American Association Of Clinical Endocrinologists And American Association Of Endocrine Surgeons Medical Guidelines For The Management Of Adrenal Incidentalomas

Abstract

AbbreviationsAACEAmerican Association of Clinical EndocrinologistsAAESAmerican Association of Endocrine Surgeons;ACCadrenocortical carcinoma;ACEangiotensin-converting enzyme;ACTHadrenocorticotropic hormone;APAaldosterone-producing adenoma;ARBsangiotensin II receptor blockers;ARRaldosterone-to-renin ratio;AVSadrenal venous sampling;BEL“best evidence” rating level;CTcomputed tomographic;ELevidence level;FDGfludeoxyglucose;FNAfine-needle aspiration;HPAhypothalamic-pituitary-adrenal;HUHounsfield units;IHAbilateral idiopathic hyperaldosteronism;MRImagnetic resonance imaging;PACplasma aldosterone concentration;PAHprimary adrenal hyperplasia;PETpositron emission tomography;PRAplasma renin activity;Rrecommendation;SCSsubclinical Cushing syndrome;UFCurine free cortisol American Association of Clinical Endocrinologists American Association of Endocrine Surgeons; adrenocortical carcinoma; angiotensin-converting enzyme; adrenocorticotropic hormone; aldosterone-producing adenoma; angiotensin II receptor blockers; aldosterone-to-renin ratio; adrenal venous sampling; “best evidence” rating level; computed tomographic; evidence level; fludeoxyglucose; fine-needle aspiration; hypothalamic-pituitary-adrenal; Hounsfield units; bilateral idiopathic hyperaldosteronism; magnetic resonance imaging; plasma aldosterone concentration; primary adrenal hyperplasia; positron emission tomography; plasma renin activity; recommendation; subclinical Cushing syndrome; urine free cortisol The incidence of adrenal incidentaloma, a term coined in reference to the phenomenon of detecting an otherwise unsuspected adrenal mass on radiologic imaging, has been increasing and now approaches the 8.7% incidence reported in autopsy series (1.Kloos R.T. Gross M.D. Francis I.R. Korobkin M. Shapiro B. Incidentally discovered adrenal masses.Endocr Rev. 1995; 16 ([EL 3]): 460-484Crossref PubMed Google Scholar, 3.Libè R. Dall’Asta C. Barbetta L. Baccarelli A. Beck-Peccoz P. Ambrosi B. Long-term follow-up study of patients with adrenal incidentalomas.Eur J Endocrinol. 2002; 147 ([EL 2]): 489-494Crossref PubMed Google Scholar, 2.Gajraj H. Young A.E. Adrenal incidentaloma.Br J Surg. 1993; 80 ([EL 3]): 422-426Crossref PubMed Scopus (0) Google Scholar). The definition of incidentaloma excludes patients undergoing imaging procedures as part of staging and work-up for cancer. Not only are more incidentalomas being detected by imaging but they are increasingly more likely to be functional because of the more common evaluations for subclinical syndromes (3.Libè R. Dall’Asta C. Barbetta L. Baccarelli A. Beck-Peccoz P. Ambrosi B. Long-term follow-up study of patients with adrenal incidentalomas.Eur J Endocrinol. 2002; 147 ([EL 2]): 489-494Crossref PubMed Google Scholar, 2.Gajraj H. Young A.E. Adrenal incidentaloma.Br J Surg. 1993; 80 ([EL 3]): 422-426Crossref PubMed Scopus (0) Google Scholar). During the evaluation of an adrenal mass, 3 questions need to be addressed: (1) Is the tumor hormonally active? (2) Does it have radiologic characteristics suggestive of a malignant lesion? and (3) Does the patient have a history of a previous malignant lesion? The patient should be tested for evidence of hypercortisolism, aldosteronism (if hypertensive), and the presence of a pheochromocytoma. A summary of the literature revealed that approximately 80% of patients with incidentalomas had a nonfunctioning adenoma, 5% had subclinical Cushing syndrome (SCS), 5% had a pheochromocytoma, 1% had an aldosteronoma, <5% had an adrenocortical carcinoma (ACC), and 2.5% had a metastatic lesion; the remaining incidentalomas were ganglioneuromas, myelolipomas, or benign cysts (4.Young Jr., W.F. Management approaches to adrenal incidentalomas: a view from Rochester, Minnesota.Endocrinol Metab Clin North Am. 2000; 29 (x. [EL 4]): 159-185Abstract Full Text Full Text PDF PubMed Google Scholar, 5.Grumbach M.M. Biller B.M. Braunstein G.D. et al.Management of the clinically inapparent adrenal mass (“incidentaloma”).Ann Intern Med. 2003; 138 ([EL 4]): 424-429Crossref PubMed Google Scholar). Before consideration of surgical resection, a high degree of certainty of the diagnosis is critical and can be achieved with a combination of biochemical and radiographic studies. Patients who present with an adrenal incidentaloma should be referred to an endocrinologist or endocrine surgeon for assessment. Pheochromocytomas necessitate careful preoperative preparation to avoid intraoperative and postoperative morbidity and mortality. In patients with primary aldosteronism, a thorough evaluation should be performed to ensure that they do not have adrenocortical hyperplasia and a nonfunctioning adrenal adenoma. Patients with adrenal Cushing syndrome develop adrenal insufficiency after resection and will require steroid coverage and careful withdrawal. Whether those with SCS require surgical treatment is controversial. Those patients with ACC require preoperative planning in collaboration with an endocrinologist or oncologist because the effectiveness of the initial resection can be a major predictor of survival. Finally, nonfunctioning adrenal tumors >4 cm (Fig. 1) should be considered for surgical resection. In contrast, small myelolipomas, benign cysts, or nonfunctioning adenomas can be diagnosed with considerable certainty and usually do not necessitate surgical resection unless symptomatic. Depending on the clinical circumstances, resection may be indicated. The only previously published clinical practice guidelines on the management of patients with adrenal incidentalomas originated from a National Institutes of Health consensus conference and was published in 2002 (6.NIH Consens State Sci Statements. 2002; 19 ([EL 4]): 1-25Google Scholar, 4.Young Jr., W.F. Management approaches to adrenal incidentalomas: a view from Rochester, Minnesota.Endocrinol Metab Clin North Am. 2000; 29 (x. [EL 4]): 159-185Abstract Full Text Full Text PDF PubMed Google Scholar). This current set of clinical practice guidelines summarizes the relevant literature as it pertains to the differential diagnosis, laboratory and radiologic evaluation, and clinical management and includes recommendations (each labeled “R” in the subsequent section) based on the “best evidence” rating level (BEL) of the published sources. •R1. Patients with an adrenal incidentaloma should undergo evaluation clinically, biochemically, and radiographically for signs and symptoms of hypercortisolism, aldosteronism (if hypertensive), the presence of a pheochromocytoma, or a malignant tumor (Grade C; BEL 3).•R2. Patients with adrenal incidentalomas who do not fulfill the criteria for surgical resection need to have radiographic reevaluation at 3 to 6 months and then annually for 1 to 2 years. For all adrenal tumors, hormonal evaluation should be performed at the time of diagnosis and then annually for 5 years (Grade C; BEL 3).•R3. All patients found to have an incidental adrenal mass should be screened for cortisol excess. Although the best strategy for patients with incidentalomas has not been established, the simplest screening test for autonomous cortisol secretion from an incidentaloma is a 1-mg overnight dexamethasone suppression test. If clinical suspicion is high, such as in patients with hypertension, obesity, diabetes mellitus, or osteoporosis, 3 tests (salivary cortisol, dexamethasone suppression, and urine free cortisol [UFC]) can be used (Grade C; BEL 3).•R4. After adrenalectomy for a cortisol-producing adenoma, patients should be treated with exogenous glucocorticoids until the hypothalamic-pituitary-adrenal (HPA) axis has recovered. This process may take 6 to 18 months after unilateral adrenalectomy (Grade C; BEL 3).•R5. A diagnosis of SCS is made if the serum cortisol level is more than 5.0 μg/dL after a 1-mg dexamethasone suppression test, in a patient with an adrenal adenoma and absence of typical physical stigmas of hypercortisolism. A low or suppressed level of adrenocorticotropic hormone (ACTH) or a low dehydroepiandrosterone sulfate concentration supports the diagnosis (Grade D; BEL 4). A second abnormal test result of HPA axis function, such as a 2-day low-dose dexamethasone suppression test, may also be needed to establish the diagnosis of SCS (Grade B; BEL 2).•R6. In patients with SCS, until further evidence is available regarding the long-term benefits of adrenalectomy, surgical resection should be reserved for those with worsening of hypertension, abnormal glucose tolerance, dyslipidemia, or osteoporosis (Grade D; BEL 4).•R7. Perioperative glucocorticoid therapy and postoperative assessment of HPA axis recovery are indicated in patients with SCS (Grade C; BEL 3).•R8. Patients thought to have a pheochromocytoma should undergo measurement of plasma fractionated metanephrines and normetanephrines or 24-hour total urinary metanephrines and fractionated catecholamines (or both plasma and urine studies) (Grade A; BEL 1).•R9. About one-quarter of patients with a pheochromocytoma will have associated familial syndromes caused by mutations in the RET gene (multiple endocrine neoplasia type 2), VHL gene (von Hippel-Lindau disease), or succinate dehydrogenase genes; genetic study and counseling should be performed, especially for young patients or patients with an extra-adrenal pheochromocytoma (Grade C; BEL 3).•R10. Surgical resection should be performed for all pheochromocytomas (Grade C; BEL 3).•R11. In all patients with a pheochromocytoma, an α-adrenergic blocking agent should be administered preoperatively, in an effort to prevent intraoperative hemodynamic instability (Grade C; BEL 3).•R12. In patients who have undergone resection of a pheochromocytoma, long-term follow-up is necessary because 10% to 15% may have recurrence (Grade B; BEL 2).•R13. Screening for aldosteronism should be performed in patients with an aldosterone-to-renin ratio (ARR) of >20 (Grade C; BEL 3).•R14. Primary aldosteronism is confirmed in the setting of an adrenal incidentaloma by demonstrating lack of aldosterone suppression (24-hour urine study) with salt loading (Grade C; BEL 3).•R15. Subtype evaluation should be achieved with highresolution computed tomographic (CT) scanning in all patients and adrenal venous sampling (AVS) in the majority of patients older than 40 years (Grade C; BEL 3).•R16. In patients with primary aldosteronism and a unilateral source of aldosterone excess, laparoscopic total adrenalectomy is the treatment of choice because it yields excellent outcomes with low associated morbidity relative to open approaches (Grade C; BEL 3).•R17. Patients with bilateral idiopathic hyperaldosteronism (IHA) or those not amenable or agreeable to surgical intervention should be managed with selective and nonselective mineralocorticoid receptor blockers (Grade A; BEL 1).•R18. Any adrenal mass with concerning radiographic characteristics and most lesions ≥4 cm should be resected because of increased risk of adrenal cancer (Grade C; BEL 3).•R19. The presence of pheochromocytoma should be ruled out biochemically before an attempted resection of any adrenal mass (Grade C; BEL 3).•R20. All patients suspected of having an ACC should undergo biochemical evaluation to identify any potential hormone excess that serves as a tumor marker and to determine whether the patient requires steroid replacement perioperatively in cases of hypercortisolism (Grade D; BEL 4).•R21. Open adrenalectomy should be performed if ACC is suspected (Grade C; BEL 3).•R22. A metastatic lesion should be suspected in a patient with a history of cancer and an adrenal mass that does not fulfill the criteria for an incidentaloma (Grade C; BEL 3).•R23. In very rare instances, pathologic confirmation with CT-guided needle biopsy may be required for staging and planning of oncologic treatments (Grade D; BEL 4).•R24. The presence of pheochromocytoma should be ruled out with biochemical testing before performance of a biopsy (Grade C; BEL 3).•R25. Patients with bilateral adrenal metastatic lesions should undergo evaluation for adrenal insufficiency (Grade D; BEL 4).•R26. Adrenal metastasectomy is rarely indicated but should be considered in the case of an isolated adrenal metastatic lesion (Grade C; BEL 3). In 2004, the American Association of Clinical Endocrinologists (AACE) Protocol for Standardized Production of Clinical Practice Guidelines was published in Endocrine Practice (7.Mechanick J.I. Bergman D.A. Braithwaite S.S. Palumbo P.J. (AACE Ad Hoc Task Force for Standardized Production of Clinical Practice Guidelines) American Association of Clinical Endocrinologists protocol for standardized production of clinical practice guidelines.Endocr Pract. 2004; 10 ([EL 4]): 353-361Abstract Full Text Full Text PDF PubMed Google Scholar, 4.Young Jr., W.F. Management approaches to adrenal incidentalomas: a view from Rochester, Minnesota.Endocrinol Metab Clin North Am. 2000; 29 (x. [EL 4]): 159-185Abstract Full Text Full Text PDF PubMed Google Scholar). Those recommendations were used for the preparation of this document. The American Association of Endocrine Surgeons (AAES) and AACE cochairpersons and primary writers are experts in the clinical management of adrenal diseases. After the completion of the first draft created by the primary writers, the chairpersons reviewed the technical assignment of evidence levels (inserted in the reference list and in the text) and recommendation grades (in the Executive Summary). The document was subsequently reviewed by the AAES and AACE publication and executive committees and then finally completed by the chairpersons. Patients who have an adrenal incidentaloma identified on CT or magnetic resonance imaging (MRI) need to undergo a thorough clinical evaluation. The history should be aimed at excluding a functional tumor. For patients with hypercortisolism or Cushing syndrome, the investigation should include inquiries about substantial weight gain or development of centripetal obesity, easy bruisability, severe hypertension, diabetes, virilization, proximal muscle weakness, or fatigue. For patients with pheochromocytoma, inquiries should address the development of sudden or severe headaches, weight loss, anxiety attacks, sweating, cardiac arrhythmias, or palpitations. For patients with aldosteronism, the clinician should ask about the presence of hypertension, fluid retention, or a history of hypokalemia. The clinician should inquire about a history of cancer, recent weight loss, and a smoking history because an adrenal mass may be a metastatic lesion. Physical examination should include measurement of the patient’s blood pressure and pulse as well as assessment for evidence of central obesity, ecchymoses, striae, muscle wasting, hirsutism, or other signs of virilization. A review of photographs taken over several years, such as those on a driver’s license, may make changes in appearance obvious. The detection of an adrenal lesion should prompt biochemical evaluation unless it is an obvious myelolipoma. Adrenal myelolipomas are of low CT attenuation and also contain fat (–10 to –20 Hounsfield units [HU]); therefore, the diagnosis is generally clear (8.Caoili E.M. Korobkin M. Francis I.R. et al.Adrenal masses: characterization with combined unenhanced and delayed enhanced CT.Radiology. 2002; 222 ([EL 2]): 629-633Crossref PubMed Google Scholar, 2.Gajraj H. Young A.E. Adrenal incidentaloma.Br J Surg. 1993; 80 ([EL 3]): 422-426Crossref PubMed Scopus (0) Google Scholar). Any hormonally hyperfunctioning adenoma needs to be surgically resected. Patients are screened for SCS with a 1-mg overnight dexamethasone suppression test. A diagnosis of SCS is suspected if the serum cortisol level exceeds 5.0 μg/dL after a 1-mg dexamethasone suppression test. A low or suppressed level of ACTH or a low dehydroepiandrosterone sulfate concentration further supports the diagnosis. A second abnormal test result of HPA axis function, such as a 2-day low-dose dexamethasone suppression test, may be needed to establish the diagnosis of SCS (9.Mantero F. Terzolo M. Arnaldi G. et al.(Study Group on Adrenal Tumors of the Italian Society of Endocrinology). A survey on adrenal incidentaloma in Italy.J Clin Endocrinol Metab. 2000; 85 ([EL 2]): 637-644Crossref PubMed Scopus (0) Google Scholar, 2.Gajraj H. Young A.E. Adrenal incidentaloma.Br J Surg. 1993; 80 ([EL 3]): 422-426Crossref PubMed Scopus (0) Google Scholar). Patients with hypertension who have a ratio of plasma aldosterone concentration (PAC) (ng/dL) to plasma renin activity (PRA) (ng/mL per hour) of >20 while not taking spironolactone and mineralocorticoid receptor blockers should undergo further assessment for the presence of primary aldosteronism (4.Young Jr., W.F. Management approaches to adrenal incidentalomas: a view from Rochester, Minnesota.Endocrinol Metab Clin North Am. 2000; 29 (x. [EL 4]): 159-185Abstract Full Text Full Text PDF PubMed Google Scholar, 10.Young Jr., W.F. Primary aldosteronism: a common and curable form of hypertension.Cardiol Rev. 1999; 7 ([EL 4]): 207-214Crossref PubMed Google Scholar). Finally, elevated plasma free metanephrine and normetanephrine levels and 24-hour total urinary metanephrines and fractionated catecholamines suggest the presence of a pheochromocytoma (11.Lenders J.W. Pacak K. Walther M.M. et al.Biochemical diagnosis of pheochromocytoma: which test is best.JAMA. 2002; 287 ([EL 4]): 1427-1434Crossref PubMed Google Scholar, 4.Young Jr., W.F. Management approaches to adrenal incidentalomas: a view from Rochester, Minnesota.Endocrinol Metab Clin North Am. 2000; 29 (x. [EL 4]): 159-185Abstract Full Text Full Text PDF PubMed Google Scholar, 12.Sawka A.M. Jaeschke R. Singh R.J. Young Jr., W.F. A comparison of biochemical tests for pheochromocytoma: measurement of fractionated plasma metanephrines compared with the combination of 24-hour urinary metanephrines and catecholamines.J Clin Endocrinol Metab. 2003; 88 ([EL 3]): 553-558Crossref PubMed Scopus (371) Google Scholar, 3.Libè R. Dall’Asta C. Barbetta L. Baccarelli A. Beck-Peccoz P. Ambrosi B. Long-term follow-up study of patients with adrenal incidentalomas.Eur J Endocrinol. 2002; 147 ([EL 2]): 489-494Crossref PubMed Google Scholar). In general, testing the patient for the production of excess sex hormones is not indicated unless the patient has obvious clinical stigmas. The primary goal of imaging is to distinguish among adrenal adenoma, adrenal carcinoma, pheochromocytoma, and metastatic lesions. It is important to emphasize that imaging cannot reliably distinguish between functioning and nonfunctioning adrenal adenomas. The diagnosis of an adenoma relies on the presence of intracellular lipid in the adrenal lesion, which can be identified by density measurement on noncontrast CT or in-phase and out-of-phase MRI. Alternatively, an adenoma can be identified by measuring contrast-washout kinetics on CT. Lesions that have an attenuation value below 10 HU on noncontrast CT scan are adenomas (8.Caoili E.M. Korobkin M. Francis I.R. et al.Adrenal masses: characterization with combined unenhanced and delayed enhanced CT.Radiology. 2002; 222 ([EL 2]): 629-633Crossref PubMed Google Scholar, 2.Gajraj H. Young A.E. Adrenal incidentaloma.Br J Surg. 1993; 80 ([EL 3]): 422-426Crossref PubMed Scopus (0) Google Scholar, 13.Korobkin M. Brodeur F.J. Yutzy G.G. et al.Differentiation of adrenal adenomas from nonadenomas using CT attenuation values.AJR Am J Roentgenol. 1996; 166 ([EL 3]): 531-536Crossref PubMed Google Scholar, 3.Libè R. Dall’Asta C. Barbetta L. Baccarelli A. Beck-Peccoz P. Ambrosi B. Long-term follow-up study of patients with adrenal incidentalomas.Eur J Endocrinol. 2002; 147 ([EL 2]): 489-494Crossref PubMed Google Scholar, 14.Hamrahian A.H. Ioachimescu A.G. Remer E.M. et al.Clinical utility of noncontrast computed tomography attenuation value (Hounsfield units) to differentiate adrenal adenomas/hyperplasias from nonadenomas: Cleveland Clinic experience.J Clin Endocrinol Metab. 2005; 90 ([EL 3]): 871-877Crossref PubMed Scopus (178) Google Scholar). Adenomas constitute about 70% of adrenal masses seen in the clinical setting. The differential diagnosis can be further delineated by CT scans done immediately after intravenous administration of a contrast agent and then again after a 10-to 15-minute delay. Benign adrenal lesions will commonly enhance up to 80 to 90 HU and wash out more than 50% on the delayed scan, whereas lesions such as metastatic tumors, carcinomas, or pheochromocytomas will not (8.Caoili E.M. Korobkin M. Francis I.R. et al.Adrenal masses: characterization with combined unenhanced and delayed enhanced CT.Radiology. 2002; 222 ([EL 2]): 629-633Crossref PubMed Google Scholar, 2.Gajraj H. Young A.E. Adrenal incidentaloma.Br J Surg. 1993; 80 ([EL 3]): 422-426Crossref PubMed Scopus (0) Google Scholar). Pheochromocytomas usually show enhancement to more than 100 HU, diagnostically separating them from adenomas. On noncontrast CT, some benign adrenal lesions do not have attenuation values of less than 10 HU and may have values of 20 to 40 HU. This result is found in lipid-poor adenomas. In these cases, a washout of >50% will often allow the diagnosis of an adenoma to be made. This observation, however, needs to be confirmed with larger studies. Patients with adrenal incidentalomas smaller than 4 cm and radiologic characteristics consistent with a benign adenoma need to have radiographic reevaluation at 3 to 6 months and then annually for 1 to 2 years (6.NIH Consens State Sci Statements. 2002; 19 ([EL 4]): 1-25Google Scholar, 4.Young Jr., W.F. Management approaches to adrenal incidentalomas: a view from Rochester, Minnesota.Endocrinol Metab Clin North Am. 2000; 29 (x. [EL 4]): 159-185Abstract Full Text Full Text PDF PubMed Google Scholar, 15.Barry M.K. van Heerden J.A. Farley D.R. Grant C.S. Thompson G.B. Ilstrup D.M. Can adrenal incidentalomas be safely observed [with discussion].World J Surg. 1998; 22 ([EL 3]): 599-604Crossref PubMed Scopus (0) Google Scholar, 3.Libè R. Dall’Asta C. Barbetta L. Baccarelli A. Beck-Peccoz P. Ambrosi B. Long-term follow-up study of patients with adrenal incidentalomas.Eur J Endocrinol. 2002; 147 ([EL 2]): 489-494Crossref PubMed Google Scholar, 16.Kim H.Y. Kim S.G. Lee K.W. et al.Clinical study of adrenal incidentaloma in Korea.Korean J Intern Med. 2005; 20 ([EL 3]): 303-309Crossref PubMed Google Scholar). Hormonal evaluation should be performed at the time of diagnosis and then annually for up to 5 years (3.Libè R. Dall’Asta C. Barbetta L. Baccarelli A. Beck-Peccoz P. Ambrosi B. Long-term follow-up study of patients with adrenal incidentalomas.Eur J Endocrinol. 2002; 147 ([EL 2]): 489-494Crossref PubMed Google Scholar, 2.Gajraj H. Young A.E. Adrenal incidentaloma.Br J Surg. 1993; 80 ([EL 3]): 422-426Crossref PubMed Scopus (0) Google Scholar). The risk of the mass enlarging during 1, 2, and 5 years is 6%, 14%, and 29%, respectively, and the risk of the mass becoming hormonally active during those time periods is 17%, 29%, and 47%, respectively (3.Libè R. Dall’Asta C. Barbetta L. Baccarelli A. Beck-Peccoz P. Ambrosi B. Long-term follow-up study of patients with adrenal incidentalomas.Eur J Endocrinol. 2002; 147 ([EL 2]): 489-494Crossref PubMed Google Scholar, 2.Gajraj H. Young A.E. Adrenal incidentaloma.Br J Surg. 1993; 80 ([EL 3]): 422-426Crossref PubMed Scopus (0) Google Scholar). The most common hormonally active lesion in patients with previously inactive adenomas is SCS. The rate of a benign adenoma or hyperplasia developing into an ACC is not well known, but such a change seems to be extremely rare (15.Barry M.K. van Heerden J.A. Farley D.R. Grant C.S. Thompson G.B. Ilstrup D.M. Can adrenal incidentalomas be safely observed [with discussion].World J Surg. 1998; 22 ([EL 3]): 599-604Crossref PubMed Scopus (0) Google Scholar, 3.Libè R. Dall’Asta C. Barbetta L. Baccarelli A. Beck-Peccoz P. Ambrosi B. Long-term follow-up study of patients with adrenal incidentalomas.Eur J Endocrinol. 2002; 147 ([EL 2]): 489-494Crossref PubMed Google Scholar, 17.Barzon L. Scaroni C. Sonino N. Fallo F. Paoletta A. Boscaro M. Risk factors and long-term follow-up of adrenal incidentalomas.J Clin Endocrinol Metab. 1999; 84 ([EL 2]): 520-526Crossref PubMed Scopus (225) Google Scholar, 2.Gajraj H. Young A.E. Adrenal incidentaloma.Br J Surg. 1993; 80 ([EL 3]): 422-426Crossref PubMed Scopus (0) Google Scholar, 18.Höfle G. Gasser R.W. Lhotta K. Janetschek G. Kreczy A. Finkenstedt G. Adrenocortical carcinoma evolving after diagnosis of preclinical Cushing’s syndrome in an adrenal incidentaloma: a case report.Horm Res. 1998; 50 ([EL 3]): 237-242Crossref PubMed Google Scholar, 19.Ghose R.P. Hall P.M. Bravo E.L. Medical management of aldosterone-producing adenomas.Ann Intern Med. 1999; 131 ([EL 3]): 105-108Crossref PubMed Google Scholar, 20.Sirén J. Tervahartiala P. Sivula A. Haapiainen R. Natural course of adrenal incidentalomas: seven-year follow-up study.World J Surg. 2000; 24 ([EL 3]): 579-582Crossref PubMed Scopus (0) Google Scholar). Should the tumor grow more than 1 cm or become hormonally active during follow-up, surgical excision should be considered. Currently, it is unclear what the recommendations should be after 5 years of follow-up for a stable, nonfunctioning adrenal mass. Adrenocortical adenoma can cause both overt Cushing syndrome and SCS. Those patients with an incidental radiographic finding of the adrenal lesion are more likely than others to have SCS. With better understanding of SCS and more frequent testing for it (4.Young Jr., W.F. Management approaches to adrenal incidentalomas: a view from Rochester, Minnesota.Endocrinol Metab Clin North Am. 2000; 29 (x. [EL 4]): 159-185Abstract Full Text Full Text PDF PubMed Google Scholar, 21.Linos D.A. Management approaches to adrenal incidentalomas (adrenalomas): a view from Athens, Greece.Endocrinol Metab Clin North Am. 2000; 29 ([EL 4]): 141-157Abstract Full Text Full Text PDF PubMed Google Scholar, 22.Brunt L.M. Moley J.F. Adrenal incidentaloma.World J Surg. 2001; 25 ([EL 4]): 905-913Crossref PubMed Scopus (148) Google Scholar, 23.Sippel R.S. Chen H. Subclinical Cushing’s syndrome in adrenal incidentalomas.Surg Clin North Am. 2004; 84 ([EL 4]): 875-885Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar), this disease entity is being identified more frequently. Of the hormonally active incidentalomas, this diagnosis constitutes the most common form—5.3% of more than 2,000 cases reported in the world literature (4.Young Jr., W.F. Management approaches to adrenal incidentalomas: a view from Rochester, Minnesota.Endocrinol Metab Clin North Am. 2000; 29 (x. [EL 4]): 159-185Abstract Full Text Full Text PDF PubMed Google Scholar). Overt clinical signs and symptoms of Cushing disease are not always present; thus, biochemical testing is necessary to secure the diagnosis. Overt adrenal Cushing syndrome is characterized by all the typical stigmas of hypercortisolism. Particular attention should be directed at eliciting a history of fatigue, depression, sleep disturbances, weight gain, menstrual irregularities, hypertension, glucose intolerance, easy bruising, or fracture with minimal trauma. On physical examination, the physician should measure the patient’s blood pressure and pulse and look for central obesity, supraclavicular fat accumulation, a dorsocervical fat pad, facial plethora, thinned skin, purple and wide (>1 cm) striae, acne, ecchymoses, hirsutism, and proximal muscle weakness or wasting. Changes on photographs taken over several years (such as those on driver’s licenses) may be of particular help. All these signs and symptoms should raise the level of suspicion for Cushing syndrome. Many patients with mild Cushing syndrome, however, will have only a few of these signs and symptoms present, and many patients without Cushing syndrome may also exhibit one or more of these findings. Therefore, Cushing syndrome cannot be diagnosed on purely clinical grounds, and a careful biochemical evaluation is necessary. Biochemical evaluation for adrenal Cushing syndrome is a 2-step process that first includes screening with 1 or 2 screening tests. If the screening test results are positive, confirmatory tests are then performed. Testing is based on demonstrating 3 pathophysiologic derangements typical of Cushing syndrome: (1) loss of a normal diurnal pattern, with abnormally high late-night cortisol secretion (late-night salivary cortisol test); (2) failure to discontinue the production of cortisol, despite the absence of ACTH stimulation (dexamethasone suppression test); and (3) excess production of cortisol (24-hour UFC test). The late-night salivary cortisol test is the most recent assay to be used for screening for Cushing syndrome and is now available through most laboratories. Patients with a regular sleep pattern can collect a specimen of saliva at bedtime at home and then bring or mail the samples to the laboratory for testing. Several investigators have shown that elevated nighttime cortisol levels appear to be the earliest and most sensitive markers for Cushing syndrome (24.Findling J.W. Raff H. Newer diagnostic techniques and problems in Cushing’s disease.Endocrinol Metab Clin North Am. 1999; 28 ([EL 4]): 191-210Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 4.Young Jr., W.F. Management approaches to adrenal incidentalomas: a view from Rochester, Minnesota.Endocrinol Metab Clin North Am. 2000; 29 (x. [EL 4]): 159-185Abstract Full Text Full Text PDF PubMed Google Scholar, 25.Findling J.W. Raff H. Diagnosis and differential diagnosis of Cushing’s syndrome.Endocrinol Metab Clin North Am. 2001; 30 ([EL 4]): 729-747Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar), with sensitivity and specificity approaching 90% to 95% (26.Findling J.W. Raff H. Cushing’s syndrome: important issues in diagnosis and management.J Clin Endocrinol Metab. 2006; 91 ([EL 3]): 3746-3753C