HORMONE RESEARCH
Horm Res 2007;68(suppl 5):191-194 DOI: 10.1159/000110623
Adrenal Incidentalomas: Presentation and Clinical Work-Up
Felix Beuschlein
Medizinische Klinik, Innenstadt, Ludwig Maximilian University, Munich, Germany
Key Words
Adrenal tumours . Incidentaloma . Subclinical Cushing syndrome
Abstract
Background: Through the widespread use of imaging tech- niques with great sensitivity, adrenal tumours are often di- agnosed as an incidental finding. The majority of these ad- renal lesions are benign and without evidence of endocrine activity or malignancy. However, in addition to the classic forms of overt adrenal hypersecretion, it has become evi- dent in recent years that even modest adrenal hormonal au- tonomy, as exhibited in clinically silent phaeochromocyto- ma, normokalaemic primary aldosteronism and subclinical Cushing syndrome, is associated with significant morbidity. Thus, hormone hypersecretion and growth kinetics must be ruled out for each patient using specific tests to avoid associ- ated morbidity. Conclusions: Detection and differential di- agnosis of subtle changes in adrenal hormone secretion can pose a diagnostic challenge to the clinician, and accurate di- agnosis is dependent on use of tests with reliable sensitivity and specificity. Copyright @ 2007 S. Karger AG, Basel
Review
The most common adrenal disorder encountered by clinicians today is the incidentally discovered adrenal mass, termed ‘adrenal incidentaloma’. The rate of detec- tion of clinically silent adrenal masses has increased sub- stantially in recent decades through widespread use of modern abdominal imaging techniques. As a conse- quence, management of adrenal incidentalomas has be- come a common clinical problem. The reported inci- dence of adrenal masses varies depending on the screen- ing procedure used and ranges from 1.4 to 9% in autopsy series [1, 2] and from 0.4 to 4% in a series of abdominal computed tomography (CT) scans [3-5].
In the absence of a known malignancy of nonadrenal origin, the vast majority of adrenal incidentalomas are benign. Nonfunctioning cortical adenomas are the most common lesions, accounting for 36-94% of cases, while hormonally active or malignant adrenocortical tumours and metastases from distant tumours are much less com- mon (0-25% adrenocortical carcinoma and 0-21% me- tastases in nonselected series) [6]. Adrenal glands are common targets for metastatic spread of a variety of ma- lignancies, such as lung cancer, renal cell carcinoma, mel- anoma and many other tumour entities. However, adre- nal metastases from distant malignant tumours are a sign of the general spread of disease and usually occur at mul-
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tiple sites while a solitary adrenal metastasis is a rare event. Thus, a single adrenal metastasis as the initial and only finding of malignant disease is an unusual clinical situation.
Phaeochromocytoma
Phaeochromocytomas are rare tumours with an ap- proximated annual incidence of 2-8 cases per million [7]. Depending on the size of the tumour at presentation, 1- 8% of patients with adrenal incidentaloma are diagnosed with adrenal phaeochromocytoma [8]. Although the classic signs of hypertension, headache, palpitation and hyperhidrosis can raise early suspicion for the presence of catecholamine excess, around 10% of phaeochromocy- toma are clinically silent [7].
Adrenocortical Carcinoma (ACC)
Similar to phaeochromocytoma, ACC is a rare endo- crine tumour entity with an annual worldwide incidence of approximately two new cases per million people [9]. Retrospective studies of combined surgical and medical therapy indicate that it has highly malignant clinical be- havior with an overall 5-year survival of only 15-35% [10]. Overall, the long-term therapeutic results are devas- tating and largely dependent on tumour stage, with the most severe prognostic factor being the presence of me- tastases. While in children ACCs are commonly func- tional, in elderly patients ACC tumours are usually detected at an advanced stage because of mass effect or incidentally by radiological investigations [11]. The prob- ability of malignancy is clearly related to the size of the tumour, as almost all lesions <3 cm are benign, whereas a diameter of >6 cm indicates a high risk of malignancy [12]. Accordingly, up to 12% of patients surgically treated for adrenal incidentalomas due to large tumour size have malignant ACC [13].
Imaging Techniques
CT and magnetic resonance imaging (MRI) both play a major role in the characterization of adrenal masses. Using unenhanced CT, attenuation of a homogeneous mass with a smooth border of ≤10 Hounsfield units can establish a diagnosis of a lipid-rich adenoma. Similarly, >50% washout of contrast enhancement fluid within 10- 15 min of administration suggests a benign lesion [14, 15]. In contrast, adrenal carcinomas and metastases detected by CT scan are defined by irregular margins and inho- mogeneous enhancement. With MRI, both rapid en- hancement followed by rapid washout and loss of signal intensity using an opposed-phase image in chemical shift
analysis indicate the presence of an adenoma [16, 17]. Other imaging techniques (e.g., positron emission to- mography) possibly offer additional information, such as identification of small metastases from adrenal carcino- ma [18], but these capabilities have not yet been fully es- tablished in large prospective clinical studies.
Although a high proportion of adrenal lesions are identified incidentally in the course of abdominal imag- ing procedures, overt hormonal activity translates into clinical syndromes that can raise early suspicion of the presence of functional adrenal tumours. Conversely, typ- ical clinical signs and symptoms of hormonal excess can be lacking, and subtle changes might be missed by clini- cal examination.
Importance of Clinical Work-Up
Catecholamine excess due to the presence of phaeo- chromocytoma can be verified or excluded with high sensitivity (97-99%) and specificity (82%) through as- sessment of plasma metanephrines, which is a superior method for detection compared with measurement of urinary catecholamines [19, 20]. As unidentified phaeo- chromocytoma can pose a considerable threat for un- treated patients in cases of tumour manipulation during surgery [21], catecholamine excess has to be ruled out in each patient with an adrenal incidentaloma.
Autonomous secretion of cortisol from an adrenal adenoma accounts for 9-22% of patients with Cushing syndrome with an annual incidence of 1.1 per million women and 0.1 per million men [22]. Endocrinologic di- agnosis of adrenal Cushing syndrome depends on dem- onstration of a blunted diurnal rhythm of cortisol secre- tion and failure of overnight suppression by administra- tion of low doses of dexamethasone [23]. In a recent retrospective analysis of the diagnostic utility of urinary free cortisol, the overnight low-dose dexamethasone sup- pression test and midnight serum cortisol, the best test characteristics were obtained using the midnight serum cortisol test, which has a sensitivity of 92% and a specific- ity of 96% [24].
Over the last decade, an increasing body of evidence has demonstrated that subtle abnormalities in cortisol production and subsequent abnormalities in the hypo- thalamic-pituitary-adrenal axis occur more frequently than previously thought. This entity, which has been termed ‘subclinical Cushing syndrome’, has been report- ed to occur in 12-16% of patients with adrenal inciden- talomas [6, 25, 26]. The criteria for diagnosis of subclini- cal Cushing syndrome are less well defined than for the overt form, but they include demonstration of some de-
gree of autonomous cortisol secretion by means of elevat- ed midnight cortisol, urinary cortisol, low baseline adre- nocorticotropic hormone (ACTH), incomplete suppres- sion with low-dose dexamethasone and blunted increase of ACTH secretion during corticotrophin-releasing hor- mone stimulation [25, 27, 28]. A recent follow-up evalua- tion of patients with clinically nonfunctioning adrenal masses revealed that the estimated cumulative risk for a nonsecreting adrenal incidentaloma to develop subclini- cal hyperfunction was 3.8% after 1 year and 6.6% after 5 years [29]. Similarly, the rate of progression from sub- clinical to overt Cushing syndrome is likely to be low [27]. Recently, a number of studies have reported data on the morbidity associated with subclinical Cushing syndrome in patients with a clinically inapparent adrenal adenoma. Findings indicate that patients with subclinical Cushing syndrome have a higher cardiovascular risk profile and less favorable metabolic parameters with higher systolic blood pressure and altered glucose tolerance [28, 30].
Primary aldosteronism has recently been recognized as the most frequent cause of secondary hypertension, occurring with a prevalence of 5-18% within the hyper- tensive population [31-34]. Only 10-30% of these pa- tients, however, are characterized by the classic triad of hypertension, hypokalaemia and alkalosis; the large ma- jority present with a normal serum potassium level, thus indicating a milder variant of this disorder [34]. The al- dosterone:renin ratio is currently the most frequently recommended screening test for primary aldosteronism, and application of the ratio is increasingly advocated even for patients under treatment with antihypertensive
medication [35-38]. In any case, a positive test result re- quires confirmation by functional testing, as the specific- ity of the aldosterone:renin ratio is low. Various confir- matory tests have been proposed, but currently there is no ideal test that is simple, sensitive and specific. A com- mon approach to confirm the diagnosis of primary aldo- steronism is to demonstrate insufficient suppression of aldosterone after oral sodium loading, acute saline infu- sion and administration of captopril or fludrocortisone [39-41].
Conclusions
Taken together, secretory autonomy and growth po- tential have to be evaluated in each patient with an inci- dentally detected adrenal tumour. To meet these clinical aims, a National Institutes of Health Consensus Meeting recently recommended the use of endocrine tests to ex- clude autonomous cortisol secretion, primary aldoste- ronism and catecholamine excess for up to 4 years after the initial diagnosis as well as imaging follow-up after 6-12 months to rule out tumour growth [42]. Further well-designed studies are needed on the long-term out- come of this patient cohort to enable identification of ef- fective diagnostic and therapeutic approaches.
Disclosure Statement
There is no conflict of interest.
References
1 Abecassis M, McLoughlin MJ, Langer B, Kudlow JE: Serendipitous adrenal masses: prevalence, significance, and management. Am J Surg 1985;149:783-788.
2 Hedeland H, Ostberg G, Hokfelt B: On the prevalence of adrenocortical adenomas in an autopsy material in relation to hypertension and diabetes. Acta Med Scand 1968;184:211- 214.
3 Prinz RA, Brooks MH, Churchill R, Graner JL, Lawrence AM, Paloyan E, Sparagana M: Incidental asymptomatic adrenal masses de- tected by computed tomographic scanning. Is operation required? JAMA 1982;248:701- 704.
4 Glazer HS, Weyman PJ, Sagel SS, Levitt RG, McClennan BL: Nonfunctioning adrenal masses: incidental discovery on computed tomography. AJR Am J Roentgenol 1982;139: 81-85.
5 Belldegrun A, Hussain S, Seltzer SE, Lough- lin KR, Gittes RF, Richie JP: Incidentally dis- covered mass of the adrenal gland. Surg Gy- necol Obstet 1986;163:203-208.
6 Kloos RT, Gross MD, Francis IR, Korobkin M, Shapiro B: Incidentally discovered adre- nal masses. Endocr Rev 1995;16:460-484.
7 Yeo H, Roman S: Pheochromocytoma and functional paraganglioma. Curr Opin Oncol 2005;17:13-18.
8 Mansmann G, Lau J, Balk E, Rothberg M, Mi- yachi Y, Bornstein SR: The clinically inap- parent adrenal mass: update in diagnosis and management. Endocr Rev 2004;25:309-340.
9 Lipsett MB, Hertz R, Ross GT: Clinical and pathophysiologic aspects of adrenocortical carcinoma. Am J Med 1963;35:374.
10 Ahlman H, Khorram-Manesh A, Jansson S, Wangberg B, Nilsson O, Jacobsson CE, Lind- stedt S: Cytotoxic treatment of adrenocorti- cal carcinoma. World J Surg 2001;25:927- 933.
11 Wooten MD, King DK: Adrenal cortical car- cinoma. Epidemiology and treatment with mitotane and a review of the literature. Can- cer 1993;72:3145-3155.
12 Fassnacht M, Kenn W, Allolio B: Adrenal tu- mors: how to establish malignancy? J Endo- crinol Invest 2004;27:387-399.
13 Mantero F, Terzolo M, Arnaldi G, Osella G, Masini AM, Ali A, Giovagnetti M, Opocher G, Angeli A: A survey on adrenal inciden- taloma in Italy. Study Group on Adrenal Tu- mors of the Italian Society of Endocrinology. J Clin Endocrinol Metab 2000;85:637-644.
14 Korobkin M, Brodeur FJ, Francis IR, Quint LE, Dunnick NR, Londy F: CT time-attenu- ation washout curves of adrenal adenomas and nonadenomas. AJR Am J Roentgenol 1998;170:747-752.
15 Pena CS, Boland GW, Hahn PF, Lee MJ, Mueller PR: Characterization of indetermi- nate (lipid-poor) adrenal masses: use of washout characteristics at contrast-en- hanced CT. Radiology 2000;217:798-802.
16 Korobkin M, Lombardi TJ, Aisen AM, Fran- cis IR, Quint LE, Dunnick NR, Londy F, Sha- piro B, Gross MD, Thompson NW: Charac- terization of adrenal masses with chemical shift and gadolinium-enhanced MR imag- ing. Radiology 1995;197:411-418.
17 Honigschnabl S, Gallo S, Niederle B, Prager G, Kaserer K, Lechner G, Heinz-Peer G: How accurate is MR imaging in characterisation of adrenal masses: update of a long-term study. Eur J Radiol 2002;41:113-122.
18 Frilling A, Tecklenborg K, Weber F, Kuhl H, Muller S, Stamatis G, Broelsch C: Impor- tance of adrenal incidentaloma in patients with a history of malignancy. Surgery 2004; 136:1289-1296.
19 Lenders JW, Pacak K, Walther MM, Linehan WM, Mannelli M, Friberg P, Keiser HR, Goldstein DS, Eisenhofer G: Biochemical di- agnosis of pheochromocytoma: which test is best? JAMA 2002;287:1427-1434.
20 Westphal SA: Diagnosis of a pheochromocy- toma. Am J Med Sci 2005;329:18-21.
21 Weismann D, Fassnacht M, Weinberger F, Hamelmann W, Diehl S, Lorenz K, Baerleh- ner E, Reincke M, Beuschlein F, Knoefel W, Nies C, Hahner S, Allolio B: Intraoperative haemodynamic stability in patients with phaeochromocytoma - minimally invasive vs conventional open surgery. Clin Endocri- nol (Oxf) 2006;65:352-358.
22 Lindholm J, Juul S, Jorgensen JO, Astrup J, Bjerre P, Feldt-Rasmussen U, Hagen C, Jor- gensen J, Kosteljanetz M, Kristensen L, Laur- berg P, Schmidt K, Weeke J: Incidence and late prognosis of Cushing’s syndrome: a pop- ulation-based study. J Clin Endocrinol Metab 2001;86:117-123.
23 Putignano P, Toja P, Dubini A, Giraldi FP, Corsello SM, Cavagnini F: Midnight salivary cortisol versus urinary free and midnight se- rum cortisol as screening tests for Cushing’s syndrome. J Clin Endocrinol Metab 2003;88: 4153-4157.
24 Reimondo G, Allasino B, Bovio S, Paccotti P, Angeli A, Terzolo M: Evaluation of the effec- tiveness of midnight serum cortisol in the diagnostic procedures for Cushing’s syn- drome. Eur J Endocrinol 2005;153:803-809.
25 Reincke M, Nieke J, Krestin GP, Saeger W, Allolio B, Winkelmann W: Preclinical Cush- ing’s syndrome in adrenal ‘incidentalomas’: comparison with adrenal Cushing’s syn- drome. J Clin Endocrinol Metab 1992;75: 826-832.
26 Ross NS: Epidemiology of Cushing’s syn- drome and subclinical disease. Endocrinol Metab Clin North Am 1994;23:539-546.
27 Terzolo M, Osella G, Ali A, Borretta G, Ce- sario F, Paccotti P, Angeli A: Subclinical Cushing’s syndrome in adrenal incidentalo- ma. Clin Endocrinol 1998;48:89-97.
28 Terzolo M, Pia A, Ali A, Osella G, Reimondo G, Bovio S, Daffara F, Procopio M, Paccotti P, Borretta G, Angeli A: Adrenal incidentalo- ma: a new cause of the metabolic syndrome? J Clin Endocrinol Metab 2002;87:998-1003.
29 Barzon L, Fallo F, Sonino N, Boscaro M: De- velopment of overt Cushing’s syndrome in patients with adrenal incidentaloma. Eur J Endocrinol 2002;146:61-66.
30 Terzolo M, Bovio S, Pia A, Conton PA, Rei- mondo G, Dall’Asta C, Bemporad D, Angeli A, Opocher G, Mannelli M, Ambrosi B, Mantero F: Midnight serum cortisol as a marker of increased cardiovascular risk in patients with a clinically inapparent adrenal adenoma. Eur J Endocrinol 2005;153:307- 315.
31 Fardella CE, Mosso L, Gomez-Sanchez C, Cortes P, Soto J, Gomez L, Pinto M, Huete A, Oestreicher E, Foradori A, Montero J: Pri- mary hyperaldosteronism in essential hy- pertensives: prevalence, biochemical profile, and molecular biology. J Clin Endocrinol Metab 2000;85:1863-1867.
32 Gordon RD, Klemm SA, Stowasser M, Tunny TJ, Storie WJ, Rutherford JC: How common is primary aldosteronism? Is it the most fre- quent cause of curable hypertension? J Hy- pertens 1993;11(suppl):S310-S311.
33 Lim PO, Rodgers P, Cardale K, Watson AD, MacDonald TM: Potentially high prevalence of primary aldosteronism in a primary-care population. Lancet 1999;353:40.
34 Mulatero P, Stowasser M, Loh KC, Fardella CE, Gordon RD, Mosso L, Gomez-Sanchez CE, Veglio F, Young WF Jr: Increased diag- nosis of primary aldosteronism, including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab 2004;89:1045-1050.
35 Stowasser M, Gordon RD, Rutherford JC, Nikwan NZ, Daunt N, Slater GJ: Diagnosis and management of primary aldosteronism. J Renin Angiotensin Aldosterone Syst 2001; 2:156-169.
36 Young WF Jr: Minireview: primary aldoste- ronism - changing concepts in diagnosis and treatment. Endocrinology 2003; 144: 2208-2213.
37 Tiu SC, Choi CH, Shek CC, Ng YW, Chan FK, Ng CM, Kong AP: The use of aldoste- rone-renin ratio as a diagnostic test for pri- mary hyperaldosteronism and its test char- acteristics under different conditions of blood sampling. J Clin Endocrinol Metab 2005;90:72-78.
38 Seiler L, Rump LC, Schulte-Monting J, Slawik M, Borm K, Pavenstadt H, Beuschlein F, Reincke M: Diagnosis of primary aldoste- ronism: value of different screening param- eters and influence of antihypertensive med- ication. Eur J Endocrinol 2004;150:329-337.
39 Agharazii M, Douville P, Grose JH, Lebel M: Captopril suppression versus salt loading in confirming primary aldosteronism. Hyper- tension 2001;37:1440-1443.
40 Ganguly A: Primary aldosteronism. N Engl J Med 1998;339:1828-1834.
41 Stokes GS, Monaghan JC, Mennie BA: Use of an intravenous sodium load in screening for primary hyperaldosteronism. Aust NZ J Med 1984;14:201-207.
42 Grumbach MM, Biller BM, Braunstein GD, Campbell KK, Carney JA, Godley PA, Harris EL, Lee JK, Oertel YC, Posner MC, Schlechte JA, Wieand HS: Management of the clinical- ly inapparent adrenal mass (‘incidentalo- ma’). Ann Intern Med 2003;138:424-429.
Copyright: S. Karger AG, Basel 2007. Reproduced with the permission of 5. Karger AG, Basel. Further reproduction or distribution (electronic or otherwise) is prohibited without permission from the copyright holder.
Copyright: S. Karger AG, Basel 2007. Reproduced with the permission of 5. Karger AG, Basel. Further reproduction or distribution (electronic or otherwise) is prohibited without permission from the copyright holder.