Abstract
Background: Adrenal incidentalomas are mostly non-functioning adrenal tumors (NFAT) or adenomas with mild autonomous cortisol excess (MACE), of which the natural history is unclear. We conducted a systematic review and meta-analysis to study the long-term follow-up of NFAT and MACE to determine: (i) proportion of tumor growth and malignant transformation, (ii) incident change of hormone function, and (iii) incident cardio-metabolic comorbidities and mortality. Methods: Literature search of multiple databases including MEDLINE, EMBASE, Cochrane, and Scopus (January 1990 to February 2018). We included studies of adults with NFAT or MACE (as defined by authors), with ≥20 patients undergoing conservative management, and reported outcomes of interest at baseline and after ≥12 months follow-up. Results: We included 31 studies reporting on 4138 patients with incidental NFAT and MACE; 61.9% females, mean age 60.1 years, and mean follow-up 48.9 months. Overall, the data quality was medium-high, but there was significant heterogeneity in MACE and comorbidities definitions. Mean tumor growth in NFAT and MACE was 1.8mm over 60.6 months, which was similar between both groups. Adenomas were less likely to grow when the baseline mean size was ≥2.5cm, compared to smaller adenomas (<2.5 cm); mean size difference 0.8mm and 2.3mm, respectively. While 10% of patients demonstrated tumor enlargement, growth of ≥1cm occurred in only 4.5% over 62.0 months, which was relatively higher in MACE (MACE 4.5% vs. NFAT 2.3%). None of 2690 NFAT and MACE patients developed adrenal malignancy over 42.4 months. Development of overt Cushing’s syndrome and pheochromocytoma was very rare (0.4%). None of 2690 patients developed primary hyperaldosteronism. Of 2088 NFAT patients, 5.6% developed MACE, while pre-existing MACE resolved in 1.9% of 780 patients during 50.6 months. Hypertension, obesity, dyslipidemia, and type 2 diabetes were highly prevalent, 59.8%, 46.6%, 34.2%, and 19.3% of patients, respectively, and more likely to develop and worsen in MACE compared to NFAT. Cardiovascular events were twice as common in MACE compared to NFAT, and cardiovascular mortality occurred more in MACE (6.6%) than NFAT (5.0%) during 58.7 months follow-up. Conclusions: Patients with NFAT and MACE do not require radiological or hormonal follow-up. However, they carry an increased risk of cardio-metabolic comorbidities, warranting evaluation and appropriate therapy.