Renal epithelioid angiomyolipoma: A multi-institutional, international cohort study with emphasis on clinicopathologic prognostic indicators

Background: Renal angiomyolipoma (AML) is a benign perivascular epithelioid cell neoplasm that is often associated with tuberous sclerosis complex (TSC). Epithelioid AML (eAML), a very rare and potentially malignant variant, can be challenging to radiologically differentiate from benign AML and other renal tumors. Adverse histological features have previously been associated to poorer oncological outcomes. This study aimed to characterize this rare disease entity and validate previously reported adverse prognostic factors. Methods: This multicenter, retrospective cohort study analyzed 76 patients diagnosed with eAML between 2001 and 2024 across 15 participating centers. Inclusion criteria were histological diagnosis of eAML with negative cytokeratin markers and positive melanocytic markers. Patients were stratified according to previously described adverse pathological features. Results: A total of 76 patients were studied. Most were female (70%), with a median age of 48 years and, 19 patients had TSC. Median tumor size was 45 mm, with a rate of atypical epithelioid cells >70% in 26 (34.2%) patients. According to the Nese's and Brimo's classifications, 4% and 14% of patients were at high risk, respectively. During a median follow- up of 30-months, 5 (6.7 %) patients developed metastases, and 4 (5.3 %) died. At univariable analysis, the number of adverse pathological risk factors, according to both classifications, was significantly associated with worse metastasis free survival (MFS) and cancer specific survival (CSS). Due to the low number of events, a multivariable analysis was not carried out. Conclusions: eAML is extremely rare, and primarily affects middle-aged women. This cohort validated previously described pathological risk factors for worse prognosis, suggesting that patients with multiple adverse features may require more intensive follow-up.