Background Uterine leiomyosarcoma (ULMS) is an aggressive, rapidly progressive tumor lacking clinical and molecular predictors of outcome. Methods ULMS patients (n = 349) were classified by disease status at presentation to MDACC as having intra-abdominal (n = 157) or distant metastatic disease (n = 192). Patient, tumor, treatment, and outcome variables were retrospectively retrieved. Formalin-fixed, paraffin-embedded tumor and control tissues from these patients (n = 109) were assembled in a tissue microarray and evaluated for hormone receptors and markers of angiogenesis, cell-cycle progression and survival. Patient, tumor, and treatment variables were correlatively analyzed. Results The 5- and 10-year disease-specific survival (DSS) for the cohort was 42 and 27 %, respectively. Patients with primary intra-abdominal tumors had better outcomes than those with recurrent intraperitoneal tumors. Whites had a more favorable prognosis. In patients with intra-abdominal tumors, only mitotic count >10M/10HPF portended poorer prognosis. Patients with pulmonary metastasis had improved outcomes with “curative” metastasectomy. ULMS samples exhibited loss of ER and PR expression, overexpressed Ki-67, and altered p53, Rb, p16, cytoplasmic β-catenin, EGFR, PDGFR-α, PDGFR-β, and AXL levels. Metastatic tumors had increased VEGF, Ki-67, and survivin expression versus localized disease. Survivin and β-catenin expression were associated with intraperitoneal recurrence; high bcl-2 expression predicted longer DSS. Conclusions Analysis of both clinicopathologic factors and immunohistochemical biomarkers in ULMS identified several prognostic clinical and molecular factors, suggesting that further study may lead to improved ULMS understanding and treatment.

Purpose Uterine leiomyosarcoma (ULMS) is a poorly understood cancer with few effective treatments. This study explores the molecular events involved in ULMS with the goal of developing novel therapeutic strategies. Experimental Design Genome-wide transcriptional profiling, Western blotting, and real-time PCR were used to compare specimens of myometrium, leiomyoma, and leiomyosarcoma. Aurora A kinase was targeted in cell lines derived from metastatic ULMS using siRNA or MK-5108, a highly specific small-molecule inhibitor. An orthotopic model was used to evaluate the ability of MK-5108 to inhibit ULMS growth in vivo. Results We found that 26 of 50 gene products most overexpressed in ULMS regulate mitotic centrosome and spindle functions. These include UBE2C, Aurora A and B kinase, TPX2, and Polo-like kinase 1 (PLK1). Targeting Aurora A inhibited proliferation and induced apoptosis in LEIO285, LEIO505, and SK-LMS1, regardless of whether siRNA or MK-5108 was used. In vitro, MK-5108 did not consistently synergize with gemcitabine or docetaxel. Gavage of an orthotopic ULMS model with MK-5108 at 30 or 60 mg/kg decreased the number and size of tumor implants compared with sham-fed controls. Oral MK-5108 also decreased the rate of proliferation, increased intratumoral apoptosis, and increased expression of phosphohistone H3 in ULMS xenografts. Conclusions Our results show that dysregulated centrosome function and spindle assembly are a robust feature of ULMS that can be targeted to slow its growth both in vitro and in vivo. These observations identify novel directions that can be potentially used to improve clinical outcomes for this disease.

Aims Well-differentiated leiomyosarcoma show morphologically recognizable smooth muscle differentiation, while poorly differentiated tumors may form a spectrum with a subset of undifferentiated pleomorphic sarcomas. Expression of certain muscle markers has been reported to have prognostic impact. We investigated the correlation between morphologic spectrum and muscle-marker expression profile of leiomyosarcoma and the impact of these factors on patient outcomes. Methods and Results Tissue microarrays including 203 non-uterine and 181 uterine leiomyosarcoma with a spectrum of tumor morphologies were evaluated for expression of immunohistochemical markers of muscle differentiation. Poorly differentiated tumors frequently lost one or more conventional smooth muscle markers (smooth muscle actin, desmin, h-caldesmon and smooth muscle myosin (p<0.0001)), as well as more recently described markers SLMAP, MYLK and ACTG2 (p<0.0001). In primary tumors, both desmin and CFL2 expression predicted improved overall survival in multivariate analyses (p=0.0111 and p=0.043, respectively). Muscle-marker enriched tumors (expressing all 4 conventional markers or any 3 of ACTG2, CFL2, CASQ2, MYLK, and SLMAP, had improved overall survival (p<0.05) in univariate analyses. Conclusions Morphologically and immunohistochemically, poorly differentiated leiomyosarcoma can masquerade as undifferentiated pleomorphic sarcoma with progressive loss of muscle markers. Expression of muscle markers has prognostic significance in primary leiomyosarcoma independent of tumor morphology.