title: Uterine leiomyosarcomas: tumor size, mitotic index, and biomarkers Ki67, and Bcl-2 identify two groups with different prognosis.
abstract: BACKGROUND
  Prognostic factors for uterine leiomyosarcomas are not well established. Although most tumors are associated with poor prognosis even when apparently confined to the uterus (stage I), some cases that exhibited morphologic features of malignancy had prolonged survival.
  
  
  METHODS
  Using tissue microarrays of 84 uterine leiomyosarcomas, we investigated conventional clinico-pathologic parameters, including International Federation of Gynecology and Obstetrics (FIGO) stage, together with expression of Ki67, p53, p16, and Bcl-2, attempting to distinguish leiomyosarcomas with different prognosis. The rate of CD163 immunoreactive tumor macrophages was also investigated.
  
  
  RESULTS
  Tumor size and mitotic index were significant prognostic factors by univariate (p=0.018 and p=0.003, respectively) and multivariate (p=0.006 and p=0.001) analyses. Of the biomarkers investigated, only Ki67 immunoreaction was significant by univariate analysis and was associated with adverse prognosis (p=0.01). However, combination of tumor size, mitotic index, Ki67, and Bcl-2 worked even better. Using these 4 parameters, unsupervised hierarchical clustering identified 2 groups of tumors with different prognosis (p=0.001): group 1 consisted mostly of smaller leiomyosarcomas (<10cm) with mitotic index <20 MF/10 HPF, negative Ki67, and positive or negative Bcl-2 immunostaining. These tumors were associated with better prognosis. In contrast, group 2 leiomyosarcomas which were mostly≥10cm in diameter had higher mitotic index (≥ 20 MF/10 HPF), and were positive for Ki67 and negative for Bcl-2 had worse prognosis. Also, the number of CD163-macrophages was greater in group 2 than group 1 (p=0.007).
  
  
  CONCLUSIONS
  Tumor size and mitotic index are morphologic predictors of malignancy in uterine leiomyosarcomas. Combination of tumor size, mitotic index, Ki67, and Bcl-2 protein expression allows distinguishing 2 groups of leiomyosarcomas with different survival. Leiomyosarcomas associated with poor outcome had a higher number of CD163 stromal macrophages.
authors.affiliation: Department of Pathology, Institut of Biomedical Research, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain.
authors.forename: Emanuela
authors.initials: E
authors.lastname: D'Angelo
authors.forename: Inigo
authors.initials: I
authors.lastname: Espinosa
authors.forename: Rola
authors.initials: R
authors.lastname: Ali
authors.forename: C Blake
authors.initials: CB
authors.lastname: Gilks
authors.forename: Matt van de
authors.initials: Mv
authors.lastname: Rijn
authors.forename: Cheng-Han
authors.initials: CH
authors.lastname: Lee
authors.forename: Jaime
authors.initials: J
authors.lastname: Prat
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000096:biosynthesis*; D019941:Cyclin-Dependent Kinase Inhibitor p16; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000096:biosynthesis*; D007890:Leiomyosarcoma / Q000378:metabolism* / Q000473:pathology*; D046228:Microarray Analysis / Q000379:methods; D008875:Middle Aged; D008940:Mitotic Index; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009367:Neoplasm Staging; D016612:Paraffin Embedding; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D014594:Uterine Neoplasms / Q000378:metabolism* / Q000473:pathology*
chemical_list: D014408:Biomarkers, Tumor; C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019394:Ki-67 Antigen; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53