Retrospective Study of Clinical Characteristics, Natural History and Predictive Factors for Mild Autonomous Cortisol Secretion (MACS) in Patients with Adrenal Incidentalomas in Malaysia

Authors

  • Vanusha Devaraja Selayang Hospital, Selangor Malaysia
  • Subashini Rajoo Hospital Kuala Lumpur, Malaysia
  • Vijaya Mala Valayatham Hospital Putrajaya
  • Foo Siew Hui Selayang Hospital, Selangor Malaysia

DOI:

https://doi.org/10.15605/jafes.041.01.5143

Keywords:

adrenal incidentalomas, mild autonomous cortisol secretion (MACS), metabolic disorders, osteoporosis, bilateral adrenal incidentalomas

Abstract

Introduction. Adrenal incidentalomas (AIs) are frequently discovered during imaging performed for unrelated conditions. While most are benign and non-functional, a subset demonstrates hormonal activity or malignant potential. This study aimed to describe the clinical and radiological characteristics, natural history and predictors of mild autonomous cortisol secretion (MACS) in a Malaysian cohort.

Methodology. This retrospective multicentre study reviewed medical records of 251 patients with AIs from three tertiary hospitals in Malaysia. Data on demographics, imaging findings, hormonal evaluations, histopathological diagnoses and longitudinal follow-up, including serial imaging and hormonal assessments, were collected and analysed.

Results. The median age of the cohort was 58 years (IQR 19), with a slight female predominance (53%). The population was predominantly Malay (n = 126, 50.2%), followed by Chinese (36.3%) and Indian (12.7%). The median follow-up duration was 39 months.

Most AIs were non-malignant (92%) and non-functioning (72%). Bilateral lesions were present in 9.6% of patients. Among non-malignant AIs, 27% were functioning, with higher rates of hypertension and osteoporosis, larger tumour size and greater tumour density. Adrenalectomy was more commonly performed in the functioning group, mainly for MACS and pheochromocytoma. In contrast, 94% of benign non-functioning AIs were managed conservatively, with no cases of malignant transformation and only one case developing hormonal activity over a median follow-up of 30 months. Among the 20 malignant AIs, 12 were primary adrenal carcinomas. Malignant AIs were associated with larger size, overt Cushing’s syndrome, higher Hounsfield units, lower contrast washout and increased mortality.

MACS was identified in 12.7% of the cohort. It was associated with bilateral lesions, larger tumour size, and higher prevalence of diabetes, dyslipidaemia, obesity and osteoporosis. On multivariate analysis, only bilaterality and osteoporosis remained significant predictors of MACS.

Conclusion. This study reinforces that most benign non-functioning AIs carry minimal risk of progression, supporting less intensive follow-up in stable cases. Bilaterality and osteoporosis were identified as independent predictors of MACS, emphasizing the importance of targeted hormonal and bone health monitoring in these patients.

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Author Biographies

Vanusha Devaraja, Selayang Hospital, Selangor Malaysia

Endocrine Unit, Department of Medicine, Selayang Hospital, Selangor Malaysia

Subashini Rajoo, Hospital Kuala Lumpur, Malaysia

Consultant, Endocrine Unit, Department of Medicine, Hospital Kuala Lumpur, Malaysia

Vijaya Mala Valayatham, Hospital Putrajaya

Consultant, Endocrine Unit, Department of Medicine, Hospital Putrajaya, Malaysia

Foo Siew Hui, Selayang Hospital, Selangor Malaysia

Consultant, Endocrine Unit, Department of Medicine, Selayang Hospital, Selangor Malaysia

References

Kloos RT, Gross MD, Francis IR, et al. Incidentally discovered adrenal masses. Endocr Rev. 1995;16(4):460-84. https://pubmed.ncbi.nlm.nih.gov/8521790 https://doi.org/10.1210/edrv-16-4-460 DOI: https://doi.org/10.1210/edrv-16-4-460

Grumbach MM, Biller BMK, Braunstein GD, et al. Management of the clinically inapparent adrenal mass ("incidentaloma"). Ann Intern Med. 2003;138(5):424-9. https://pubmed.ncbi.nlm.nih.gov/12614096 https://doi.org/10.7326/0003-4819-138-5-200303040-00013 DOI: https://doi.org/10.7326/0003-4819-138-5-200303040-00013

Lam KY, Lo CY. A critical examination of adrenal tuberculosis and a 28-year autopsy experience of active tuberculosis. Clin Endocrinol (Oxf). 2001;54(5):633-9. https://pubmed.ncbi.nlm.nih.gov/11380494 https://doi.org/10.1046/j.1365-2265.2001.01266.x DOI: https://doi.org/10.1046/j.1365-2265.2001.01266.x

Fassnacht M, Arlt W, Bancos I, et al. 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. 2016;175(2):G1-G34. https://pubmed.ncbi.nlm.nih.gov/27390021 https://doi.org/10.1530/EJE-16-0467 DOI: https://doi.org/10.1530/EJE-16-0467

Fassnacht M, Tsagarakis S, Terzolo M, et al. European society of endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European network for the study of adrenal tumors. Eur J Endocrinol. 2023;189(1):G1-G42. https://doi.org/10.1093/ejendo/lvad066 DOI: https://doi.org/10.1093/ejendo/lvad066

Zeiger MA, Thompson GB, Duh QY, et al. American association of clinical endocrinologists and American association of endocrine surgeons medical guidelines for the management of adrenal incidentalomas: Executive summary of recommendations. Endocr Pract. 2009;15(5):450-3. https://pubmed.ncbi.nlm.nih.gov/19632968 https://doi.org/10.4158/EP.15.5.450 DOI: https://doi.org/10.4158/EP.15.5.450

Lee JM, Kim MK, Ko SH, et al. Clinical guidelines for the management of adrenal incidentaloma. Endocrinol Metab (Seoul). 2017;32(2):200-18. https://pubmed.ncbi.nlm.nih.gov/28685511 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503865 https://doi.org/10.3803/EnM.2017.32.2.200 DOI: https://doi.org/10.3803/EnM.2017.32.2.200

Pelsma ICM, Fassnacht M, Tsagarakis S, et al. Comorbidities in mild autonomous cortisol secretion and the effect of treatment: Systematic review and meta-analysis. Eur J Endocrinol. 2023;189(4):S88-S101. https://pubmed.ncbi.nlm.nih.gov/37801655 https://doi.org/10.1093/ejendo/lvad134 DOI: https://doi.org/10.1093/ejendo/lvad134

Adamska A, Ulychnyi V, Siewko K, et al. Cardiovascular risk factors in mild adrenal autonomous cortisol secretion in a Caucasian population. Endocr Connect. 2022;11(9):e220074. https://pubmed.ncbi.nlm.nih.gov/35900803 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9422244 https://doi.org/10.1530/EC-22-0074 DOI: https://doi.org/10.1530/endoabs.81.EP18

Araujo-Castro M, Reincke M, Lamas C. Epidemiology and management of hypertension and diabetes mellitus in patients with mild autonomous cortisol secretion: A review. Biomedicines. 2023;11(12):3115. https://pubmed.ncbi.nlm.nih.gov/38137336 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10740610 https://doi.org/10.3390/biomedicines11123115 DOI: https://doi.org/10.3390/biomedicines11123115

Iacobone M, Citton M, Viel G, et al. Adrenalectomy may improve cardiovascular and metabolic impairment and ameliorate quality of life in patients with adrenal incidentalomas and subclinical Cushing's syndrome. Surgery. 2012;152(6):991-7. https://pubmed.ncbi.nlm.nih.gov/23158173 https://doi.org/10.1016/j.surg.2012.08.054 DOI: https://doi.org/10.1016/j.surg.2012.08.054

Koh JM, Song K, Kwak MK, et al. Adrenalectomy improves body weight, glucose, and blood pressure control in patients with mild autonomous cortisol secretion: Results of a randomized controlled trial by the Co-work of Adrenal Research (COAR) study. Ann Surg. 2024;279(6):945-52. https://pubmed.ncbi.nlm.nih.gov/38126763 https://doi.org/10.1097/SLA.0000000000006183 DOI: https://doi.org/10.1097/SLA.0000000000006183

Terzolo M, Pia A, Alì A, et al. Adrenal incidentaloma: A new cause of the metabolic syndrome? J Clin Endocrinol Metab. 2002;87(3):998-1003. https://pubmed.ncbi.nlm.nih.gov/11889151 https://doi.org/10.1210/jcem.87.3.8277 DOI: https://doi.org/10.1210/jc.87.3.998

Favero V, Cremaschi A, Parazzoli C, et al. Pathophysiology of mild hypercortisolism: From the bench to the bedside. Int J Mol Sci. 2022;23(2):673. https://pubmed.ncbi.nlm.nih.gov/35054858 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8775422 https://doi.org/10.3390/ijms23020673 DOI: https://doi.org/10.3390/ijms23020673

Terzolo M, Stigliano A, Chiodini I, et al. AME position statement on adrenal incidentaloma. Eur J Endocrinol. 2011;164(6):851-70. https://pubmed.ncbi.nlm.nih.gov/21471169 https://doi.org/10.1530/EJE-10-1147 DOI: https://doi.org/10.1530/EJE-10-1147

Androulakis II, Kaltsas GA, Kollias GE, et al. Patients with apparently nonfunctioning adrenal incidentalomas may be at increased cardiovascular risk due to excessive cortisol secretion. J Clin Endocrinol Metab. 2014;99(8):2754-62. https://doi.org/10.1210/jc.2013-4064 DOI: https://doi.org/10.1210/jc.2013-4064

Park SH, Kim MJ, Kim JH, et al. Differentiation of adrenal adenoma and nonadenoma in unenhanced CT: New optimal threshold value and the usefulness of size criteria for differentiation. Korean J Radiol. 2007;8(4):328-35. https://pubmed.ncbi.nlm.nih.gov/17673844 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2627166 https://doi.org/10.3348/kjr.2007.8.4.328 DOI: https://doi.org/10.3348/kjr.2007.8.4.328

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(2):871-7. https://pubmed.ncbi.nlm.nih.gov/15572420 https://doi.org/10.1210/jc.2004-1627 DOI: https://doi.org/10.1210/jc.2004-1627

Bancos I, Prete A. Approach to the patient with adrenal incidentaloma. J Clin Endocrinol Metab. 2021;106(11):3331-53. https://pubmed.ncbi.nlm.nih.gov/34260734 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8530736 https://doi.org/10.1210/clinem/dgab512 DOI: https://doi.org/10.1210/clinem/dgab512

Stavropoulos K, Imprialos KP, Katsiki N, et al. Primary aldosteronism in patients with adrenal incidentaloma: Is screening appropriate for everyone? J Clin Hypertens (Greenwich). 2018;20(5):942-8. https://pubmed.ncbi.nlm.nih.gov/29722113 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8031295 https://doi.org/10.1111/jch.13291 DOI: https://doi.org/10.1111/jch.13291

Funder JW, Carey RM, Mantero F, et al. The management of primary aldosteronism: Case detection, diagnosis, and treatment: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2016;101(5):1889-916. https://pubmed.ncbi.nlm.nih.gov/26934393 https://doi.org/10.1210/jc.2015-4061 DOI: https://doi.org/10.1210/jc.2015-4061

Elhassan YS, Alahdab F, Prete A, et al. Natural history of adrenal incidentalomas with and without mild autonomous cortisol excess: A systematic review and meta-analysis. Ann Intern Med. 2019;171(2):107-16. https://pubmed.ncbi.nlm.nih.gov/31234202 https://doi.org/10.7326/M18-3630 DOI: https://doi.org/10.7326/M18-3630

Morelli V, Reimondo G, Giordano R, et al. Long-term follow-up in adrenal incidentalomas: An Italian multicenter study. J Clin Endocrinol Metab. 2014;99(3):827-34. https://pubmed.ncbi.nlm.nih.gov/24423350 https://doi.org/10.1210/jc.2013-3527 DOI: https://doi.org/10.1210/jc.2013-3527

Pasternak JD, Seib CD, Seiser N, et al. Differences between bilateral adrenal incidentalomas and unilateral lesions. JAMA Surg. 2015;150(10):974-8. https://pubmed.ncbi.nlm.nih.gov/26200882 https://doi.org/10.1001/jamasurg.2015.1683 DOI: https://doi.org/10.1001/jamasurg.2015.1683

Vassiliadi DA, Ntali G, Stratigou T, et al. Aberrant cortisol responses to physiological stimuli in patients presenting with bilateral adrenal incidentalomas. Endocrine. 2011;40(3):437-44. https://pubmed.ncbi.nlm.nih.gov/21598069 https://doi.org/10.1007/s12020-011-9490-1 DOI: https://doi.org/10.1007/s12020-011-9490-1

Di Dalmazi G, Vicennati V, Garelli S, et al. 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. 2014;2(5):396-405. https://pubmed.ncbi.nlm.nih.gov/24795253 https://doi.org/10.1016/S2213-8587(13)70211-0 DOI: https://doi.org/10.1016/S2213-8587(13)70211-0

Chiodini I, Morelli V, Salcuni AS, et al. Beneficial metabolic effects of prompt surgical treatment in patients with an adrenal incidentaloma causing biochemical hypercortisolism. J Clin Endocrinol Metab. 2010;95(6):2736-45. https://pubmed.ncbi.nlm.nih.gov/20375210 https://doi.org/10.1210/jc.2009-2387 DOI: https://doi.org/10.1210/jc.2009-2387

Barzon L, Sonino N, Fallo F, et al. Prevalence and natural history of adrenal incidentalomas. Eur J Endocrinol. 2003;149(4):273-85. https://pubmed.ncbi.nlm.nih.gov/14514341 https://doi.org/10.1530/eje.0.1490273 DOI: https://doi.org/10.1530/eje.0.1490273

Giovanelli L, Aresta C, Favero V, et al. Hidden hypercortisolism: A too frequently neglected clinical condition. J Endocrinol Invest. 2021;44(8):1581-96. https://pubmed.ncbi.nlm.nih.gov/33394454 https://doi.org/10.1007/s40618-020-01484-2 DOI: https://doi.org/10.1007/s40618-020-01484-2

Hardy RS, Zhou H, Seibel MJ, et al. Glucocorticoids and bone: Consequences of endogenous and exogenous excess and replacement therapy. Endocr Rev. 2018;39(5):519-48. https://pubmed.ncbi.nlm.nih.gov/29905835 https://doi.org/10.1210/er.2018-00097 DOI: https://doi.org/10.1210/er.2018-00097

Morelli V, Eller-Vainicher C, Salcuni AS, et al. Risk of new vertebral fractures in patients with adrenal incidentaloma with and without subclinical hypercortisolism: A multicenter longitudinal study. J Bone Miner Res. 2011;26(8):1816-21. https://pubmed.ncbi.nlm.nih.gov/21472775 https://doi.org/10.1002/jbmr.398 DOI: https://doi.org/10.1002/jbmr.398

Hadjidakis D, Tsagarakis S, Roboti C, et al. Does subclinical hypercortisolism adversely affect the bone mineral density of patients with adrenal incidentalomas? Clin Endocrinol (Oxf). 2003;58(1):72-7. https://pubmed.ncbi.nlm.nih.gov/12519415 https://doi.org/10.1046/j.1365-2265.2003.01676.x DOI: https://doi.org/10.1046/j.1365-2265.2003.01676.x

Pal R, Banerjee M, Prasad TN, et al. Fracture risk and bone health in adrenal adenomas with mild autonomous cortisol secretion/subclinical hypercortisolism: A systematic review, meta-analysis and meta-regression. J Bone Miner Res. 2024;39(7):885-97. https://pubmed.ncbi.nlm.nih.gov/38703381 https://doi.org/10.1093/jbmr/zjae067 DOI: https://doi.org/10.1093/jbmr/zjae067

Tabarin A, Espiard S, Deutschbein T, et al. Surgery for the treatment of arterial hypertension in patients with unilateral adrenal incidentalomas and mild autonomous cortisol secretion (CHIRACIC): A multicentre, open-label, superiority randomised controlled trial. Lancet Diabetes Endocrinol. 2025;13(7):580-90. https://pubmed.ncbi.nlm.nih.gov/40373786 https://doi.org/10.1016/S2213-8587(25)00062-2 DOI: https://doi.org/10.1016/S2213-8587(25)00062-2

Ren X, Nan M, Zhang X. Evaluating the efficacy of surgical and conservative approaches in mild autonomous cortisol secretion: A meta-analysis. Front Endocrinol (Lausanne). 2024;15:1399311. https://pubmed.ncbi.nlm.nih.gov/39086899 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11288901 https://doi.org/10.3389/fendo.2024.1399311 DOI: https://doi.org/10.3389/fendo.2024.1399311

Cho YY, Suh S, Joung JY, et al. Clinical characteristics and follow-up of Korean patients with adrenal incidentalomas. Korean J Intern Med. 2013;28(5):557-64. https://pubmed.ncbi.nlm.nih.gov/24009451 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759761 https://doi.org/10.3904/kjim.2013.28.5.557 DOI: https://doi.org/10.3904/kjim.2013.28.5.557

Liu M, Zhao W, Zhang W, et al. Comparable cognitive impairment was detected in MACS and CS and alleviated after remission of hypercortisolism in MACS. Front Endocrinol (Lausanne). 2024;15:1373101. https://pubmed.ncbi.nlm.nih.gov/39145316 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11322108 https://doi.org/10.3389/fendo.2024.1373101 DOI: https://doi.org/10.3389/fendo.2024.1373101

Luk Y, Tsang VHM, Lo C, Lee R, Cheung YT, Wong KK, et al. Prevalence of mild autonomous cortisol secretion in adrenal incidentalomas and the significance of subcentimeter adrenal nodules: A single-center cohort study. Endocr Pract. 2025;31(12):1576-84. https://doi.org/10.1016/j.eprac.2025.07.018 DOI: https://doi.org/10.1016/j.eprac.2025.07.018

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2026-04-30

How to Cite

Devaraja, V., Rajoo, S., Valayatham, V. M., & Hui, F. S. (2026). Retrospective Study of Clinical Characteristics, Natural History and Predictive Factors for Mild Autonomous Cortisol Secretion (MACS) in Patients with Adrenal Incidentalomas in Malaysia. Journal of the ASEAN Federation of Endocrine Societies, 41(1). https://doi.org/10.15605/jafes.041.01.5143

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