Renal Epithelioid Angiomyolipoma

Epithelioid angiomyolipoma (eAML) is an uncommon subtype of angiomyolipoma, a subset of which can demonstrate malignant behavior. While some studies have proposed histopathologic features predictive of aggressive behavior in eAML, there is limited data on the use of immunohistochemistry (IHC) and/or next-generation sequencing (NGS) to identify biomarkers for poor clinical outcome. Moreover, there is limited data on the proposed genetic dichotomy (tuberous sclerosis complex [ TSC ] alteration versus TFE3 rearrangement) of eAML. Clinicopathologic features (including purported histologic features associated with adverse outcome) of 30 eAML were recorded with IHC performed on 1 whole-slide section per tumor for the following markers (interpretations): p16 (positive or negative), p53 (wild type or mutant), TRIM63 ISH (>10% as positive or ≤10% as negative), ATRX (retained or lost), and RB1 (retained or lost). NGS was performed on 23 tumors. The 30 eAML tumors were from 30 patients (23 female, 7 male) of an age range 22 to 77 years (mean=51.9 y). Clinical follow-up was available from 27 patients (mean=36 mo). The features significantly associated with metastatic disease included ≥70% atypical epithelial cells ( P =0.04), ≥2 mitotic figures per 10 high-power fields ( P =0.0013), atypical mitotic figures ( P =0.0003), and necrosis ( P =0.0213). Other features such as local invasion, vascular invasion, tumor size, and immunohistochemical profile (p16, TRIM63, p53, ATRX, and RB1) showed no significant association with the development of metastasis. Interestingly, among the 7 tumors with clinical follow-up showing TFE3 rearrangement, 5 developed metastases (OR=4.50), while 6 of 14 TSC/MTOR mutated tumors with clinical follow-up had metastatic disease (OR=0.222). Notably, TRIM63 ISH showed high sensitivity (100%) for eAML with TFE3 rearrangement but with poor specificity (38%). The genetic dichotomy of eAML comes in the form of TSC/MTOR alterations or TFE3 rearrangement elucidated by NGS, both of which may be associated with poor outcome, and therefore show potential therapeutic implications. As eAML may show overlap with TFE3 -rearranged/ TFEB -altered renal cell carcinoma, shared TRIM63 ISH positivity for these tumor types represents an important potential diagnostic pitfall.