Downstream mTOR effectors and VEGFR as biomarkers of malignant stratification in pathologic and genomic heterogeneity of PEComas.

Abstract

e23527 Background: Perivascular epithelioid cell tumours (PEComas) are rare mesenchymal neoplasms characterized by co-expression of melanocytic and myogenic markers. This spectrum includes typically benign angiomyolipoma (AML), and PEComa-NOS, a diagnostically challenging entity with highly variable malignant potential and no established molecular criteria for stratification. PEComas are classically divided into tumors driven by loss-of-function mutations in TSC1 or TSC2 and a smaller subset harboring TFE3 rearrangements, both converging on activation of the mTORC1 pathway. Although mTOR inhibitors are the standard treatment, clinical resistance is common and may reflect incomplete suppression of downstream translational output. The aim of this study was to evaluate downstream mTOR effectors and VEGFR as biomarkers of malignant stratification in PEComas. Methods: FFPE tissue from 21 tumors was examined, including 8 AML and 13 PEComa-NOS, with central expert confirmation; 5 cases showed clinically and/or pathologically confirmed malignant behavior. Immunohistochemistry was performed for 4E-BP1, phosphorylated 4E-BP1 (p-4E-BP1), eIF4E, and VEGFR, with expression quantified using the H-score method. Targeted next-generation sequencing was performed in 6 PEComa-NOS cases using the Ion Torrent Oncomine Comprehensive Assay v3 on the Genexus System. Results: Expression levels of 4E-BP1, eIF4E, and VEGFR were higher in PEComa-NOS compared with AML (p < 0.001, p = 0.034, and p = 0.003, respectively), whereas no difference was observed for p-4E-BP1 (p = 0.670). High tumor cellularity was associated with increased expression of 4E-BP1 and VEGFR (p = 0.006 and p = 0.007). VEGFR expression showed a negative correlation with mitotic count (R = −0.43, p = 0.053) and was higher in tumors with necrosis than in those without (p = 0.011). Within the PEComa-NOS group, eIF4E expression also correlated negatively with mitotic activity (R = −0.54, p = 0.067). NGS analysis revealed a heterogeneous mutational landscape. Pathogenic loss-of-function mutations in TSC1 or TSC2 were identified in n = 3 cases; notably, all n = 3 TSC-negative malignant tumors harbored pathogenic variants affecting DNA damage response–related genes, including BRCA2 and PMS2 , with additional alterations involving NOTCH pathway components. Conclusions: Increased expression of 4E-BP1, eIF4E, and VEGFR was observed in PEComa-NOS compared with benign AML, suggesting differences in downstream mTOR signaling. Pathogenic alterations in DNA damage response genes identified in TSC-negative malignant cases point to underlying molecular heterogeneity. These findings indicate that combined immunohistochemical and targeted genomic evaluation may provide complementary information for stratifying PEComa beyond canonical mTOR pathway alterations.