Etiology, Pathogenesis, and Malignant Potential of Uterine Leiomyoma – A Review

In uterine smooth muscle tumors (SMT), benign leiomyoma (LM) consist of smooth muscle cells, side population cells, and fibroblasts acting together within a network regulating cell proliferation and production of extracellular matrix molecules. Chromosomal alterations, activation of the WNT/ß-catenin pathway, and overexpression of genes of the HMG group are important pathogenetic steps. The features of malignancy are tumor cell necrosis (TCN), cytological atypia, and mitotic activity. However, hormones and hypoxic stress induce reactive mitotic activity. Therefore, the mitotic index by itself is not an independent predictor of malignancy. SMT with mitotic activity up to 15 mitoses/10 HPF in the absence of atypia and TCN are designated mitotically active LM. These tumors are mostly benign. SMT with cytological atypia and a mitotic count below 10 figures /10 HPF without TCN are classified as atypical LM. Tumors with questionable TCN or without TCN and atypia but with a mitotic activity of > 15 figures/10 HPF belong to the SMT of “uncertain malignant potential”. In the presence of definite TCN, LMS are diagnosed irrespective of mitotic count. In the absence of TCN, a mitotic activity of ≥ 10 figures /10 HPF and severe atypia argue for LMS. Uterine LMS are not graded. Whether uterine LMS arise from LM or de novo is still debated, although molecular studies suggest that both are formed through distinct molecular pathways.