Mutation Analysis of MED12 in Benign and Malignant Uterine Smooth Muscle Tumors
Elizabeth Bertsch, Xiaofei Xu, Bushra Ayub, Wanan Qiang, Kush Mittal, Takeshi Kurita, Jian-Jun Wei. Northwestern Memorial Hospital, Feinberg School of Medicine, Chicago, IL
Background: Progression from leiomyoma to leiomyosarcoma in the uterus has been suggested but molecular evidence is generally lacking. The distinction between atypical leiomyoma, cellular leiomyoma and low grade leiomyosarcoma can be challenging and requires identifying biomarkers for a differential diagnosis. Recent identification of frequent MED12 mutations in uterine leiomyomas provides a valuable molecular marker for the study of uterine smooth muscle tumors. Although it is still unclear whether MED12 mutations lead to leiomyoma development, high frequent MED12 mutations in uterine leiomyomas may help us to reevaluate the molecular relationship between leiomyoma, its histologic variants and malignant counterparts—leiomyosarcomas.
Design: To examine the MED12 mutations in different types of uterine smooth muscle tumors, we collected usual type leiomyomas (28 cases), cellular leiomyomas (18 cases), and leiomyosarcomas (32 cases). An additional four cases of leiomyosarcoma with leiomyoma-like areas were also collected for MED12 mutation analysis. All DNA samples were extracted from formalin fixed and paraffin embedded tissue samples. MED12 mutations were examined and analyzed by Applied Biosystem's DNA Analyzer and DNASTAR Lasergene 8 software.
Results: DNA for MED12 mutation analysis from tumor and matched myometrium was collected and prepared in a total of 78 cases. All cases were revaluated histologically. Since cellular leiomyomas can mimic endometrial stromal nodules or low grade sarcomas, immunohistochemical (IHC) staining for CD10, SMA and desmin was performed in all cellular leiomyomas, which showed diffuse positivity for desmin, a Ki-67 index of <10% and no more than focal positivity for CD10. The leiomyoma-like areas were evaluated by p53, p16 and Ki-67, all of which demonstrated a different IHC pattern from their leiomyosarcoma counterparts. Over 60% of usual type leiomyomas were found to have MED12 mutations, which is consistent with several independent studies. MED12 mutation rates were very low in both cellular leiomyomas and leiomyosarcomas, accounting for 11.8% and 9.7%, respectively. In contrast to the MED12 point mutations seen in leiomyomas, leiomyosarcomas demonstrate frameshift MED12 mutations. No MED12 mutations were identified in benign appearing leiomyoma-like areas in the additional leiomyosarcoma cases.
Conclusions: The low rate of MED12 mutations in cellular leiomyomas and leiomyosarcomas suggests a different tumorigenic pathways from leiomyomas. Examination of MED12 mutations may be valuable for a differential diagnosis of uterine smooth muscle tumors.
Category: Gynecologic & Obstetrics
Tuesday, March 5, 2013 1:00 PM
Poster Session IV # 244, Tuesday Afternoon