Expression of phospho-S6 and its correlation with clinicopathological characteristics in retroperitoneal extravisceral perivascular epithelioid cell tumors

Objective To explore pS6 expression and its associations with clinicopathological features in retroperitoneal extravisceral PEComas. Pathological risk stratification of PEComas largely depends on subjective morphological assessment, and objective immunohistochemical biomarkers for malignancy and recurrence risk remain limited. Methods Thirty-two patients with retroperitoneal extravisceral PEComas were retrospectively enrolled. pS6 immunohistochemistry was quantified using the H-score system. Clinicopathological and follow-up data were collected. Statistical analyses included Spearman rank correlation, Mann-Whitney U test, Kruskal-Wallis H-test with Dunn-Bonferroni post-hoc test, multiple linear regression, and receiver-operating-characteristic (ROC) analysis. Histological category was modelled with dummy variables (benign as reference) in regression. Results pS6 H-score showed moderate positive correlation with Ki-67 index (r=0.613, P<0.001), and moderate negative correlation with maximum tumor diameter (r=-0.397, P = 0.024). Higher pS6 H-scores were observed in non-fat-rich, recurrent, UMP and malignant subgroups (all P<0.05). In multivariable linear regression, Ki-67 index and malignant histological status (vs benign) were independently associated with elevated pS6 H-score; UMP status, tumor size, fat-rich status and nodule pattern showed no significant independent association. ROC analysis yielded AUC = 0.994 (95% CI 0.976-1.000) for discriminating malignant from non-malignant lesions; H-score 130 represents an exploratory cut-off and requires external validation. Recurrence was descriptively more frequent in the high-H-score group, though this association is substantially confounded by histological risk category. Observations from three mTOR-treated patients are hypothesis-generating and cannot validate pS6 as a predictive biomarker. Conclusion As a tissue-level surrogate readout downstream of the mTORC1-S6K axis, pS6 exhibits higher expression in malignant retroperitoneal extravisceral PEComas. Elevated pS6 is independently associated with Ki-67 proliferation index and malignant histology. The H-score cut-off of 130 is exploratory and not ready for direct clinical use. Further independent validation is warranted to evaluate the potential biomarker value of quantitative pS6 immunohistochemistry in PEComas.