A predictive model for calculating the likelihood of recurrent uterine fibroids after surgical intervention

Aim. To develop a predictive model for calculating the likelihood of recurrent uterine fibroids after myomectomy.Materials and Methods. We consecutively recruited 149 women aged 19 to 45 years who underwent myomectomy. Prediction of uterine fibroids was carried out using multivariate analysis including a classification tree (IBM SPSS Statistics). To construct a classification tree for predicting recurrent uterine fibroids, the following patient-related parameters were used as the input features: age, family history, nulliparity, past medical history of myomectomy, obesity, rapid fibroid growth, multiple fibroids at myomectomy, BCL-2, Ki-67, and VEGF expression.Results. When analyzing the resulting classification tree, we can conclude that the most significant factors defining the recurrence of uterine fibroids are low parity, multiple fibroids at myomectomy, intensive VEGF expression, and weak expression of BCL-2.Conclusion. Our original model allows the identification of the most significant predictors of recurrent uterine fibroids and might be proposed as a useful tool for clinical practice.

Multiple Mutations in Exon-2 of Med-12 Identified in Uterine Leiomyomata

Background: Uterine leiomyomata (UL), commonly known as uterine fibroids, are benign smooth muscle tumors of the myometrium. They cause pelvic pain, abnormal uterine bleeding, and infertility in women of reproductive age. The ovarian hormone estrogen is the main stimulator for the fibroid growth. The etiology is not yet clearly understood; however, UL are believed to be monoclonal tumors arising from a common progenitor cell. Chromosomal cytogenetic abnormalities have been demonstrated in 40-50% of the fibroids. The most frequent tumor specific genetic alterations in UL were identified in exon-2 of Mediator Complex Subunit 12 (MED-12). Methods: In the present study, twenty-two multiple fibroids were evaluated both from the same uterus and from different uteri, of four women, for somatic mutations in hotspot region of MED-12. The tissue DNA of the UL's was isolated, amplified by PCR visualized on gel and sent for Sanger sequencing. Results: The results indicate several variants in exon-2 and flanking intronic regions, seven exonic variants and five intronic variants which provide evidence that multiple UL in the same uterus may not be clonal in origin. Conclusion: This study indicates genetic heterogeneity. UL may not have a clonal origin, these exon-2 variants of MED-12 gene could be involved in UL progression.

Vascular Biology of Uterine Fibroids: Connecting Fibroids and Vascular Disorders

Fibroids are benign tumors caused by proliferation of myometrial smooth muscle cells in the uterus that can lead to symptoms such as abdominal pain, constipation, urinary retention, and infertility. While traditionally thought of as a disease process intrinsic to the uterus, accumulating evidence suggests that fibroid growth may be linked with the systemic vasculature system, although cell-intrinsic factors are certainly of principal importance in their inception. Fibroids are associated with essential hypertension and preeclampsia, as well as atherosclerosis, for reasons that are becoming increasingly elucidated. Factors such as the renin-angiotensin-aldosterone system, estrogen, and endothelial dysfunction all likely play a role in fibroid pathogenesis. In this review, we lay out a framework for reconceptualizing fibroids as a systemic vascular disorder, and discuss how pharmaceutical agents and other interventions targeting the vasculature may aid in novel treatment of fibroids.

Mechanical Signaling and Extracellular Matrix in Uterine Fibroids

Fibroids (uterine leiomyomas) are the most common benign tumors of the female reproductive tract. Steroid hormones, growth factors, and cytokines have long been implicated in fibroid growth; however, research suggests that changes in the extracellular matrix and mechanical signaling play a critical role in fibroid growth and differentiation. Studies have shown that growth of fibroids is related to the change in the volume and composition of extracellular matrix with increased deposition of abnormal collagen, glycoproteins, laminins, fibronectins, and an increased osmotic stress. These changes generate mechanical stress which is converted to chemical signals in the cells through mechanotransduction and eventually affects gene expression and protein synthesis. Current studies also suggest that mechanical signaling in fibroid cells is abnormal as evidenced by decreased apoptosis of abnormal cells and deposition of a stiff extracellular matrix promoting fibrosis. Understanding and defining these mechanisms could help design new therapies for the treatment of fibroids.

Differences in the cellular composition of small versus large uterine fibroids

Uterine fibroids are clonally derived from a single cell; however, despite being monoclonal, the cellular phenotypes that make up uterine fibroids are heterogeneous consisting of predominantly smooth muscle cells (SMC) and fibroblasts. This raises the question as to when clonal cell differentiation occurs during fibroid development, and does this information provide clues about possible mechanisms regulating the growth process that leads to fibroids of symptom-causing size? This study investigated the differences in the cellular composition of fibroids by immunohistochemistry (IHC). A tissue microarray (n = 21 hysterectomy cases) was used for the investigation of large uterine fibroids and normal myometrium. An investigation of small fibroids (≤ 5mm) used a separate group of samples (n = 7 hysterectomy cases, total ofn = 17 fibroids). A panel of cell phenotypic markers was selected based on our previousin situinvestigations and included aldehyde dehydrogenase 1 (ALDH1A1) and vimentin for different fibroblast sub-populations, smooth muscle actin (SMA) as a marker for SMCs, CD31 for endothelial cells and CD45 for leucocytes. Proliferating cell nuclear antigen (PCNA) was also studied to identify proliferating cells. The cellular composition of small fibroids differs significantly from large fibroids. Small fibroids are more cellular (increased cells/mm2) than large fibroids, have more blood vessels and also have a higher ratio of SMC to fibroblasts than large fibroids. Large fibroids have more cell proliferation (measured by PCNA) and fewer leucocytes (measured by CD45) than adjacent myometrium, whereas small fibroids are less proliferative and have similar number of leucocytes to myometrium. Different cellular composition between fibroids of different sizes may provide important clues as to the mechanisms that drive fibroid growth.