Clinicopathologic Features, Molecular Landscape, and Prognostic Implications of Ovarian Low-Grade Serous Tumors with Histologic Transformation

Abstract Purpose: To characterize the clinicopathologic features, molecular genetic landscape, and clinical behavior of ovarian low-grade serous tumors with histologic transformation (LGS-HT) to indeterminate/high-grade carcinoma. Experimental Design: LGS-HTs were retrospectively identified from an institutional cohort of ovarian cancer patients and underwent central pathology re-review. Data on clinicopathologic characteristics, including age, stage, surgical outcomes, systemic treatments, and overall survival (OS) were collected. Immunohistochemical profiling and next-generation sequencing were performed. OS comparisons were performed with our institutional cohorts of ovarian low-grade serous carcinoma (LGSC, n=109) and high-grade serous carcinoma (HGSC, n=1672). Results: From 4371 ovarian serous cancers, 40 (0.9%) LGS-HTs were identified: 30 with synchronous low-grade and higher-grade tumor components at initial diagnosis (LGS-HT-Sync) and 10 with an ovarian low-grade serous neoplasm that recurred as a higher-grade carcinoma (LGS-HT-Metac). The most common somatic driver mutations included TP53 (38.5%), KRAS (21.8%), NF1 (15.6%), BRAF (15.6%) and NRAS (12.5%), with co-existing TP53 and RAS/RAF mutations in 18.8% of cases. Alterations of DNA damage response genes (BRCA2, PALB2, CHEK2, ATM, NBN, RECQL4) were identified in LGS-HTs lacking TP53 genetic alterations. LGS-HT-Sync was associated with poorer OS (median 59.7 months) compared to LGSC (median 105.4 months; p=0.026), and was similar to HGSC (median 48.8 months, p=0.61). Severe nuclear atypia and absence of RAS/RAF-driver mutations were significant adverse prognostic factors. Conclusions: LGS-HT exhibit both low-grade and high-grade morphologic and molecular features, representing an exception to the dualistic classification of ovarian serous neoplasms.