Abstract
PURPOSE: The purpose of this study was 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-HT were retrospectively identified from an institutional cohort of patients with ovarian cancer and underwent central pathology re-review. Data on clinicopathologic characteristics, including age, stage, surgical outcomes, systemic treatments, and overall survival (OS), were collected. IHC profiling and next-generation sequencing were performed. OS comparisons were performed with our institutional cohorts of ovarian low-grade serous carcinoma (n = 109) and high-grade serous carcinoma (n = 1,672). RESULTS: From 4,371 ovarian serous cancers, 40 (0.9%) LGS-HT were identified: 30 with synchronous low-grade and higher-grade tumor components at initial diagnosis and 10 with an ovarian low-grade serous neoplasm that recurred as a higher-grade carcinoma. The most common somatic driver mutations included TP53 (38.5%), KRAS (21.8%), NF1 (15.6%), BRAF (15.6%), and NRAS (12.5%), with coexisting TP53 and RAS/RAF mutations in 18.8% of cases. Alterations in DNA damage response genes (BRCA2, PALB2, CHEK2, ATM, NBN, and RECQL4) were identified in LGS-HT lacking TP53 genetic alterations. Synchronous low-grade and higher-grade tumor components at initial diagnosis were associated with poorer OS (median, 59.7 months) compared with low-grade serous carcinoma (median, 105.4 months; P = 0.026) and were similar to high-grade serous carcinoma (median, 48.8 months; P = 0.61). Severe nuclear atypia and the 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. The presence of a definitive high-grade carcinoma component in a low-grade serous tumor portends aggressive clinical behavior.