The diagnosis of a uterine smooth muscle lesion is, in the majority of cases, straightforward. However, in a small number of cases, the morphological criteria used in such lesions cannot differentiate with certainty a benign from a malignant lesion and a diagnosis of smooth muscle tumor with uncertain malignant potential (STUMP) is made. Uterine leiomyosarcomas are often easy to diagnose but it is difficult or even impossible to identify a prognostic factor at the moment of the diagnosis with the exception of the stage. We hypothesize, for uterine smooth muscle lesions, that there is a gradient of genomic complexity that correlates to outcome. We first tested this hypothesis on STUMP lesions in a previous study and demonstrated that this 'gray category' could be split according to genomic index into two groups. A benign group, with a low to moderate alteration rate without recurrence and a malignant group, with a highly rearranged profile akin to uterine leiomyosarcomas. Here, we analyzed a large series of 77 uterine smooth muscle lesions (from 76 patients) morphologically classified as 19 leiomyomas, 14 STUMP and 44 leiomyosarcomas with clinicopathological and genomic correlations. We confirmed that genomic index with a cut-off=10 is a predictor of recurrence (P<0.0001) and with a cut-off=35 is a marker for poor overall survival (P=0.035). For the tumors confined to the uterus, stage as a prognostic factor was not useful in survival prediction. At stage I, among the tumors reclassified as molecular leiomyosarcomas (ie, genomic index ≥10), the poor prognostic markers were: 5p gain (overall survival P=0.0008), genomic index at cut-off=35 (overall survival P=0.0193), 13p loss including RB1 (overall survival P=0.0096) and 17p gain including MYOCD gain (overall survival P=0.0425). Based on these findings (and the feasibility of genomic profiling by array-comparative genomic hybridization), genomic index, 5p and 17p gains prognostic value could be evaluated in future prospective chemotherapy trials.

Argot Lab Lausanne Switzerland

Centre for Gynecologic Oncology Amsterdam Antoni Van Leeuwenhoek Netherlands Cancer Institute Amsterdam The Netherlands

Department of Biopathology Institut Bergonié Comprehensive Cancer Centre Bordeaux France

Department of Medical Oncology Institut Bergonié Comprehensive Cancer Centre Bordeaux France

Department of Pathology Centre Alexis Vautrin Comprehensive Cancer Centre Vandoeuvre les Nancy France

Department of Pathology Centre Jean Perrin Comprehensive Cancer Centre Clermont Ferrand France

Department of Pathology Centre JF Leclerc Comprehensive Cancer Centre Dijon France

Department of Pathology Centre Oscar Lambret Comprehensive Cancer Centre Lille France

Department of Pathology Clinic of Gynecopathology and Senology Erasme University Hospital Brussels Belgium

Department of Pathology Hôpital Universitaire Lyon Sud Pierre Benite France

Department of Pathology ICO Site Paul Papin Comprehensive Cancer Centre Angers France

Department of Pathology Institut Gustave Roussy Comprehensive Cancer Centre Villejuif France

Department of Pathology University Hospital Poitiers France

Department of Surgery Institut Bergonié Comprehensive Cancer Centre Bordeaux France

Gynaecological Oncology Center Department of Obstetrics and Gynaecology Charles University Prague 1st Faculty of Medicine and General University Hospital Prague Czech Republic

Institut National de la Santé et de la Recherche Medicale U1218 Bordeaux France

Institut Universitaire de Pathologie Lausanne Switzerland

KU Leuven University of Leuven Department of Oncology Gynaecologic Oncology; University Hospitals Leuven Department of Obstetrics and Gynaecology Leuven Belgium

Oncology Department Centre Antoine Lacassagne Comprehensive Cancer Centre Nice France

Oncology Department Centre Oscar Lambret Comprehensive Cancer Centre Lille France

University of Bordeaux Bordeaux France

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Immunohistochemical and selected genetic reflex testing of all uterine leiomyosarcomas and STUMPs for ALK gene rearrangement may provide an effective screening tool in identifying uterine ALK-rearranged mesenchymal tumors