Elhassan, Alahdab, Prete, Delivanis, Khanna, Prokop, Murad, O'Reilly, Arlt, Bancos (2019) Natural History of Adrenal Incidentalomas With and Without Mild Autonomous Cortisol Excess: A Systematic Review and Meta-analysis Annals of internal medicine 171(2) 107-116


Adrenal incidentalomas are mostly benign nonfunctioning adrenal tumors (NFATs) or adenomas causing mild autonomous cortisol excess (MACE), but their natural history is unclear. To summarize the follow-up data of adults with NFAT or MACE to determine the proportions of tumor growth, malignant transformation, and incident changes in hormone function; the prevalence of incident cardiometabolic comorbid conditions; and mortality. MEDLINE, Embase, Cochrane, and Scopus (January 1990 to February 2019) and bibliographies of identified articles, without language restriction. Studies that included 20 or more conservatively managed patients with NFAT or MACE and reported outcomes at baseline and after at least 12 months of follow-up. Pairs of reviewers extracted outcomes and assessed methodological quality. Thirty-two studies reported outcomes of 4121 patients with NFAT or MACE, 61.5% of whom were women; the mean age was 60.2 years, and mean follow-up was 50.2 months. Mean tumor growth was 2 mm over 52.8 months. Clinically significant tumor enlargement (≥10 mm) occurred in 2.5% of patients, and none developed adrenal cancer. Clinically overt hormone excess was unlikely to develop (<0.1%) in patients with NFAT or MACE. Only 4.3% of patients with NFAT developed MACE, and preexisting MACE was unlikely to resolve (<0.1%). Hypertension, obesity, dyslipidemia, and type 2 diabetes were highly prevalent (60.0%, 42.0%, 33.7%, and 18.1% of patients, respectively) and were more likely to develop and worsen in MACE than NFAT. New cardiovascular events were more prevalent in MACE (15.5%) than NFAT (6.4%). Mortality was 11.2% and was similar between NFAT and MACE. Evidence was scarce, and definitions of MACE and comorbid conditions were heterogeneous. During follow-up, NFAT and MACE do not show clinically relevant changes in size or hormonal function, but they may carry an increased risk for cardiometabolic comorbid conditions. None.