Natural history of adrenal incidentalomas with and without mild autonomous cortisol excess: a systematic review and meta-analysis

Research output: Contribution to journalArticlepeer-review


  • Fares Alahdab
  • Danae Delivanis
  • Aakanksha Khanna
  • Larry Prokop
  • Mohammad H Murad
  • Irina Bancos

Colleges, School and Institutes


Background: Adrenal incidentalomas are mostly non-functioning adrenal tumours (NFAT) or adenomas with mild autonomous cortisol excess (MACE), of which the natural history is unclear. We conducted a systematic review and meta-analysis focussing on NFAT and MACE to determine the: (i) proportion and degree of tumour growth, (ii) incident change in hormone function, and (iii) proportion of malignant transformation.

Methods: We searched MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE, and CENTRAL (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 32 studies (17 retrospective, 15 prospective) reporting 2690 patients with incidental NFAT and MACE; 61.9% females, mean age 60.1 years, and mean follow-up 49 months. Studies used heterogeneous definitions for MACE and for studied outcomes. Overall, the data quality was medium-high. Development of overt Cushing’s syndrome and phaeochromocytoma in NFAT and MACE was very rare, 0.4% of 2482 patients and 0.4% of 2690 patients, respectively. None of 2690 NFAT and MACE patients developed primary hyperaldosteronism. Of 2088 NFAT patients, only 5.2% developed MACE, while pre-existing MACE resolved in 1.5% of 780 patients during follow-up. Mean tumour growth in NFAT and MACE was 1.4 mm (CI95% 0.46–2.3) over mean follow-up 41.6 months. While 10.5% of NFAT and MACE patients demonstrated tumour enlargement, growth of ≥1 cm occurred in only 4.7% of patients. None of 2690 NFAT and MACE patients developed adrenal malignancy.

Conclusions: New diagnosis of overt Cushing’s syndrome, primary hyperaldosteronism, or phaeochromocytoma is rare. Only 5.2% of NFAT developed MACE, while only 1.5% of MACE became non-functional, possibly suggestive of initially false-positive results. Tumour growth ≥1 cm occurred in 4.7% of patients. None of NFAT and MACE patients developed adrenal malignancy during follow-up.


Original languageEnglish
Pages (from-to)107-116
JournalAnnals of internal medicine
Issue number2
Early online date25 Jun 2019
Publication statusPublished - 16 Jul 2019