Recent molecular genetic findings on endometriosis and normal endometrium suggest a modified model in which circulating epithelial progenitor or stem cells intended to regenerate uterine endometrium after menstruation may become overreactive and trapped outside the uterus. These trapped epithelium-committed progenitor cells form nascent glands through clonal expansion and recruit polyclonal stromal cells, leading to the establishment of deep infiltrating endometriosis. Once formed, the ectopic tissue becomes subject to immune surveillance, resulting in chronic inflammation. The inflammatory response orchestrated by nuclear factor-κB signaling is exacerbated by aberrations in the estrogen receptor-β and progesterone receptor pathways, which are also affected by local inflammation, forming a dysregulated inflammation–hormonal loop. Glandular epithelium within endometriotic tissue harbors cancer-associated mutations that are frequently detected in endometriosis-related ovarian cancers. In this review, we summarize recent advances that have illuminated the origin and pathogenesis of endometriosis and have provided new avenues for research that promise to improve the early diagnosis and management of endometriosis.

Unlike other human cancers, in which all primary tumors arise de novo, ovarian epithelial cancers are primarily imported from either endometrial or fallopian tube epithelium. The prevailing paradigm in the genesis of high-grade serous carcinoma (HGSC), the most common ovarian cancer, posits to its development in fallopian tubes through stepwise tumor progression. Recent progress has been made not only in gathering terabytes of omics data but also in detailing the histologicemolecular correlations required for looking into, and making sense of, the tissue origin of HGSC. This emerging paradigm is changing many facets of ovarian cancer research and routine gynecology practice. The precancerous landscape in fallopian tubes contains multiple concurrent precursor lesions, including serous tubal intraepithelial carcinoma (STIC), with genetic heterogeneity providing a platform for HGSC evolution. Mathematical models imply that a prolonged time (decades) elapses from the development of a TP53 mutation, the earliest known molecular alteration, to an STIC, followed by a shorter span (6 years) for progression to an HGSC. Genetic predisposition accelerates the trajectory. This timeline may allow for the early diagnosis of HGSC and STIC, followed by intent-to-cure surgery. This review discusses the recent advances in this tubal paradigm and its biological and clinical implications, alongside the promise and challenge of studying STIC and other precancerous lesions of HGSC.

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