Frequent antecedent nodules and diagnostic gaps in adrenocortical carcinoma

Adrenocortical carcinoma (ACC) is a rare and often fatal malignancy currently only cured by surgery. Large-scale studies have failed to capture benign to malignant transition events, and patients often present with metastatic disease. These observations suggest ACC develops rapidly without a measurable precursor lesion, forming the basis of widely implemented adrenal incidentaloma guidelines.

We aimed to characterize the prevalence of antecedent adrenal nodules, quality of preoperative diagnostic workup, and the impact on survival for adults with ACC.

We analyzed clinical data from 108 consecutive patients referred to a single tertiary academic medical center from 2000 to 2025.

Median follow-up was 86.7 months. Strikingly, 31.7% harbored antecedent nodules, indolent for a median 4.68 years before ACC presentation, and ultimately associated with a higher risk of death (adjusted hazard ratio [HR], 2.9; 95% CI, 1.39-6.0). Regarding preoperative evaluation, 46.4% were referred to endocrinology, associated with more complete hormonal assessment; 31.4% had adrenal biopsy, accompanied by increased risk of progression (adjusted HR, 2.53; 95% CI, 1.24-5.2) and death (adjusted HR, 2.22; 95% CI, 1.07-4.6). Patients with high-grade disease received more interventions; those who received mitotane and/or locoregional therapies had improved survival (adjusted HR, 0.31; 95% CI, 0.14-0.71, and adjusted HR, 0.47; 95% CI, 0.23-0.98, respectively).

The unexpectedly high prevalence of indolent antecedent adrenal nodules suggests a prolonged, clinically premalignant phase in a subset of ACC. Initial diagnostic evaluation was often incomplete or inappropriately invasive, compromising the preoperative window and patient survival. These findings challenge current surveillance paradigms, revealing an extended but vulnerable window for surgical cure.