April 03, 2026
Differentiating malignant from benign adrenal lesions can be challenging, especially in lipid poor masses. Most lipid poor adrenal lesions are benign, but malignancy also must be considered. Unfortunately, there is no definitive imaging characteristic to completely distinguish them. Adrenal biopsy is rarely indicated as it is often unable to differentiate benign adrenal cortical adenoma from malignant adrenal cortical carcinoma (ACC). Additionally, adrenal biopsy carries risk of seeding the biopsy tract with tumor. Fortunately, measuring metabolic "fingerprints" of steroidogenesis, termed metabolomics, has emerged as a practical tool to refine the estimated risk of ACC in indeterminant adrenal lesions.
The strongest evidence supporting use of urine steroid metabolomics comes from the multinational EURINE-ACT study published in The Lancet Diabetes & Endocrinology and led by Irina Bancos, M.D., M.S., an endocrinologist at Mayo Clinic in Rochester, Minnesota. Using mass spectrometry-based profiling of urinary steroid metabolites and machine learning analysis in more than 2,000 patients, investigators demonstrated that ACC produces a distinctive pattern of excess steroid precursors reflecting disorganized tumor steroidogenesis. When urine metabolomics was added to tumor size and imaging criteria, identification of ACC significantly improved while excellent negative predictive value was maintained. In practice, this approach helps prioritize surgical referral and informs surgeons of the need for an oncologic-minded resection.
"Knowing whether an indeterminant adrenal lesion likely represents ACC based on metabolomics may steer the operation to be conducted in a more aggressive open fashion, which has been shown to improve patient survival," says Trenton R. Foster, M.D., an endocrine surgeon at Mayo Clinic in Rochester, Minnesota. "Conversely, lesions that are unlikely to be ACC can often be offered less morbid minimally invasive surgical options."
Because specialized urine testing is not universally available, interest in serum alternatives also has arisen. A recent prospective cohort study published in the Journal of Clinical Endocrinology and Metabolism evaluated a simple panel of three circulating steroid precursors: 11-deoxycortisol, 17OH-progesterone and 17OH-pregnenolone. These markers were found to be severalfold higher in ACC compared with adrenal cortical adenoma, including in lipid-poor tumors. A machine learning-derived serum steroid score showed good discrimination between ACC and other adrenal lesions. While not yet as comprehensive as urine metabolomics, serum profiling may offer a more scalable and accessible option for many centers.
At Mayo Clinic, clinicians routinely include urine metabolomics — determined through a standardized 24-hour urine mass spectrometry panel — to estimate risk of ACC when evaluating indeterminant adrenal nodules. As more data validate the role of serum steroid precursors, their measurement and use in the clinical setting is expected to increase. Overall, use of steroid metabolomics is helping patients and their care teams at Mayo Clinic understand adrenal mass risk, which is vital to developing optimal treatment strategies.
For more information
Bancos I, et al. Urine steroid metabolomics for the differential diagnosis of adrenal incidentalomas in the EURINE-ACT study: A prospective test validation study. The Lancet Diabetes & Endocrinology. 2020;8:773.
Yu K, et al. Serum steroid profiling in the diagnosis of adrenocortical carcinoma: A prospective cohort study. Journal of Clinical Endocrinology and Metabolism. 2025;110:1177.
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