Utility of Morphologic Risk Stratification Modeling and Immunohistochemical Surrogates for Key Molecular Alterations in Uterine Leiomyosarcoma

Accurate diagnosis and prognostic stratification of uterine leiomyosarcoma (LMS) is becoming more important with more nuanced clinical management. Two recent studies by Momeni-Boroujeni and Chapel reported a 7-marker surrogate immunohistochemistry (IHC) diagnostic panel and a morphologic risk stratification schema, respectively. Our objective was to test these approaches in a local cohort. Thirty-four consecutive LMS cases diagnosed at Foothills Medical Center, Calgary, Alberta, Canada (2016-2022) underwent detailed histopathologic review and surrogate IHC panel (TP53, RB1, ATRX, PTEN, DAXX, MTAP, and MDM2). Associations of molecular alterations, morphologic features and survival were studied. Abnormal staining was detected for RB1 (65%), TP53 (62%), ATRX (44%), PTEN (32%), MTAP (15%), DAXX (9%), and MDM2 (6%). Seventy-nine percent of cases showed abnormality in ≥2 molecular markers, confirming a LMS diagnosis. However, 21% of cases showed only one or no abnormality and these cases were associated with a lower nuclear grade and mitotic count, which may cause diagnostic difficulties. While molecular alterations did not predict survival, morphologic risk stratification distinguished low-risk, intermediate-risk, and high-risk groups with significant differences in disease-specific survival (log-rank P = 0.030). While these findings validate the sensitivity of an IHC-based diagnostic panel in confirming the vast majority of LMS diagnoses, a subset, which more likely shows ambiguous diagnostic features, probably requires genomic testing. The previously proposed morphologic criteria seem to provide a robust prognostic stratification.