Annual Review of Pathology: Mechanisms of Disease

The Origin and Pathogenesis of Endometriosis

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.

Molecular Pathogenesis of Uterine Sarcomas: Mechanisms and Implications for Treatment

Uterine sarcomas are rare cancers with diverse clinical, histologic, and genomic profiles. At the genetic level, they can be classified into simple and complex genomic sarcomas, exemplified by endometrial stromal sarcoma (ESS) and uterine leiomyosarcoma (uLMS), respectively. Sequencing technologies in research and clinical settings have significantly advanced the molecular understanding of these tumors. New entities characterized by distinctive morphologies and genomic alterations have expanded the category of uterine sarcomas with simple genomes beyond ESS to include variant uLMS and fibrosarcoma-like uterine sarcoma (FUS). Molecular profiling of uLMS has also uncovered possible therapeutic targets in the most common type of uterine sarcoma, where prognostication and clinical management remain challenging. This review discusses the current histologic and molecular classification of low- and high-grade ESS, FUS, and conventional and variant uLMS and explores the potential impact of the genetic alterations observed in these uterine sarcomas on treatment.