The fallopian tube, "precursor escape" and narrowing the knowledge gap to the origins of high-grade serous carcinoma.

Most ovarian carcinomas are high-grade serous carcinomas (HGSC) that contain TP53 mutations, present at advanced stage, and eventually become resistant to chemotherapy. The rapid evolution of this disease has been attributed to an origin in the distal fallopian tube, in the form of serous tubal intraepithelial carcinomas (STICs). This has led to a disease model where malignancy develops first in the tube and spreads to the peritoneum or regional lymph nodes. However, although most early or incidentally discovered HGSCs manifest in the tube with STICs, many advanced HGSCs are not accompanied by a malignancy in the fimbria. To resolve this paradox, the focus has shifted to earlier, premalignant serous proliferations (ESPs) in the tubes, which lack the cytomorphologic features of malignancy but contain TP53 mutations. These have been termed p53 signatures or serous tubal intraepithelial lesions (STILs). Although they have not been presumed to have cancer-causing potential by themselves, some ESPs have recently been shown to share identical TP53 mutations with concurrent HGSCs, indicating a shared lineage between these early mucosal changes and metastatic malignancy. This discovery supports a paradigm by which HGSCs can emerge not only from STICs but also from exfoliated precursor cells (precursor escape) that eventually undergo malignant transformation within the peritoneal cavity. This paradigm unifies both localized and widespread HGSCs to a visible pre-existing cellular alteration in the tubal epithelium, and highlights a consistent and necessary biologic event (TP53 mutation) rarely encountered in the ovary or secondary Mullerian system. This dual pathway to HGSCs underscores the subtle nature of many serous cancer origins in the tube, explains contrasting clinico-pathologic presentations, and explains why, until recently, the fallopian tube was unappreciated as the principal origin of HGSCs. Moreover, it highlights additional challenges faced in preventing or intercepting HGSCs at a curable stage.