Adrenal incidentalomas and subclinical Cushing's syndrome: Diagnosis and treatment

Current Opinion in Endocrinology, Diabetes and Obesity

Volumn 16, Issue 3, 2009, Pages 203-210

  Mazzuco, Tânia Longo ^a   Bourdeau, Isabelle ^a   Lacroix, André ^a  

^a CENTRE HOSPITALIER DE L UNIVERSITÉ DE MONTRÉAL   (Canada)

Author keywords

Adrenal incidentalomas; Adrenocortical tumors; Primary adrenal Cushing's syndrome; Subclinical Cushing's syndrome

Indexed keywords

CORTICOTROPIN; GLUCOCORTICOID; HYDROCORTISONE; BIOLOGICAL MARKER;

ADRENAL INCIDENTALOMA; BIOCHEMISTRY; CANCER DIAGNOSIS; CANCER SCREENING; CANCER SURGERY; CLINICAL FEATURE; CUSHING SYNDROME; DIAGNOSTIC ACCURACY; FOLLOW UP; HUMAN; HYDROCORTISONE RELEASE; HYPERCORTISOLISM; PRACTICE GUIDELINE; PREVALENCE; REVIEW; ADRENAL TUMOR; ALGORITHM; BLOOD; DISEASE COURSE; ENDOCRINE FUNCTION TEST; HOSPITALIZATION; INCIDENTAL FINDING; PREDICTION AND FORECASTING;

ADRENAL CORTEX FUNCTION TESTS; ADRENAL GLAND NEOPLASMS; ALGORITHMS; BIOLOGICAL MARKERS; CUSHING SYNDROME; DISEASE PROGRESSION; HUMANS; HYDROCORTISONE; INCIDENTAL FINDINGS; PREDICTIVE VALUE OF TESTS; SEVERITY OF ILLNESS INDEX;

EID: 66349131397     PISSN: 1752296X     EISSN: None     Source Type: Journal    
DOI: 10.1097/MED.0b013e32832b7043     Document Type: Review

References (73)

1. Barzon L, Sonino N, Fallo F, et al. Prevalence and natural history of adrenal incidentalomas. Eur J Endocrinol 2003; 149:273-285. (Pubitemid 37304697)
2. Mansmann G, Lau J, Balk E, et al. The clinically inapparent adrenal mass: update in diagnosis and management. Endocr Rev 2004; 25:309-340. (Pubitemid 38528713)
3. Rossi R, Tauchmanova L, Luciano A, et al. Subclinical Cushing's syndrome in patients with adrenal incidentaloma: clinical and biochemical features. J Clin Endocrinol Metab 2000; 85:1440-1448. (Pubitemid 32289484)
4. Terzolo M, Pia A, Ali A, et al. Adrenal incidentaloma: a new cause of the metabolic syndrome? J Clin Endocrinol Metab 2002; 87:998-1003.
5. Terzolo M, Bovio S, Pia A, et al. Subclinical Cushing's syndrome. Arq Bras Endocrinol Metabol 2007; 51:1272-1279.
6. Thompson GB, Young WF Jr. Adrenal incidentaloma. Curr Opin Oncol 2003; 15:84-90.
7. Singh PK, Buch HN. Adrenal incidentaloma: evaluation and management. J Clin Pathol 2008; 61:1168-1173.
8. Nawar R, Aron D. Adrenal incidentalomas: a continuing management dilemma. Endocr Relat Cancer 2005; 12:585-598. (Pubitemid 41482994)
9. Mantero F, Terzolo M, Arnaldi G, et al. A survey on adrenal incidentaloma in Italy. Study Group on Adrenal Tumors of the Italian Society of Endocrinology. J Clin Endocrinol Metab 2000; 85:637-644.
10. Young WF Jr. Clinical practice. The incidentally discovered adrenal mass. N Engl J Med 2007; 356:601-610. Starting from a clinical case of adrenal incidentaloma, an educational reasoning on differential diagnosis is presented including cortisol-secreting masses in this article.
11. Hamrahian AH, Ioachimescu AG, Remer EM, 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; 90:871-877.
12. Tabarin A, Bardet S, Bertherat J, et al. Exploration and management of adrenal incidentalomas. French Society of Endocrinology Consensus. Ann Endocrinol (Paris) 2008; 69:487-500. In the above article, several issues concerning adrenal incidentalomas are systematically reviewed, including particularly informative discussion on imaging evaluation. In the screening for SCS, the French Endocrinology Society recommends the 1mg overnight dexamethasone test.
13. Duenschede F, Bittinger F, Heintz A, et al. Malignant and unclear histological findings in incidentalomas. Eur Surg Res 2008; 40:235-238. (Pubitemid 351255502)
14. McLeod MK, Thompson NW, Gross MD, et al. Sub-clinical Cushing's syndrome in patients with adrenal gland incidentalomas. Pitfalls in diagnosis and management. Am Surg 1990; 56:398-403.
15. Reincke M, Nieke J, Krestin GP, et al. Preclinical Cushing's syndrome in adrenal 'incidentalomas': comparison with adrenal Cushing's syndrome. J Clin Endocrinol Metab 1992; 75:826-832.
16. Osella G, Terzolo M, Borretta G, et al. Endocrine evaluation of incidentally discovered adrenal masses (incidentalomas). J Clin Endocrinol Metab 1994; 79:1532-1539.
17. Barzon L, Scaroni C, Sonino N, et al. Risk factors and long-term follow-up of adrenal incidentalomas. J Clin Endocrinol Metab 1999; 84:520-526. (Pubitemid 29075678)
18. Valli N, Catargi B, Ronci N, et al. Biochemical screening for subclinical cortisol-secreting adenomas amongst adrenal incidentalomas. Eur J Endocrinol 2001; 144:401-408. (Pubitemid 32409594)
19. Libe R, Dall'Asta C, Barbetta L, et al. Long-term follow-up study of patients with adrenal incidentalomas. Eur J Endocrinol 2002; 147:489-494. (Pubitemid 35238144)
20. Bhargav PR, Mishra A, Agarwal G, et al. Adrenal incidentalomas: experience in a developing country. World J Surg 2008; 32:1802-1808.
21. Vassilatou E, Vryonidou A, Michalopoulou S, et al. Hormonal activity of adrenal incidentalomas: results from a long term follow-up study. Clin Endocrinol (Oxf) 2009; 70:674-679. In this large group of adrenal incidentalomas, a significant number of patients had either constant or intermittent subclinical cortisol hypersecretion. Bilateral adrenal masses were frequent, and the development of overt Cushing's syndrome was related to the increase of mass size.
22. Reznik Y, Lefebvre H, Rohmer V, et al. Aberrant adrenal sensitivity to multiple ligands in unilateral incidentaloma with subclinical autonomous cortisol hypersecretion: a prospective clinical study. Clin Endocrinol (Oxf) 2004; 61:311-319. (Pubitemid 39287059)
23. Erbil Y, Ademoglu E, Ozbey N, et al. Evaluation of the cardiovascular risk in patients with subclinical Cushing syndrome before and after surgery. World J Surg 2006; 30:1665-1671. (Pubitemid 44411221)
24. Masserini B, Morelli V, Bergamaschi S, et al. The limited role of midnight salivary cortisol levels in the diagnosis of subclinical hypercortisolism in patients with adrenal incidentaloma. Eur J Endocrinol 2008; 160:87-92. In the above article, though the determination of salivary cortisol at bedtime is a very sensitive and easy-to-perform marker for the diagnosis of Cushing's syndrome, authors showed that its sensitivity was 22% in the context of subclinical hypercortisolism; thus, it should not be used as the first screening test.
25. Shen WT, Lee J, Kebebew E, et al. Selective use of steroid replacement after adrenalectomy: lessons from 331 consecutive cases. Arch Surg 2006; 141:771-774; discussion 774-776. (Pubitemid 44268517)
26. Siren JE, Haapiainen RK, Huikuri KT, Sivula AH. Incidentalomas of the adrenal gland: 36 operated patients and review of literature. World J Surg 1993; 17:634-639.
27. Luton JP, Martinez M, Coste J, Bertherat J. Outcome in patients with adrenal incidentaloma selected for surgery: an analysis of 88 cases investigated in a single clinical center. Eur J Endocrinol 2000; 143:111-117. (Pubitemid 30482208)
28. Mitchell IC, Auchus RJ, Juneja K, et al. Subclinical Cushing's syndrome' is not subclinical: improvement after adrenalectomy in 9 patients. Surgery 2007; 142:900-905. (Pubitemid 350184118)
29. Young WF Jr, du Plessis H, Thompson GB, et al. The clinical conundrum of corticotropin-independent autonomous cortisol secretion in patients with bilateral adrenal masses. World J Surg 2008; 32:856-862.
30. Bourdeau I, D'Amour P, Hamet P, et al. Aberrant membrane hormone receptors in incidentally discovered bilateral macronodular adrenal hyperplasia with subclinical Cushing's syndrome. J Clin Endocrinol Metab 2001; 86:5534-5540. (Pubitemid 33070285)
31. Tatsuno I, Uchida D, Tanaka T, et al. Vasopressin responsiveness of subclinical Cushing's syndrome due to ACTH-independent macronodular adrenocortical hyperplasia. Clin Endocrinol (Oxf) 2004; 60:192-200. (Pubitemid 38200900)
32. Groussin L, Perlemoine K, Contesse V, et al. The ectopic expression of the gastric inhibitory polypeptide receptor is frequent in adrenocorticotropin- independent bilateral macronodular adrenal hyperplasia, but rare in unilateral tumors. J Clin Endocrinol Metab 2002; 87:1980-1985. (Pubitemid 34521477)
33. Cartier D, Lihrmann I, Parmentier F, et al. Overexpression of serotonin4 receptors in cisapride-responsive adrenocorticotropin-independent bilateral macronodular adrenal hyperplasia causing Cushing's syndrome. J Clin Endocrinol Metab 2003; 88:248-254. (Pubitemid 36115174)
34. Minami S, Sugihara H, Sato J, et al. ACTH independent Cushing's syndrome occurring in siblings. Clin Endocrinol (Oxf) 1996; 44:483-488. (Pubitemid 26142880)
35. Nies C, Bartsch DK, Ehlenz K, et al. Familial ACTH-independent Cushing's syndrome with bilateral macronodular adrenal hyperplasia clinically affecting only female family members. Exp Clin Endocrinol Diabetes 2002; 110:277-283. (Pubitemid 35246744)
36. Vezzosi D, Cartier D, Regnier C, et al. Familial adrenocorticotropin- independent macronodular adrenal hyperplasia with aberrant serotonin and vasopressin adrenal receptors. Eur J Endocrinol 2007; 156:21-31. In the above article, various degrees of hypercortisolism in the first in-vivo and in-vitro study of adrenal serotoninergic receptors are expressed in familial AIMAH. Several isoforms of 5-HT receptors and vasopressin receptors were identified in adrenal tissues.
37. Gagliardi L, Hotu C, Casey G, et al. Familial vasopressin-sensitive ACTH-independent macronodular adrenal hyperplasia (VPs-AIMAH): clinical studies of three kindreds. Clin Endocrinol (Oxf) 2008; doi: 10.1111/j.1365-2265. 2008.03471.x.
38. Ross NS, Aron DC. Hormonal evaluation of the patient with an incidentally discovered adrenal mass. N Engl J Med 1990; 323:1401-1405.
39. McNicol AM. A diagnostic approach to adrenal cortical lesions. Endocr Pathol 2008; 19:241-251.
40. Bourdeau I, Lampron A, Costa MH, et al. Adrenocorticotropic hormone-independent Cushing's syndrome. Curr Opin Endocrinol Diabetes Obes 2007; 14:219-225. An exhaustive classification of adrenal lesions and possible molecular pathogenesis of adrenocorticotropic hormone-independent Cushing's syndrome are presented. Of note, authors discuss the role of aberrant hormone receptors in adrenal Cushing's syndrome and related pharmacological therapies.
41. Latronico AC, Chrousos GP. Extensive personal experience: adrenocortical tumors. J Clin Endocrinol Metab 1997; 82:1317-1324. (Pubitemid 27200395)
42. Lindholm J, Juul S, Jorgensen JO, et al. Incidence and late prognosis of Cushing's syndrome: a population-based study. J Clin Endocrinol Metab 2001; 86:117-123. (Pubitemid 32111743)
43. Costa MH, Lacroix A. Cushing's syndrome secondary to ACTH-independent macronodular adrenal hyperplasia. Arq Bras Endocrinol Metabol 2007; 51:1226-1237.
44. Lacroix A, Bourdeau I. Bilateral adrenal Cushing's syndrome: macronodular adrenal hyperplasia and primary pigmented nodular adrenocortical disease. Endocrinol Metab Clin North Am 2005; 34:441-458. (Pubitemid 40602731)
45. Muller M, Longo Mazzuco T, Martinie M, et al. Diagnosis of Cushing's syndrome: a retrospective evaluation of clinical practice. Eur J Intern Med 2006; 17:334-338. (Pubitemid 44080546)
46. Newell-Price J, Bertagna X, Grossman AB, Nieman LK. Cushing's syndrome. Lancet 2006; 367:1605-1617.
47. Nieman LK, Biller BM, Findling JW, et al. The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice guideline. J Clin Endocrinol Metab 2008; 93:1526-1540. Expert panel recommendations on initial screening and diagnosis of Cushing's syndrome. Includes useful recommendations concerning special situations (pregnancy, renal failure) and methodological issues such as sample collection and drugs interfering with dexamethasone metabolism.
48. Reincke M. Subclinical Cushing's syndrome. Endocrinol Metab Clin North Am 2000; 29:43-56.
49. Terzolo M, Bovio S, Reimondo G, et al. Subclinical Cushing's syndrome in adrenal incidentalomas. Endocrinol Metab Clin North Am 2005; 34:423-439. (Pubitemid 40602730)
50. Christopoulos S, Bourdeau I, Lacroix A. Clinical and subclinical ACTH-independent macronodular adrenal hyperplasia and aberrant hormone receptors. Horm Res 2005; 64:119-131. (Pubitemid 41507294)
51. Lacroix A, Ndiaye N, Tremblay J, Hamet P. Ectopic and abnormal hormone receptors in adrenal Cushing's syndrome. Endocr Rev 2001; 22:75-110. (Pubitemid 32187804)
52. Mircescu H, Jilwan J, N'Diaye N, et al. Are ectopic or abnormal membrane hormone receptors frequently present in adrenal Cushing's syndrome? J Clin Endocrinol Metab 2000; 85:3531-3536.
53. Barry MK, van Heerden JA, Farley DR, et al. Can adrenal incidentalomas be safely observed? World J Surg 1998; 22:599-603; discussion 603-604
54. Barzon L, Fallo F, Sonino N, Boscaro M. Development of overt Cushing's syndrome in patients with adrenal incidentaloma. Eur J Endocrinol 2002; 146:61-66. (Pubitemid 34126421)
55. Bulow B, Jansson S, Juhlin C, et al. Adrenal incidentaloma: follow-up results from a Swedish prospective study. Eur J Endocrinol 2006; 154:419-423.
56. Caetano MS, Silva Rdo C, Kater CE. Increased diagnostic probability of subclinical Cushing's syndrome in a population sample of overweight adult patients with type 2 diabetes mellitus. Arq Bras Endocrinol Metabol 2007; 51:1118-1127. The above article presents interesting data on biochemical investigation of HPA axis including the interpretation of salivary (23 : 00 h and post-1 mg DST) and serum cortisol (after 1 mg and 2 mg DST) based on P80 values (upper quintile) and the correlation of concurrent serum and salivary cortisol levels after 1 mg DST.
57. Catargi B, Rigalleau V, Poussin A, et al. Occult Cushing's syndrome in type-2 diabetes. J Clin Endocrinol Metab 2003; 88:5808-5813. (Pubitemid 38033055)
58. Francucci CM, Caudarella R, Rilli S, et al. Adrenal incidentaloma: effects on bone metabolism. J Endocrinol Invest 2008; 31:48-52.
59. Ermetici F, Malavazos AE, Corbetta S, et al. Adipokine levels and cardiovascular risk in patients with adrenal incidentaloma. Metabolism 2007; 56:686-692. Authors have studied the plasma levels of inflammatory mediators that can be produced by adipose tissue (IL-6, adiponectin, resistin, TNFα and monocyte chemoattractant protein-1) in patients with adrenal incidentalomas and a wide spectrum of HPA abnormalities; they are discussed in view of the cardiovascular metabolism. (Pubitemid 46574732)
60. Ermetici F, Dall'Asta C, Malavazos AE, et al. Echocardiographic alterations in patients with nonfunctioning adrenal incidentaloma. J Endocrinol Invest 2008; 31:573-577.
61. Lee S, Hwang R, Lee J, et al. Ectopic expression of vasopressin V1b and V2 receptors in the adrenal glands of familial ACTH-independent macronodular adrenal hyperplasia. Clin Endocrinol (Oxf) 2005; 63:625-630. (Pubitemid 41779634)
62. Miyamura N, Taguchi T, Murata Y, et al. Inherited adrenocorticotropin- independent macronodular adrenal hyperplasia with abnormal cortisol secretion by vasopressin and catecholamines: detection of the aberrant hormone receptors on adrenal gland. Endocrine 2002; 19:319-326. (Pubitemid 36250313)
63. Emral R, Uysal AR, Asik M, et al. Prevalence of subclinical Cushing's syndrome in 70 patients with adrenal incidentaloma: clinical, biochemical and surgical outcomes. Endocr J 2003; 50:399-408. (Pubitemid 37129032)
64. Grumbach MM, Biller BM, Braunstein GD, et al. Management of the clinically inapparent adrenal mass ('incidentaloma'). Ann Intern Med 2003; 138:424-429. (Pubitemid 36262654)
65. Findling JW, Raff H, Aron DC. The low-dose dexamethasone suppression test: a reevaluation in patients with Cushing's syndrome. J Clin Endocrinol Metab 2004; 89:1222-1226. (Pubitemid 38368417)
66. Herrera MF, Grant CS, van Heerden JA, et al. Incidentally discovered adrenal tumors: an institutional perspective. Surgery 1991; 110:1014-1021.
67. Midorikawa S, Sanada H, Hashimoto S, et al. The improvement of insulin resistance in patients with adrenal incidentaloma by surgical resection. Clin Endocrinol (Oxf) 2001; 54:797-804. (Pubitemid 34208891)
68. Tanabe A, Naruse M, Nishikawa T, et al. Autonomy of cortisol secretion in clinically silent adrenal incidentaloma. Horm Metab Res 2001; 33:444-450. (Pubitemid 32721529)
69. Flecchia D, Mazza E, Carlini M, et al. Reduced serum levels of dehydroepiandrosterone sulphate in adrenal incidentalomas: a marker of adrenocortical tumour. Clin Endocrinol (Oxf) 1995; 42:129-134.
70. Terzolo M, Osella G, Ali A, et al. Subclinical Cushing's syndrome in adrenal incidentaloma. Clin Endocrinol (Oxf) 1998; 48:89-97. (Pubitemid 28122438)
71. Guerrieri M, De Sanctis A, Crosta F, et al. Adrenal incidentaloma: surgical update. J Endocrinol Invest 2007; 30:200-204.
72. Simforoosh N, Majidpour HS, Basiri A, et al. Laparoscopic adrenalectomy: 10-year experience, 67 procedures. Urol J 2008; 5:50-54.
73. Shalet S, Mukherjee A. Pharmacological treatment of hypercortisolism. Curr Opin Endocrinol Diabetes Obes 2008; 15:234-238.