of the Adrenal gland Scaled Score (PASS) to separate benign from malignant neoplasms: a clinicopathologic and immunophenotypic study of 100 cases, Am J Surg Pathol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    The question of whether the Ki67 labeling index should be calculated as the average of the entire tumor specimen or the summation of hot spots in the specimens has not been resolved.

    “In particular, the question of whether the Ki67 labeling index should be calculated as the average of the entire tumor specimen or the summation of hot spots in the specimens has not been resolved (113).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [113] Nakamura, 2015, Adrenocortical carcinoma: review of the pathologic features, production of adrenal steroids, and molecular pathogenesis, Endocrinol Metab Clin North Am. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    The etiology of an AI is variable and includes tumors from the adrenal cortex, the adrenal medulla, and metastatic deposits.

    “The etiology of an AI is variable and includes tumors from the adrenal cortex, the adrenal medulla, and metastatic deposits.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Steroidogenic factor 1 is increasingly recognized as a key marker of adrenocortical cell lesions.

    “Steroidogenic factor 1 is increasingly recognized as a key marker of adrenocortical cell lesions (109).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [109] Erickson, 2018, Challenges in surgical pathology of adrenocortical tumours, Histopathology. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationcitation

    The authors of that study concluded that this detection bias may result in under-recognition of small (<30 mm) right-sided lesions and bilateral disease.

    “The authors concluded that this detection bias may result in under-recognition of small (<30 mm) right-sided lesions and bilateral disease (90).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [90] Hao, 2018, The lateralizing asymmetry of adrenal adenomas, J Endocr Soc. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The Helsinki score incorporates the Ki67 labeling index and has been proposed to be a better predictor of outcome.

    “The Helsinki score used in some centers incorporates the Ki67 labeling index and has been proposed to be a better predictor of outcome (118).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [118] Duregon, 2017, Validation of the prognostic role of the “Helsinki Score” in 225 cases of adrenocortical carcinoma, Hum Pathol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Kimura et al. developed the GAPP scoring system for prediction of metastases, consisting of a smaller number of pathological parameters with weighted scoring.

    “Subsequently, Kimura et al. (121) developed a less involved scoring system for prediction of metastases, Grading of Adrenal Pheochromocytoma and Paraganglioma (GAPP) consisting of a smaller number of pathological parameters with weighted scoring (1 or 2 points) including histological pattern; cellularity; comedo necrosis; capsular/vascular invasion; Ki67 proliferative index; and catecholamine phe”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [121] Kimura, 2014, Pathological grading for predicting metastasis in phaeochromocytoma and paraganglioma, Endocr Relat Cancer. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Many AIs, while picked up incidentally, may have clinical symptoms or associated signs on closer questioning and clinical examination.

    “Many AIs, while picked up incidentally, may have clinical symptoms or associated signs on closer questioning and clinical examination.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    The final diagnosis of ACC is histological and requires the input of an experienced adrenal pathologist.

    “Although there are several clinical, endocrinological and radiological features that help risk stratify an adrenal lesion with regard to the likelihood of ACC (see “Etiology and clinical presentation of AI”), the final diagnosis is a histological one and requires the input of an experienced adrenal pathologist (110).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [110] Papotti, 2014, Pathology of the adrenal cortex: a reappraisal of the past 25 years focusing on adrenal cortical tumors, Endocr Pathol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    A GAPP score of 0 to 2 is considered low risk, 3 to 6 intermediate risk, and 7 to 10 high risk.

    “A GAPP score of 0 to 2 is considered low risk, 3 to 6 intermediate risk, and 7 to 10 high risk.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [121] Kimura, 2014, Pathological grading for predicting metastasis in phaeochromocytoma and paraganglioma, Endocr Relat Cancer. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Adrenocortical tumors are usually (but not always) positive for Cytokeratin CAM 5.2, α-inhibin and calretinin, and pheochromocytomas are negative for these markers.

    “Adrenocortical tumors are also usually (but not always) positive (and pheochromocytomas negative) for Cytokeratin CAM 5.2, α-inhibin and calretinin.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [109] Erickson, 2018, Challenges in surgical pathology of adrenocortical tumours, Histopathology. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The higher detection of left-sided adrenal tumors may reflect a detection bias as left-sided adrenal tumors may be more readily apparent to the radiologist.

    “This observation may reflect a detection bias as left-sided adrenal tumors may be more readily apparent to the radiologist.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Both adrenocortical tumors and pheochromocytomas stain positive for synaptophysin, but adrenocortical tumors are negative for chromogranin.

    “Both adrenocortical tumors and pheochromocytomas stain positive for synaptophysin but adrenocortical tumors are negative for chromogranin (109).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [109] Erickson, 2018, Challenges in surgical pathology of adrenocortical tumours, Histopathology. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Primary adrenocortical carcinoma is rare, with an estimated population incidence of 1 to 2 per million per year.

    “Primary ACC is rare, with an estimated population incidence of 1 to 2 per million per year (126,127).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [126] Allolio, 2006, Clinical review: adrenocortical carcinoma: clinical update, J Clin Endocrinol Metab. source

      Not checked in the free run.

    • cites [127] Ng, 2003, Adrenocortical carcinoma: diagnosis, evaluation and treatment, J Urol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both adrenocortical cancers and melanomas stain positive for Melan A, but adrenocortical tumors are negative for S100 (a positive marker for melanoma).

    “Both adrenocortical cancers and melanomas stain positive for Melan A, but adrenocortical tumors are negative for S100 (a positive marker for melanoma).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [109] Erickson, 2018, Challenges in surgical pathology of adrenocortical tumours, Histopathology. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the initial study by Weiss, the features with the strongest association to outcome were mitotic rate >5/50 high powered field, atypical mitoses, and venous invasion; in the second study by Weiss in 1989, the strongest association with patient outcome was the mitotic rate.

    “In the initial study by Weiss, the features with the strongest association to outcome were the mitotic rate >5/50 high powered field, atypical mitoses, and venous invasion (111) and in the second study by Weiss in 1989 the strongest association with patient outcome was the mitotic rate (112).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [111] Weiss, 1984, Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors, Am J Surg Pathol. source

      Not checked in the free run.

    • cites [112] Weiss, 1989, Pathologic features of prognostic significance in adrenocortical carcinoma, Am J Surg Pathol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mutations in KCNJ5, CACNA1H, ATP1A1, ATP2B3, and CACNA1D account for approximately 50% of aldosterone-producing adrenal adenomas in patients from Europe, and this is likely to be higher in Asian patients.

    “Mutations in KCNJ5, CACNA1H, ATP1A1, ATP2B3, and CACNA1D account for approximately 50% of aldosterone-producing adrenal adenomas (159) in patients from Europe; this is likely to be higher in Asian patients.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [159] Fernandes-Rosa, 2014, Genetic spectrum and clinical correlates of somatic mutations in aldosterone-producing adenoma, Hypertension. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Loss of heterozygosity at the 11p15 locus can lead to insulin-like growth factor-2 overexpression, which is associated with malignant adrenocortical carcinomas.

    “Loss of heterozygosity at the 11p15 locus can lead to insulin-like growth factor-2 overexpression which is associated with malignant ACCs (166,167).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [166] Gicquel, 1994, Rearrangements at the 11p15 locus and overexpression of insulin-like growth factor-II gene in sporadic adrenocortical tumors, J Clin Endocrinol Metab.

      Not checked in the free run.

    • cites [167] Gicquel, 1997, Structural and functional abnormalities at 11p15 are associated with the malignant phenotype in sporadic adrenocortical tumors: study on a series of 82 tumors, J Clin Endocrinol Metab.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Adenomas with KCNJ5 mutations tend to be larger than those without the mutation and appear to be more common in women than men.

    “Adenomas with KCNJ5 mutations tend to be larger than those which do not carry the mutation and appear to be more common in women than men (154).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [154] Åkerström, 2012, Comprehensive re-sequencing of adrenal aldosterone producing lesions reveal three somatic mutations near the KCNJ5 potassium channel selectivity filter, PLoS One. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Adrenocortical carcinomas have been noted in familial adenomatous polyposis, neurofibromatosis type 1, and Carney complex.

    “ACCs have also been noted in familial adenomatous polyposis (FAP gene), neurofibromatosis type 1 (NF1 gene), and Carney complex (PRKAR1A gene) (161).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [161] Else, 2014, Adrenocortical carcinoma, Endocr Rev. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Mutations in CTNNB1 are present in adrenocortical carcinomas and may be associated with poor outcome.

    “As previously described, mutations in CTNNB1 are also present in ACCs and may be associated with poor outcome (164).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [164] Gaujoux, 2011, β-Catenin activation is associated with specific clinical and pathologic characteristics and a poor outcome in adrenocortical carcinoma, Clin Cancer Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In an Italian study of 887 patients with adrenal incidentalomas, 90% of adrenocortical carcinomas had a diameter greater than 4 cm at presentation, and a 4-cm cut-off had 93% sensitivity for detecting adrenocortical carcinoma.

    “In an Italian study of 887 patients with AIs, 90% of ACCs had a diameter of greater than 4 cm at presentation, with a 4-cm cut-off having a 93% sensitivity for detecting ACC (64).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [64] Mantero, 2000, Management approaches to adrenal incidentalomas. A view from Ancona, Italy, Endocrinol Metab Clin North Am. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The size of an adrenal mass is predictive, but not 100% predictive, of malignancy.

    “The size of the adrenal mass is predictive (but not 100%) of malignancy.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Adrenocortical carcinoma is rare and aggressive and can occur at any age, but peak incidence tends to be before age 5 and between ages 40 and 60.

    “ACC is rare and aggressive and can occur at any age. However, peak incidence tends to be before the age of 5 and between the ages of 40 and 60 years of age (126,127).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [126] Allolio, 2006, Clinical review: adrenocortical carcinoma: clinical update, J Clin Endocrinol Metab. source

      Not checked in the free run.

    • cites [127] Ng, 2003, Adrenocortical carcinoma: diagnosis, evaluation and treatment, J Urol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The Wnt signaling pathway is thought to be important in the embryonic development of the adrenal gland.

    “The Wnt signaling pathway is thought to be important in the embryonic development of the adrenal gland (139).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [139] Kim, 2008, Targeted disruption of beta-catenin in Sf1-expressing cells impairs development and maintenance of the adrenal cortex, Development. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Somatic activating mutations of PRKACA are implicated in up to 50% of patients with adenomas with clinical Cushing's syndrome, but not in adenomas producing less cortisol.

    “Somatic activating mutations of protein kinase A catalytic subunit (PRKACA) has been implicated in up to 50% of patients with adenomas with clinical Cushing’s syndrome, but not in adenomas producing less cortisol (138,142,147).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [138] Bonnet-Serrano, 2018, Genetics of tumors of the adrenal cortex, Endocr Relat Cancer. source

      Not checked in the free run.

    • cites [142] Sato, 2014, Recurrent somatic mutations underlie corticotropin-independent Cushing’s syndrome, Science. source

      Not checked in the free run.

    • cites [147] Beuschlein, 2013, Constitutive activation of PKA catalytic subunit in adrenal Cushing’s syndrome, N Engl J Med. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Mutations in beta-catenin (CTNNB1) leading to constitutive activation of the Wnt signaling pathway are a frequent finding in benign and malignant adrenocortical tumors.

    “Mutations in β -catenin (CTNNB1) leading to constitutive activation of the Wnt signaling pathway is a frequent finding in benign and malignant adrenocortical tumors (138).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [138] Bonnet-Serrano, 2018, Genetics of tumors of the adrenal cortex, Endocr Relat Cancer. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Constitutive activation of the Wnt signaling pathway is implicated in cancer development in several other organs.

    “Constitutive activation of this pathway is also implicated in cancer development in several other organs (140).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [140] Polakis, 2000, Wnt signaling and cancer, Genes Dev. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PRKACA mutations may be associated with smaller adenomas but higher levels of cortisol production than adenomas without the mutation.

    “Mutations in PRKACA may be associated with smaller adenomas but higher levels of cortisol production than adenomas where this mutation is not present (143,148).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [143] Ronchi, 2016, Genetic landscape of sporadic unilateral adrenocortical adenomas without PRKACA p.Leu206Arg mutation, J Clin Endocrinol Metab. source

      Not checked in the free run.

    • cites [148] Di Dalmazi, 2014, Novel somatic mutations in the catalytic subunit of the protein kinase A as a cause of adrenal Cushing’s syndrome: a European multicentric study, J Clin Endocrinol Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    KCNJ5 mutations have been documented in approximately 40% of patients with aldosterone-producing adenomas from European cohorts, with much higher rates reported in patients from Japan and Asia.

    “Mutations in KCNJ5 (potassium channel) have been documented in patients with aldosterone-producing adenomas in approximately 40% of patients (151) from European cohorts, though much higher rates are reported in patients from Japan and Asia (152,153).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [151] Boulkroun, 2012, Prevalence, clinical, and molecular correlates of KCNJ5 mutations in primary aldosteronism, Hypertension. source

      Not checked in the free run.

    • cites [152] Zheng, 2015, Clinical characteristics of somatic mutations in Chinese patients with aldosterone-producing adenoma, Hypertension. source

      Not checked in the free run.

    • cites [153] Felizola, 2015, Pre-B lymphocyte protein 3 (VPREB3) expression in the adrenal cortex: precedent for non-immunological roles in normal and neoplastic human tissues, Endocr Pathol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ARMC5 is a putative tumor suppressor with two hits in each adrenal nodule: a first germline alteration found in leukocyte DNA and common to all nodules, and a second somatic hit.

    “ARMC5 is a putative tumor suppressor, with 2 hits in each adrenal nodule: a first germline alteration, found in leukocyte DNA and common to all nodules, and a second somatic hit (171).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [171] Assié, 2013, ARMC5 mutations in macronodular adrenal hyperplasia with Cushing’s syndrome, N Engl J Med. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Cortisol hypersecretion leading to clinically evident Cushing's syndrome is recognized as a significant cause of morbidity and mortality due to increased risk of infection, metabolic, bone, and vascular complications.

    “However, cortisol hypersecretion leading to clinically evident Cushing’s syndrome is recognized as a significant cause of morbidity and mortality (134,135) due to increased risk of infection, metabolic, bone, and vascular complications (136).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [134] Lindholm, 2001, Incidence and late prognosis of Cushing’s syndrome: a population-based study, J Clin Endocrinol Metab.

      Not checked in the free run.

    • cites [135] Clayton, 2016, Mortality in patients with Cushing’s disease more than 10 years after remission: a multicentre, multinational, retrospective cohort study, Lancet Diabetes Endocrinol. source

      Not checked in the free run.

    • cites [136] Vanbrabant, 2018, Influence of hormonal functional status on survival in adrenocortical carcinoma: systematic review and meta-analysis, Eur J Endocrinol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    KCNJ5 mutations lead to increased sodium conductance and cellular depolarization, leading to calcium influx, increased intracellular calcium signaling, and increased CYP11B2 mRNA expression with increased aldosterone production and glomerulosa cell proliferation.

    “These mutations lead to increased sodium conductance and cellular depolarization leading to calcium influx, increased intracellular calcium signaling, and increased CYP11B2 mRNA expression with increased aldosterone production and glomerulosa cell proliferation (123).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [123] Kamilaris, 2018, An update on adrenal endocrinology: significant discoveries in the last 10 years and where the field is heading in the next decade, Hormones (Athens). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In aldosterone-producing adenomas without KCNJ5 mutations, ATP1A1 abnormalities were found in 5.2% and ATP2B3 abnormalities in 1.6%, and these mutations were associated with increased plasma aldosterone concentrations and lower potassium concentrations than cases without the mutation.

    “In aldosterone-producing adenomas that did not have KCNJ5 mutations, abnormalities in ATP1A1 (encoding a Na+/K+ ATPase α subunit) were found in 5.2% and of ATP2B3 (encoding a Ca2+ ATPase) in 1.6%, with these mutations associated with increased plasma aldosterone concentrations and lower potassium concentrations than cases without the mutation (156).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [156] Beuschlein, 2013, Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension, Nat Genet. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Pan-genomic characterization of adrenocortical carcinomas has identified several other driver genes including CDKN2A, RB1, DAXX, TERT, MED12, PRKAR1A, RPL22, TERF2, CCNE1, and NF-1.

    “Pan-genomic characterization of ACCs has identified several other driver genes including CDKN2A, RB1, DAXX, TERT, MED12, PRKAR1A, RPL22, TERF2, CCNE1, and NF-1 (165,168).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [165] Assié, 2014, Integrated genomic characterization of adrenocortical carcinoma, Nat Genet. source

      Not checked in the free run.

    • cites [168] Zheng, 2016, Comprehensive pan-genomic characterization of adrenocortical carcinoma, Cancer Cell. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Most cases of adrenocortical carcinoma are sporadic, but some occur with other tumor syndromes.

    “Most cases of ACC are sporadic but some are known to occur with other tumor syndromes (160).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [160] Koch, 2002, The molecular pathogenesis of hereditary and sporadic adrenocortical and adrenomedullary tumors, J Clin Endocrinol Metab. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Although the majority of adrenal incidentalomas are unilateral, bilateral adrenal incidentalomas may be found in 10% to 15% of cases.

    “Although the majority of AIs are unilateral, bilateral AIs may be found in 10% to 15% of cases (169).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [169] Angeli, 1997, Adrenal incidentaloma: an overview of clinical and epidemiological data from the National Italian Study Group, Horm Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Autonomous cortisol secretion in patients with adrenal incidentaloma has been associated with hypertension, insulin resistance, type 2 diabetes mellitus, obesity, metabolic syndrome, and increased mortality.

    “Despite the absence of florid signs and symptoms, ACS in patients AI has been associated with hypertension (215), insulin resistance (216), type 2 diabetes mellitus (217), obesity (218), metabolic syndrome (219), and increased mortality (75).”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [215] Terzolo, 2005, Subclinical Cushing’s syndrome in adrenal incidentalomas, Endocrinol Metab Clin North Am. source

      Not checked in the free run.

    • cites [216] Reincke, 1996, Adrenal incidentalomas: a manifestation of the metabolic syndrome?, Endocr Res. source

      Not checked in the free run.

    • cites [217] Fernández-Real, 1998, Study of glucose tolerance in consecutive patients harbouring incidental adrenal tumours. Study Group of Incidental Adrenal Adenoma, Clin Endocrinol (Oxf). source

      Not checked in the free run.

    • cites [218] Terzolo, 2005, Midnight serum cortisol as a marker of increased cardiovascular risk in patients with a clinically inapparent adrenal adenoma, Eur J Endocrinol. source

      Not checked in the free run.

    • cites [219] Tauchmanovà, 2002, Patients with subclinical Cushing’s syndrome due to adrenal adenoma have increased cardiovascular risk, J Clin Endocrinol Metab. source

      Not checked in the free run.

    • cites [75] Giordano, 2010, Long-term morphological, hormonal, and clinical follow-up in a single unit on 118 patients with adrenal incidentalomas, Eur J Endocrinol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The annual incidence of pheochromocytoma is estimated at 0.8 per 100,000 person-years.

    “The annual incidence of pheochromocytoma is estimated at 0.8 per 100 000 person-years (177).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [177] Beard, 1983, Occurrence of pheochromocytoma in Rochester, Minnesota, 1950 through 1979, Mayo Clin Proc.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ARMC5 overexpression induces apoptosis in vitro and its inactivation decreases steroidogenesis.

    “ARMC5 overexpression induces apoptosis in vitro and its inactivation decreases steroidogenesis (171).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [171] Assié, 2013, ARMC5 mutations in macronodular adrenal hyperplasia with Cushing’s syndrome, N Engl J Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hypertension is a common sign of pheochromocytoma, but 5% to 15% of patients may have normal blood pressure at presentation, particularly those with incidentaloma or familial screening.

    “Hypertension is a common sign of pheochromocytoma, but 5% to 15% of patients may have normal blood pressure at presentation, particularly in those with incidentaloma or having familial screening where the tumor may be smaller and less functionally active at presentation (190).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [190] Manger, 2002, Pheochromocytoma, J Clin Hypertens (Greenwich). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Headache occurs in up to 90% of symptomatic patients with pheochromocytoma, with sweating in 60% to 70%.

    “Headache occurs in up to 90% of symptomatic patients (190) with sweating in 60% to 70%.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [190] Manger, 2002, Pheochromocytoma, J Clin Hypertens (Greenwich). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Late-night salivary cortisol is emerging as perhaps the most accurate test in diagnosing overt Cushing's syndrome, but for autonomous cortisol secretion published studies have given mixed results; in some cases sensitivity reached 93.8% with specificity of 79.5%.

    “LNSC is emerging as perhaps the most accurate test in diagnosing overt Cushing’s syndrome (240), but for ACS the published studies have given mixed results. In some cases, sensitivity reached 93.8%, but with relatively poor specificity at 79.5% (227) (Table 6).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [240] Elamin, 2008, Accuracy of diagnostic tests for Cushing’s syndrome: a systematic review and metaanalyses, J Clin Endocrinol Metab. source

      Not checked in the free run.

    • cites [227] Ferreira, 2018, Screening tests for hypercortisolism in patients with adrenal incidentaloma

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    An Italian study diagnosed autonomous cortisol secretion based on 2 out of 3 tests: serum cortisol greater than 3 μg/dL after 1 mg overnight dexamethasone suppression, urine free cortisol greater than 70 μg/24 hours, or ACTH less than 10 pg/mL.

    “An Italian study diagnosed ACS based on 2 out of the following 3 tests: serum cortisol >3 µg/dL (83 nmol/L) after 1 mg of ONDST, UFC >70 µg/24 hours (193 nmol/24 hours) or ACTH <10 pg/mL (2.2 pmol/L) (228).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [228] Ceccato, 2017, First-line screening tests for Cushing’s syndrome in patients with adrenal incidentaloma: the role of urinary free cortisol measured by LC-MS/MS, J Endocrinol Invest. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A post-dexamethasone cortisol level of 1.8 μg/dL or less is considered normal and excludes cortisol excess in most patients.

    “A post-dexamethasone cortisol level ≤1.8 µg/dL (≤50 nmol/L) is considered “normal” and excludes cortisol excess in most patients.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Primary adrenal lymphoma accounts for less than 1% of all cases of non-Hodgkin lymphoma.

    “Conversely primary adrenal lymphoma is much rarer accounting for <1% of all cases of non-Hodgkin lymphoma (183).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [183] Singh, 2004, Adrenal involvement in non-Hodgkin’s lymphoma: four cases and review of literature, Leuk Lymphoma. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Patients with familial pheochromocytoma may be asymptomatic in 50% of cases, with only a third presenting with hypertension.

    “Patients with familial pheochromocytoma may be asymptomatic in 50% of cases, with only a third presenting with hypertension, possibly representing earlier diagnosis and smaller lesions as a result of regular screening in these patients (195,196).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [195] Pomares, 1998, Differences between sporadic and multiple endocrine neoplasia type 2A phaeochromocytoma, Clin Endocrinol (Oxf). source

      Not checked in the free run.

    • cites [196] Walther, 1999, Clinical and genetic characterization of pheochromocytoma in von Hippel-Lindau families: comparison with sporadic pheochromocytoma gives insight into natural history of pheochromocytoma, J Urol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In one series of 464 patients with metastatic adrenal gland lesions, 90% were carcinomas, with the others being hematological, sarcomas, or melanomas.

    “In one series of 464 patients with metastatic adrenal gland lesions, 90% were carcinomas, with the others being hematological, sarcomas, or melanomas.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [186] Lam, 2002, Metastatic tumours of the adrenal glands: a 30-year experience in a teaching hospital, Clin Endocrinol (Oxf). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pheochromocytoma may present incidentally, but on closer questioning approximately 50% of cases have classical paroxysmal symptoms of sweating, headache, and tachycardia.

    “Pheochromocytoma may present incidentally, but on closer questioning, approximately 50% of cases have classical paroxysmal symptoms of sweating, headache, and tachycardia (189).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [189] Pacak, 2001, Recent advances in genetics, diagnosis, localization, and treatment of pheochromocytoma, Ann Intern Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Urine free cortisol in isolation has a low sensitivity (31.8-76.0%) in diagnosing autonomous cortisol secretion, but this can be improved by LC-MS/MS methodology to a sensitivity of 98% and specificity of 91%.

    “UFC in isolation has a low sensitivity (31.8-76.0%) in diagnosing ACS but this can be improved by LC-MS/MS methodology (sensitivity 98%, specificity 91%, and negative/positive likelihood ratios of 0.02/10.83, respectively).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Of carcinomas metastatic to the adrenal gland, the most common primary site in 35% of cases was lung, followed by gastrointestinal, kidney, and breast.

    “Of the carcinomas, the most common primary site in 35% of cases was lung, followed by gastrointestinal, kidney, and breast.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [186] Lam, 2002, Metastatic tumours of the adrenal glands: a 30-year experience in a teaching hospital, Clin Endocrinol (Oxf). source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Cortisol levels between 1.9 and 5.0 μg/dL may indicate possible autonomous cortisol secretion, and cortisol levels above 5.0 μg/dL are suggested to confirm autonomous cortisol secretion.

    “Levels between 1.9 and 5.0 μg/dL (50-140 nmol/L) may indicate “possible autonomous cortisol secretion,” and cortisol levels above 5.0 μg/dL (140 nmol/L) are suggested to confirm ACS (79,220).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [79] Di Dalmazi, 2014, Cardiovascular events and mortality in patients with adrenal incidentalomas that are either non-secreting or associated with intermediate phenotype or subclinical Cushing’s syndrome: a 15-year retrospective study, Lancet Diabetes Endocrinol. source

      Not checked in the free run.

    • cites [220] Debono, 2014, Cortisol as a marker for increased mortality in patients with incidental adrenocortical adenomas, J Clin Endocrinol Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Even at a cut-off concentration of 140 nmol/L, specificity of the 1-mg dexamethasone suppression test is only 95%, and a false positive result is far more likely than a true positive.

    “Even at a cut-off concentration of 140 nmol/L specificity is only 95%; the investigator must consider that a false positive result is far more likely than a true positive (45).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Cawood, 2009, Recommended evaluation of adrenal incidentalomas is costly, has high false-positive rates and confers a risk of fatal cancer that is similar to the risk of the adrenal lesion becoming malignant; time for a rethink?, Eur J Endocrinol. source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Sensitivity of the 1-mg dexamethasone suppression test increases as the cut-off is lowered from 80% at 140 nmol/L to 95% at 50 nmol/L, but this is offset by lower specificity, such that at a cut-off of 50 nmol/L 20% of the normal population will fail to suppress cortisol.

    “Sensitivity increases as the stringency of the “cut-off” is lowered; from 80% at a cut off of 140 nmol/L to 95% at 50 nmol/L, but this is offset by lower specificity, such that at a cut off of 50 nmol/L 20% of the “normal” population will fail to suppress cortisol.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Specificity rates of 85% to 89% for metanephrine testing decrease to 77% in elderly people and can be improved by using age-adjusted reference ranges.

    “Specificity rates of 85% to 89% decrease to 77% in elderly people and can be improved by using age-adjusted reference ranges (204-206).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [204] Eisenhofer, 2013, Reference intervals for plasma free metanephrines with an age adjustment for normetanephrine for optimized laboratory testing of phaeochromocytoma, Ann Clin Biochem. source

      Not checked in the free run.

    • cites [205] Eisenhofer, 2018, Biochemical diagnosis of chromaffin cell tumors in patients at high and low risk of disease: plasma versus urinary free or deconjugated O-methylated catecholamine metabolites, Clin Chem. source

      Not checked in the free run.

    • cites [206] Papathomas, 2019, Novel methods in adrenal research: a metabolomics approach, Histochem Cell Biol. source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Plasma free or 24-hour urine fractionated metanephrines are recommended as the screening test of choice for pheochromocytoma with a sensitivity of 90% to 95%.

    “Plasma free or 24-hour urine fractionated metanephrines are recommended as the screening test of choice for pheochromocytoma with a sensitivity of 90% to 95% (202, 203).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [202] Därr, 2017, Accuracy of recommended sampling and assay methods for the determination of plasma-free and urinary fractionated metanephrines in the diagnosis of pheochromocytoma and paraganglioma: a systematic review, Endocrine. source

      Not checked in the free run.

    • cites [203] Lenders, 2002, Biochemical diagnosis of pheochromocytoma: which test is best?, JAMA. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Adrenal gland involvement is seen in up to 25% of patients with non-Hodgkin lymphoma, usually as part of disseminated disease.

    “Adrenal gland involvement is well recognized and seen in up to 25% of patients with non-Hodgkin lymphoma usually as part of disseminated disease (182).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [182] Rosenberg, 1961, Lymphosarcoma: a review of 1269 cases, Medicine (Baltimore). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mean Hounsfield unit scores for pheochromocytoma are 30 to 35, with only 0.5% of pheochromocytomas having an unenhanced CT attenuation of 10 HU or less.

    “Mean HU scores for pheochromocytoma are 30 to 35 (197) with only 0.5% of pheochromocytoma having an unenhanced CT attenuation of ≤10 HU (97,197,198).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [197] Buitenwerf, 2018, Unenhanced CT imaging is highly sensitive to exclude pheochromocytoma: a multicenter study, Eur J Endocrinol. source

      Not checked in the free run.

    • cites [97] Xing, 2015, Development of adrenal cortex zonation, Endocrinol Metab Clin North Am. source

      Not checked in the free run.

    • cites [198] Blake, 2003, Low-density pheochromocytoma on CT: a mimicker of adrenal adenoma, AJR Am J Roentgenol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Canu et al. identified 2 (0.5%) of 376 histologically proven pheochromocytomas with an unenhanced CT attenuation value of exactly 10 HU, and 99.5% had a HU greater than 10.

    “Canu et al. (188) identified 2 (0.5%) of 376 histologically proven pheochromocytomas with unenhanced CT attenuation value of exactly 10 HU, 99.5% (n = 374) had a HU > 10.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [188] Canu, 2019, CT characteristics of pheochromocytoma: relevance for the evaluation of adrenal incidentaloma, J Clin Endocrinol Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chronic glucocorticoid excess decreases bone mineral density and leads to osteoporosis.

    “the deleterious effects of chronic glucocorticoid excess on bone mineral density leading to osteoporosis are well established (258).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [258] Hardy, 2018, Glucocorticoids and bone: consequences of endogenous and exogenous excess and replacement therapy, Endocr Rev. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Metabolic improvement after adrenalectomy, including weight loss, blood pressure lowering, glucose tolerance, lower lipids, and beneficial effects on bone, has been reported.

    “Metabolic improvement after adrenalectomy, including weight loss, blood pressure lowering, glucose tolerance, lower lipids, and beneficial effects on bone have been reported (230,267).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [230] Chiodini, 2010, Beneficial metabolic effects of prompt surgical treatment in patients with an adrenal incidentaloma causing biochemical hypercortisolism, J Clin Endocrinol Metab. source

      Not checked in the free run.

    • cites [267] Perogamvros, 2015, Biochemical and clinical benefits of unilateral adrenalectomy in patients with subclinical hypercortisolism and bilateral adrenal incidentalomas, Eur J Endocrinol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Most studies of surgical intervention for ACS involve small numbers and are retrospective, uncontrolled, and lack randomization.

    “Several studies have reported the outcome of surgical intervention but most involve small numbers and are retrospective, uncontrolled, and lack randomization (230,243,250-253,255) (Table 7).”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [230] Chiodini, 2010, Beneficial metabolic effects of prompt surgical treatment in patients with an adrenal incidentaloma causing biochemical hypercortisolism, J Clin Endocrinol Metab. source

      Not checked in the free run.

    • cites [243] Tsuiki, 2008, Cardiovascular risks and their long-term clinical outcome in patients with subclinical Cushing’s syndrome, Endocr J. source

      Not checked in the free run.

    • cites [250] Perysinakis, 2013, Laparoscopic adrenalectomy in patients with subclinical Cushing syndrome, Surg Endosc. source

      Not checked in the free run.

    • cites [251] Iacobone, 2012, Adrenalectomy may improve cardiovascular and metabolic impairment and ameliorate quality of life in patients with adrenal incidentalomas and subclinical Cushing’s syndrome, Surgery. source

      Not checked in the free run.

    • cites [252] Maehana, 2012, Clinical outcomes of surgical treatment and longitudinal non-surgical observation of patients with subclinical Cushing’s syndrome and nonfunctioning adrenocortical adenoma, Indian J Urol. source

      Not checked in the free run.

    • cites [253] Guerrieri, 2010, Primary adrenal hypercortisolism: minimally invasive surgical treatment or medical therapy? A retrospective study with long-term follow-up evaluation, Surg Endosc. source

      Not checked in the free run.

    • cites [255] Toniato, 2009, Surgical versus conservative management for subclinical Cushing syndrome in adrenal incidentalomas: a prospective randomized study, Ann Surg. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A few publications have reported normotensive PA in AI; most of these patients demonstrated occasional hypokalemia.

    “A few publications have reported normotensive PA in AI; however, most of these patients demonstrated occasional hypokalemia (8,272-274).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [8] Muth, 2017, Swedish guidelines for the management of adrenal incidentalomas, Lakartidningen

      Not checked in the free run.

    • cites [272] Markou, 2013, Evidence of primary aldosteronism in a predominantly female cohort of normotensive individuals: a very high odds ratio for progression into arterial hypertension, J Clin Endocrinol Metab. source

      Not checked in the free run.

    • cites [273] Médeau, 2008, Clinical and biochemical characteristics of normotensive patients with primary aldosteronism: a comparison with hypertensive cases, Clin Endocrinol (Oxf). source

      Not checked in the free run.

    • cites [274] Moradi, 2016, A woman with normotensive primary hyperaldosteronism, Acta Med Iran.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Adrenalectomy improves cardiovascular outcome and mortality in ACS patients.

    “A recent systematic review addressed cardiovascular benefit in ACS patients (247) with adrenalectomy improving cardiovascular outcome and mortality (4,247).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [4] Fassnacht, 2016, Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors, Eur J Endocrinol. source

      Not checked in the free run.

    • cites [247] Park, 2019, Cardiovascular outcomes in autonomous cortisol secretion and nonfunctioning adrenal adenoma: a systematic review, J Endocr Soc. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A study with up to 15 years of follow-up in patients with autonomous cortisol secretion documented increased cardiovascular morbidity (43% vs 8.8%, P < .005) and mortality (22.6% vs 2.5%, P < .02) compared with nonfunctioning adrenal incidentaloma.

    “A study with up to 15 years of follow-up in patients with ACS has documented increased cardiovascular morbidity (43% vs 8.8%, P < .005) and mortality (22.6% vs 2.5%, P < .02) in ACS patients compared with nonfunctioning AI.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [220] Debono, 2014, Cortisol as a marker for increased mortality in patients with incidental adrenocortical adenomas, J Clin Endocrinol Metab. source

      Not checked in the free run.

    • cites [247] Park, 2019, Cardiovascular outcomes in autonomous cortisol secretion and nonfunctioning adrenal adenoma: a systematic review, J Endocr Soc. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Impaired glucose tolerance or diabetes has been reported to occur in 10% to 69% of patients with autonomous cortisol secretion.

    “Impaired glucose tolerance or diabetes has been reported to occur in 10% to 69% of patients with ACS (249) and improved glycemic control (and in some cases reversal of diabetes) following surgery is reported in some studies but not others (Table 7).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [249] Di Dalmazi, 2015, Steroid profiling by LC-MS/MS in nonsecreting and subclinical cortisol-secreting adrenocortical adenomas, J Clin Endocrinol Metab. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Chemical shift MRI to detect intracellular fat within lipid-rich adrenal adenomas was first described in 1992.

    “The use of chemical shift MRI to detect intracellular fat within lipid-rich adrenal adenomas and differentiate these from other lesions was first described in 1992 (310) (Fig. 7).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [310] Platzek, 2019, Chemical shift imaging for evaluation of adrenal masses: a systematic review and meta-analysis, Eur Radiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    False-negative FDG PET-CT findings are recognized in small malignant lesions, metastases from non-FDG avid tumors, and necrotic lesions.

    “False-negative findings are recognized in the setting of small malignant lesions, metastases from non-FDG avid tumors such as some subtypes of renal carcinoma and well-differentiated neuroendocrine malignancies and in necrotic lesions (315).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [315] Metser, 2006, 18F-FDG PET/CT in the evaluation of adrenal masses, J Nucl Med.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Elevated sex steroids are highly suspicious for ACC and urgent diagnostic evaluation is required.

    “Although benign cortisol-secreting adenomas may very rarely produce androgens (286), elevated sex steroids are highly suspicious for ACC and urgent diagnostic evaluation is required (287-289).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [287] Fassnacht, 2011, Adrenocortical carcinoma: a clinician’s update, Nat Rev Endocrinol. source

      Not checked in the free run.

    • cites [288] Moreno, 2006, Feminizing adreno-cortical carcinomas in male adults. A dire prognosis. Three cases in a series of 801 adrenalectomies and review of the literature, Ann Endocrinol (Paris). source

      Not checked in the free run.

    • cites [289] Moreno, 2004, Profile and outcome of pure androgen-secreting adrenal tumors in women: experience of 21 cases, Surgery. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Diabetes/metabolic syndrome, renal damage, impaired bone mineral density, and osteoporosis have been reported more prevalent in AI patients with PA.

    “Diabetes mellitus/metabolic syndrome (278,279), renal damage (280), impaired bone mineral density (81), and osteoporosis (264,281,282) have also been reported to be more prevalent in AI patients with PA.”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [278] Monticone, 2018, Cardiovascular events and target organ damage in primary aldosteronism compared with essential hypertension: a systematic review and meta-analysis, Lancet Diabetes Endocrinol. source

      Not checked in the free run.

    • cites [279] Hundemer, 2018, Cardiometabolic outcomes and mortality in medically treated primary aldosteronism: a retrospective cohort study, Lancet Diabetes Endocrinol. source

      Not checked in the free run.

    • cites [280] Rossi, 2006, Renal damage in primary aldosteronism: results of the PAPY study, Hypertension. source

      Not checked in the free run.

    • cites [81] Ahn, 2018, Characteristics of adrenal incidentalomas in a large, prospective computed tomography-based multicenter study: the COAR study in Korea, Yonsei Med J. source

      Not checked in the free run.

    • cites [264] Chiodini, 2009, Bone mineral density, prevalence of vertebral fractures, and bone quality in patients with adrenal incidentalomas with and without subclinical hypercortisolism: an Italian multicenter study, J Clin Endocrinol Metab. source

      Not checked in the free run.

    • cites [281] Arlt, 2017, Steroid metabolome analysis reveals prevalent glucocorticoid excess in primary aldosteronism, JCI Insight. source

      Not checked in the free run.

    • cites [282] Salcuni, 2017, Primary aldosteronism as a cause of secondary osteoporosis, Eur J Endocrinol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Virtual non-contrast CT images from dual-energy CT demonstrate comparable sensitivity with standard noncontrast CT for diagnosis of lipid-rich adenomas, but data limited.

    “A recent systematic review and meta-analysis reported that virtual non-contrast CT images generated from dual-energy CT demonstrate comparable sensitivity with standard noncontrast CT for diagnosis of lipid-rich adenomas, but data were only available from a small number of heterogeneous studies at high risk of bias (306).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [306] Connolly, 2017, Diagnostic accuracy of virtual non-contrast enhanced dual-energy CT for diagnosis of adrenal adenoma: a systematic review and meta-analysis, Eur Radiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Only 1 previous study evaluated test performance of CT contrast-enhanced washout in truly incidentally discovered adrenal masses; it reported sensitivity 96% and specificity 95% for differentiating benign from malignant adrenal lesions, but considered only 50 cases.

    “However, only 1 previous study has evaluated the test performance of CT contrast-enhanced washout in the evaluation of truly incidentally discovered adrenal masses (301), that is in patients not undergoing surveillance imaging for previous nonadrenal malignancy. This study reported high sensitivity (96%) and specificity (95%) for differentiating benign from malignant adrenal lesions (301); however”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [301] Angelelli, 2013, MDCT in the differentiation of adrenal masses: comparison between different scan delays for the evaluation of intralesional washout, ScientificWorldJournal. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Visual and quantitative analysis of adrenal signal intensity index and adrenal-to-spleen ratio have high accuracy (95-98%) for lipid-rich adenoma detection; diagnostic performance not significantly improved by these indices.

    “A recent systematic review and meta-analysis reported that visual analysis and quantitative analysis of adrenal signal intensity index and adrenal-to-spleen ratio all have high accuracy for lipid-rich adenoma detection (95-98%), and diagnostic performance is not significantly improved by adrenal signal intensity index or the adrenal-to-spleen ratio (310).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [310] Platzek, 2019, Chemical shift imaging for evaluation of adrenal masses: a systematic review and meta-analysis, Eur Radiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PA is associated with increased risk of stroke, coronary artery disease, atrial fibrillation, heart failure, and mortality compared with matched essential hypertension.

    “PA is associated with an increased risk of stroke (odds ratio [OR] 2.58, 95% CI 1.93-3.45), coronary artery disease (1.77, 1.10-2.83), atrial fibrillation (3.52, 2.06-5.99), heart failure (2.05, 1.11-3.78), and mortality (hazard ratio [HR] 1.34, 95% CI 1.06-1.71) compared with matched populations with essential hypertension (278,279).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [278] Monticone, 2018, Cardiovascular events and target organ damage in primary aldosteronism compared with essential hypertension: a systematic review and meta-analysis, Lancet Diabetes Endocrinol. source

      Not checked in the free run.

    • cites [279] Hundemer, 2018, Cardiometabolic outcomes and mortality in medically treated primary aldosteronism: a retrospective cohort study, Lancet Diabetes Endocrinol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a large Italian study (n=887), 90% of ACCs had diameter >4 cm at presentation; 4-cm cut-off had 93% sensitivity for detecting ACCs.

    “A large Italian study of patients with AI (n = 887) reported that 90% of ACCs had a diameter of >4 cm at presentation, a 4-cm cut-off had a 93% sensitivity for detecting ACCs (64, 137).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [64] Mantero, 2000, Management approaches to adrenal incidentalomas. A view from Ancona, Italy, Endocrinol Metab Clin North Am. source

      Not checked in the free run.

    • cites [137] Henley, 1983, Adrenal cortical carcinoma–a continuing challenge, Surgery.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Approximately 30% of benign adrenal adenomas are lipid-poor (attenuation >10 HU) and cannot be reliably characterized on unenhanced CT due to overlapping density with malignant lesions and pheochromocytomas.

    “Approximately 30% of benign adrenal adenomas do not contain large amounts of fat and have an attenuation value of >10 HU (ie, lipid-poor adenomas), these lesions cannot be reliably characterized on unenhanced CT due to an overlapping density with malignant lesions and pheochromocytomas (295,296).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [295] Peña, 2000, Characterization of indeterminate (lipid-poor) adrenal masses: use of washout characteristics at contrast-enhanced CT, Radiology. source

      Not checked in the free run.

    • cites [296] Szolar, 2005, Adrenocortical carcinomas and adrenal pheochromocytomas: mass and enhancement loss evaluation at delayed contrast-enhanced CT, Radiology. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pheochromocytomas usually show slow contrast washout, but occasionally can mimic benign lipid-poor adenomas by showing rapid washout.

    “Caution is also required because whilst pheochromocytomas usually show slow contrast washout, occasionally they can mimic benign lipid-poor adenomas by showing rapid washout (302).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [302] Park, 2007, Re-evaluation of pheochromocytomas on delayed contrast-enhanced CT: washout enhancement and other imaging features, Eur Radiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a systematic review/meta-analysis of nonfunctioning adrenal lesions, mean tumor growth was 2 mm over median 52.8 months; clinically significant enlargement (≥10 mm) occurred in 2.5%; none developed adrenal cancer.

    “This is further supported by a recent systematic review and meta-analysis of nonfunctioning adrenal lesions where a mean tumor growth of 2 mm occurred over a median of 52.8 months, and clinically significant tumor enlargement (≥10 mm) occurred in only 2.5% of patients, and none developed adrenal cancer (269).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [269] Elhassan, 2019, Natural history of adrenal incidentalomas with and without mild autonomous cortisol excess: a systematic review and meta-analysis, Ann Intern Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Disadvantages of the posterior retroperitoneoscopic approach include a smaller working space, making removal of larger tumors more challenging, and increased difficulty in patients with a high BMI.

    “Disadvantages of the posterior retroperitoneoscopic approach include a smaller working space, which makes removal of larger tumors more challenging and increased difficulty in patients with a high body mass index (BMI).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In up to 75% of patients with AI and extra-adrenal cancer, the adrenal mass is a metastasis; 25% have a primary adrenal lesion.

    “In up to 75% of patients with an AI and extra-adrenal cancer, the adrenal mass is a metastasis and bilateral adrenal metastases are seen in a significant number of patients. However, 25% of patients with extra-adrenal cancer will have a primary adrenal lesion (101).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [101] Cingam, 2019

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In mass spectrometry, steroids are identified by unique retention times and/or multiple reaction monitoring, and the area under the peak in the chromatogram is proportional to concentration and quantifiable via comparison to standard reference materials.

    “In mass spectrometry, steroids are identified by unique retention times and or multiple reaction monitoring (206) with the area under the peak in the chromatogram is proportional to its concentration and quantifiable via comparison to standard reference materials of known concentration.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [206] Papathomas, 2019, Novel methods in adrenal research: a metabolomics approach, Histochem Cell Biol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Robotic surgery offers a greater range of motion, improved magnification, and stereoscopic vision than traditional laparoscopic surgery.

    “Robotic surgery offers a greater range of motion, improved magnification, and stereoscopic vision than traditional laparoscopic surgery.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Robotic surgery has increased cost, longer operative time, and a significant learning curve.

    “However, there is an increased cost, longer operative time, and a significant learning curve (339).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [339] Ball, 2015, Robotic adrenalectomy: the jury is still out, Gland Surg.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Laparoscopic adrenalectomy is a safe technique for solitary adrenal metastases, achieves negative margins, and reduces patient morbidity.

    “Solitary adrenal metastases often are confined within the adrenal gland and laparoscopic adrenalectomy is a safe technique, which achieves negative margins and reduces patient morbidity (340).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [340] Zografos, 2009, Laparoscopic surgery for malignant adrenal tumors, Jsls.

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    LC-MS/MS is more suited to a smaller panel of corticosteroids and their metabolites and does not have the same broad scope of analysis as GC-MS.

    “As a result, LC-MS/MS is more suited to a smaller panel of corticosteroids and their metabolites and as a result does not have the same broad scope of analysis that GC-MS allows (206).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [206] Papathomas, 2019, Novel methods in adrenal research: a metabolomics approach, Histochem Cell Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Robotic-assisted laparoscopic adrenalectomy via the transperitoneal technique has been shown to be safe and effective.

    “More recently robotic-assisted laparoscopic adrenalectomy has been developed via the transperitoneal technique and has been shown to be safe and effective.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [339] Ball, 2015, Robotic adrenalectomy: the jury is still out, Gland Surg.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Bilateral adrenalectomy is recommended for bilateral pheochromocytomas; risk of adrenal insufficiency and side effects of lifelong glucocorticoid replacement have led to certain centers performing adrenal cortex sparing resections in genetic syndromes such as VHL and MEN2A where risk of malignant tumors is low.

    “Bilateral adrenalectomy is recommended for bilateral pheochromocytomas; however, the risk of adrenal insufficiency and the side effects of life long glucocorticoid replacement have led to certain centers performing adrenal cortex sparing resections particularly in the setting of genetic syndromes such as VHL and MEN2A where the risk of malignant tumors is low (325).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [325] Bourdeau, 2018, Management of endocrine disease: differential diagnosis, investigation and therapy of bilateral adrenal incidentalomas, Eur J Endocrinol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Multiple studies have demonstrated that laparoscopic adrenalectomy is associated with shorter hospital stay, reduced pain, minimal morbidity, and improved recovery.

    “Multiple studies have demonstrated a shorter hospital stay, reduced pain, minimal morbidity, and improved recovery (336).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [336] Mellon, 2008, Laparoscopic adrenalectomy: Surgical techniques, Indian J Urol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LC-MS/MS is considerably faster and less labor intensive and allows much higher throughput than GC-MS.

    “LC-MS/MS is considerably faster and less labor intensive and allows a much higher throughput than GC-MS; however, LC-MS/MS has a poorer resolving capacity (206).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [206] Papathomas, 2019, Novel methods in adrenal research: a metabolomics approach, Histochem Cell Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Vassiliadi et al. demonstrated exaggerated cortisol and ACTH response in bilateral AI during DST followed by CRH stimulation compared with unilateral AI and controls, suggesting disturbed HPA regulation.

    “Vassiliadi et al. (320) demonstrated an exaggerated response of cortisol and ACTH in patients with bilateral AI during the combined tests of a DST followed by CRH stimulation when compared with unilateral AI and to a control group suggesting that regulation of the hypothalamic–pituitary axis was disturbed in patients with bilateral AI”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [320] Vassiliadi, 2011, Aberrant cortisol responses to physiological stimuli in patients presenting with bilateral adrenal incidentalomas, Endocrine. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Posterior retroperitoneoscopic adrenalectomy has been reported to lead to reduced post-operative analgesia and length of hospital stay.

    “This technique has been reported to lead to reduced post-operative analgesia and length of hospital stay (337,338).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [337] Walz, 2006, Posterior retroperitoneoscopic adrenalectomy–results of 560 procedures in 520 patients, Surgery. source

      Not checked in the free run.

    • cites [338] Berber, 2009, Comparison of laparoscopic transabdominal lateral versus posterior retroperitoneal adrenalectomy, Surgery. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    On unenhanced CT, both adrenal glands in PBMAH are enlarged usually with multiple nodules, but diffuse enlargement without nodules is also seen.

    “On unenhanced CT, both adrenal glands are enlarged usually with multiple nodules but diffuse enlargement without nodules is also seen (325).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [325] Bourdeau, 2018, Management of endocrine disease: differential diagnosis, investigation and therapy of bilateral adrenal incidentalomas, Eur J Endocrinol. source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    The posterior retroperitoneoscopic adrenalectomy provides direct access to the adrenal gland, avoids the intra-abdominal cavity, and allows bilateral procedures without repositioning the patient.

    “It provides direct access to the adrenal gland, avoids the intra-abdominal cavity and allows bilateral procedures to take place without repositioning the patient.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Glucocorticoid metabolites are higher in men than in women and in obese than in lean persons.

    “Glucocorticoid metabolites are higher in men than in women and in obese than in lean persons (345,346).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [345] Crowley, 2014, Longitudinal changes in glucocorticoid metabolism are associated with later development of adverse metabolic phenotype, Eur J Endocrinol. source

      Not checked in the free run.

    • cites [346] Tomlinson, 2008, Reduced glucocorticoid production rate, decreased 5alpha-reductase activity, and adipose tissue insulin sensitization after weight loss, Diabetes. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    GC-MS has advantages over LC-MS/MS in the research environment, including better chromatographic resolution permitting characterization of structures, and use in scan mode allows nontargeted steroid profiling and discovery of novel compounds, metabolomes, and pathways.

    “However, GC-MS has several advantages, particularly in the research environment, over LC-MS/MS, including a better chromatographic resolution which permits the ready characterization of structures; use of GC-MS in scan mode allows for nontargeted steroid profiling and the discovery of novel compounds, metabolomes, and pathways of synthesis and metabolism.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [347] Krone, 2010, Gas chromatography/mass spectrometry (GC/MS) remains a pre-eminent discovery tool in clinical steroid investigations even in the era of fast liquid chromatography tandem mass spectrometry (LC/MS/MS), J Steroid Biochem Mol Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    This approach has been used for some time for diagnosing inborn errors of steroidogenesis such as CAH but has recently been developed for evaluation of functionality and malignant potential of patients with adrenal nodules.

    “This approach has been used for some time for diagnosing inborn errors of steroidogenesis such as CAH but has recently been developed for the evaluation of functionality and malignant potential of patients with adrenal nodules (281).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [281] Arlt, 2017, Steroid metabolome analysis reveals prevalent glucocorticoid excess in primary aldosteronism, JCI Insight. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    MIBG has been used for functional imaging of tumors arising from the adrenal medulla for over 30 years.

    “Iodine-labelled metaiodobenzylguanidine (MIBG), a guanethidine analog, has been used for functional imaging of tumors arising from the adrenal medulla for over 30 years (371).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [371] Avram, 2006, Adrenal gland scintigraphy, Semin Nucl Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    123I-MIBG has significant limitations, including a 2-day imaging protocol and the need for thyroid blockade with potassium iodide prior to tracer injection.

    “123I-MIBG has significant limitations, including a 2-day imaging protocol and the need for thyroid blockade with potassium iodide prior to tracer injection (Fig. 12).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    These tracers are limited to highly specialized centers and the published data is limited to relatively small cohorts.

    “These tracers are limited to highly specialized centers and the published data is limited to relatively small cohorts.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Kerkhofs et al. identified 15 individual steroid markers with sensitivity of 90% or above in detecting ACC, with THS again representing the most informative marker.

    “They performed GC-MS analysis of 22 steroid metabolites and identified 15 individual steroid markers with a sensitivity of 90% or above in detecting ACC, with the 11-deoxycortisol metabolite (THS) again representing the most informative marker.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [348] Kerkhofs, 2015, Diagnostic value of urinary steroid profiling in the evaluation of adrenal tumors, Horm Cancer. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Measurement of 11-deoxycortisol is not routinely used clinically, though recently serum results were reported in a cohort of benign adrenal tumors.

    “Measurement of 11-deoxycortisol is not routinely used clinically, though recently serum results were reported in a cohort of benign adrenal tumors (249).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [249] Di Dalmazi, 2015, Steroid profiling by LC-MS/MS in nonsecreting and subclinical cortisol-secreting adrenocortical adenomas, J Clin Endocrinol Metab. source

      Not checked in the free run.

    • Rests on an assumption: THS is the metabolite of 11-deoxycortisol, which is converted to cortisol by CYP11B1.

  • May combine two claims.

    Premisecitation

    123I-IMTO SPECT-CT permits highly specific characterization of adrenocortical tissue with lower radiation exposure and investigation than NP-59 scintigraphy.

    “123I-IMTO SPECT-CT permits highly specific characterization of adrenocortical tissue with lower radiation exposure and investigation than NP-59 scintigraphy (368) and also has reported value for the staging of ACC (369).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [368] Hahner, 2013, Functional characterization of adrenal lesions using [123I]IMTO-SPECT/CT, J Clin Endocrinol Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    124I-MIBG undergoes complex decay with emission of high energy gamma radiation leading to poorer image quality and unfavorable dosimetry.

    “124I-MIBG has been evaluated as a potential PET imaging tracer but this undergoes complex decay with emission of high energy gamma radiation leading to poorer image quality and unfavorable dosimetry (372).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [372] Pentlow, 1996, Quantitative imaging of iodine-124 with PET, J Nucl Med.

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationcitation

    There is a possibility that some patients with "nonsecretory" AIs and distinct urinary steroid patterns could have had an autonomously secreting lesion or a small ACC.

    “There is, therefore, the possibility that some of these patients could have had an autonomously secreting lesion or a small ACC.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [343] Kotłowska, 2009, The urinary steroid profile in patients diagnosed with adrenal incidentaloma, Clin Biochem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    18F-MFBG preliminary data report high accuracy and favorable dosimetry in a single-day protocol overcoming some limitations of other tracers.

    “Recently an 18F-labeled analog of MIBG has been developed, meta-fluorobenzylguanidine (18F-MFBG); preliminary data report high accuracy and favorable dosimetry in a single-day protocol overcoming some of the limitations of other tracers and showing promise for the future (374).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [374] Pandit-Taskar, 2018, Biodistribution and dosimetry of 18F-meta-fluorobenzylguanidine: a first-in-human PET/CT imaging study of patients with neuroendocrine malignancies, J Nucl Med. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    An AI is now established as a common endocrine diagnosis that requires a multidisciplinary approach for effective management.

    “An AI is now established as a common endocrine diagnosis that requires a multidisciplinary approach for effective management.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Modern-day surgery has improved outcomes for AI.

    “Modern-day surgery has improved outcomes and novel radiological and urinary biomarkers will improve early detection and patient stratification in future years to come.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    Functional AI lesions are commoner than ACC but still probably <10% of total.

    “Functional AI lesions are commoner (but still probably <10% of total) and the greatest challenge remains the diagnosis and optimum management of ACS.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    ACC remains a real concern but is restricted to <2% of all cases.

    “ACC remains a real concern but is restricted to <2% of all cases.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.

    Interpretationnone given

    The greatest challenge remains the diagnosis and optimum management of ACS.

    “Functional AI lesions are commoner (but still probably <10% of total) and the greatest challenge remains the diagnosis and optimum management of ACS.”
    Quote in the paperNot a substantial claim
134 of 134

  • The paper relies on this without support.

    The majority of adrenocortical adenomas are nonsecretory.

    “The majority of these lesions are nonsecretory; however, some may produce glucocorticoids independent of ACTH and mineralocorticoids independent of stimulation from the renin–angiotensin system.”

  • The paper relies on this without support.

    Imaging characteristics cannot reliably distinguish between functional and nonfunctional adrenal tumors.

    “Imaging characteristics cannot reliably distinguish between functional and nonfunctional tumors.”

  • The paper relies on this without support.

    Even functional adrenal tumors may not result in significant clinical symptoms.

    “However, it is important to note that even functional tumors may not result in significant clinical symptoms.”

  • The paper relies on this without support.

    The clinical features of Cushing's syndrome are well defined and are generally dictated by the degree and duration of cortisol hypersecretion.

    “The clinical features of Cushing’s syndrome are well defined; while individual susceptibility varies, generally, these are dictated by the degree and duration of cortisol hypersecretion.”

  • The authors state this as an assumption.

    Patients with mild adrenal Cushing's syndrome should benefit from surgery.

    “It is reasonable to assume that patients, albeit with mild forms of adrenal Cushing’s syndrome, should benefit from surgery”

  • The paper relies on this without support.

    Cortisol affects trabecular bone to a greater degree than cortical bone.

    “Cortisol affects trabecular bone to a greater degree than cortical bone, which is similar to the postmenopausal state.”

  • The paper relies on this without support.

    Adenomas typically enhance rapidly and show prompt washout, whereas malignant adrenal lesions enhance rapidly but show slower washout.

    “Adenomas typically enhance rapidly and show prompt washout of intravenous contrast, in contrast to malignant adrenal lesions which usually enhance rapidly but demonstrate a slower washout of contrast medium.”

  • The paper relies on this without support.

    Patients undergoing unilateral adrenalectomy for Cushing's syndrome or ACS are at risk of contralateral adrenal gland suppression due to chronically elevated preoperative cortisol with ACTH suppression and adrenal atrophy.

    “Any patient who has unilateral adrenalectomy for Cushing’s syndrome or evidence of ACS is at risk of contralateral adrenal gland suppression, due to the chronically elevated pre-operative cortisol levels with consequent ACTH suppression and adrenal atrophy.”

  • The paper relies on this without support.

    Hypertension and hypokalemia are the major classical clinical findings of PA.

    “Hypertension and hypokalemia are the major classical clinical findings of PA”

  • The paper relies on this without support.

    AIs that secrete estrogen or testosterone in isolation are rare.

    “AIs that secrete either estrogen or testosterone in isolation are rare.”

  • The paper relies on this without support.

    Pheochromocytomas occur bilaterally in 10% of cases.

    “Pheochromocytomas occur bilaterally in 10% cases”

  • The paper relies on this without support.

    The most common primary cancers to metastasize to the adrenal gland include lung, breast, renal, melanoma, and the gastrointestinal tract.

    “The most common primary cancers to metastasize to the adrenal gland include lung, breast, renal, melanoma, and the gastrointestinal tract”

  • The paper relies on this without support.

    The adrenal glands are the fourth most common site of metastases in malignancy.

    “The adrenal glands have been reported to be the fourth most common site of metastases in malignancy.”

  • The paper relies on this without support.

    Bilateral adrenal metastases may rarely cause adrenal insufficiency; unilateral adrenal metastasis would not cause adrenal insufficiency.

    “From an endocrine perspective, bilateral adrenal metastases may rarely cause adrenal insufficiency and patients should be clinically assessed and undergo further investigations if suspected. A unilateral adrenal metastasis would not cause adrenal insufficiency and patients do not usually require evaluation.”

  • The paper relies on this without support.

    CAH can rarely present as bilateral adrenal lesions in adult life, although the majority of patients present with symptoms of adrenal insufficiency in childhood.

    “CAH can rarely present as bilateral adrenal lesions in adult life, although the majority of patients present with symptoms of adrenal insufficiency in childhood.”

  • The paper relies on this without support.

    The most common form of CAH, affecting over 90% of individuals, involves the gene for 21-hydroxylase.

    “The most common form of CAH, affecting over 90% of individuals, involves the gene for 21-hydroxylase”

  • The paper relies on this without support.

    For ACC without metastases, surgery is the most important single therapeutic measure.

    “For ACC without metastases, surgery is the most important single therapeutic measure.”

  • The paper relies on this without support.

    The number of adrenal biopsies has significantly reduced in recent years due to improvements in noninvasive imaging techniques.

    “The number of adrenal biopsies has significantly reduced in recent years due to improvements in noninvasive imaging techniques”

  • The paper relies on this without support.

    THS is the metabolite of 11-deoxycortisol, which is converted to cortisol by CYP11B1.

    “THS is the metabolite of 11-deoxycortisol, which is converted to cortisol by the adrenal-specific steroidogenic enzyme cytochrome P450 family 11 subfamily B member 1 (CYP11B1).”

  • The paper relies on this without support.

    Most urinary steroids are conjugated and therefore require deconjugation and derivatization before analysis.

    “As most urinary steroids are conjugated, samples need to be deconjugated followed by a derivatization step before analysis which is both time consuming and labor intensive.”
20 of 20

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Hammarstedt CT frequency does not match the counts

    Major

    The table reports 534 adrenal masses among 34,044 CT scans, a frequency of about 1.57%, not 4.5%.

    Reported 4.5 · recomputed 1.568558

  • Herrera CT frequency does not match the counts

    Major

    The table reports 259 adrenal masses among 61,054 CT scans, a frequency of about 0.42%, not 3.4%.

    Reported 3.4 · recomputed 0.424215

  • Yener unilateral and bilateral counts exceed the patient total

    Minor

    The row lists 362 unilateral and 45 bilateral cases, totaling 407, although it reports only 317 patients. The right and left counts also sum to the stated 362 unilateral cases.

    Reported 317 · recomputed 407

  • Five of nine patients is not 44%

    Minor

    Five of nine patients is about 55.6%; 44% would correspond approximately to four of nine.

    Reported 44 · recomputed 55.555556

  • Early CT prevalence range omits the table's 0.3% result

    Minor

    The text says CT series published between 1982 and 1986 reported prevalences from 0.6% to 1.3%, but Table 2 includes a 1982 series reporting 0.3%.

  • Overall functional-lesion estimates conflict

    Minor

    The conclusion estimates that functional lesions account for probably less than 10% of adrenal incidentalomas, while the clinical-presentation section states that 10% to 15% secrete hormones in excess.

  • Stated autopsy prevalence range excludes a listed large study

    Minor

    The text gives 1.05% as the lower end of the range for autopsy series with more than 1,000 patients. Table 1 lists a 321,847-patient study with a prevalence of 0.03%.

7 of 7

Cites

Flagged first, then by citations

37 of the 429 references couldn’t be matched to a known paper.

Research works printed but not linked: 6

  1. Operational Information for Commissioning NE, 2019., . Diagnostic Imaging Dataset Statistical Release: Provisional monthly statistics, November 2017 to November 2018.
  2. Rinehart, 1941, Adenomatous hyperplasia of the adrenal cortex associated with essential hypertension, Arch Pathol, 32, 169
  3. Holmes, 1951, A morphologic study of adrenal glands with correla, Am J Pathol., 27, 724
  4. Willenberg, Adrenal cortex; development, anatomy, physiology
  5. Lenard, J Hist Med., 496
  6. Ferreira, 2018, Screening tests for hypercortisolism in patients with adrenal incidentaloma, 62

Cited by

Sorted by citations

Related

Authors
Sherlock, M., Scarsbrook, A., Abbas, A., Fraser, S., Limumpornpetch, P., Dineen, R., & Stewart, P. M.
Affiliations
  • Royal College of Surgeons in Ireland (IE)
  • Leeds Teaching Hospitals NHS Trust (GB)
  • University of Leeds (GB)
Corresponding author
Stewart, Paul M
ORCID
Venue
Endocrine Reviews
Publisher
The Endocrine Society
Published
2020-04-08
Volume
41
Issue
6
Pages
775-820
ISSN
  • 0163-769X (ISSN-L)
  • 1945-7189
DOI
10.1210/endrev/bnaa008
PMC
PMC7431180
OpenAlex
W4206446171
Semantic Scholar
65f611da2a57dfffc86e4fbca94cc4d15ea3b564
Cited by
347
References
429
Citations by year
2026: 55 · 2025: 75 · 2024: 60 · 2023: 55 · 2022: 63 · 2021: 37
FWCI
8.78
Type
journal article
Language
en
Open access
Licence
Locations
  • Endocrine Reviews (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
Topics
  • Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
Keywords
adrenal incidentaloma, adrenocortical carcinoma, autonomous cortisol secretion, Cushing's syndrome, adrenalectomy, urinary biomarkers, imaging biomarkers, patient stratification, multidisciplinary management
MeSH terms
Adrenal Gland Neoplasms, Adrenal Glands, Humans

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review