Serous tubal intraepithelial carcinoma—looking into the earliest events of ovarian cancer development

Among human malignancies, ovarian epithelial neoplasms are unique because they are unlikely to develop from their cognate organs, the ovaries (specifically, the surface mesothelium). The updated paradigm about the origin of high-grade serous carcinoma (HGSC) suggests that many HGSCs derive from the fallopian tubes following a sequential tumor progression, from pathologically defined p53 signature, serous tubal intraepithelial lesion, and serous tubal intraepithelial carcinoma (STIC) to HGSC that later spreads to ovarian tissues and disseminates. Despite the fact that the biological and clinical significance of each of those precursor lesions is yet to be elucidated, molecular and morphological correlative studies demonstrate unique features associated with various precancerous lesions. Chromosomal instability, aneuploidy patterns, and the activation of specific cancer signaling pathways attribute tumor progression to HGSC. The knowledge gained thus far is transforming various aspects of ovarian cancer research and gynecological practice. Opportunistic salpingectomy prevents HGSC in average-risk women, and molecular analyses in routine liquid-based cervical Pap tests hold promise to detect STIC- and HGSC-related tissue biomarkers. This review article will summarize those key findings in the earliest development of HGSC precursors and discuss the future challenges and promises of translating this paradigm shift to leverage standardization in diagnostic, early detection, and prevention of this devastating ovarian cancer.