Molecular Genetics of Uterine Malignant Mixed Mullerian Tumor.
Amy Yi-Pei Yang, Danielle Lu, Yi-Fang Liu, Lora Hedrick Ellenson. Weill Medical College of Cornell University, New York, NY
Background: The admixture of carcinomatous (CC) and sarcomatous components (SC) in uterine malignant mixed mullerian tumor (UMMMT) has raised questions regarding its histogenesis. Studies favor a monoclonal epithelial origin with metaplastic sarcomatous elements. However, its molecular pathogenesis remains largely unknown. Recent studies have shown that p16 and p53 are overexpressed concordantly in CC and SC, and microsatellite instability (MSI) has been found in 5- 23%. To date an analysis of PIK3CA, the most frequently mutated oncogene in uterine endometrioid carcinoma, has not been reported in UMMMT.
Design: Paraffin-embedded archival tissue of 35 UMMMT, 10 leiomyosarcoma (LMS), and 8 low grade stromal sarcoma (LGSS) was utilized in this study. Immunohistochemical (IHC) analysis of p16, p53, MLH1, PMS2, MSH2, and MSH6 was performed. For p16 and p53, a score of 0 to 12 was calculated as the product of intensity (0 to 3+) and percentage (1 = 1-10%, 2 = 11-50%, 3 = 51-80%, 4 = > 80%). For mutational analysis, neoplastic tissue was microdissected, and DNA was extracted. Exons 9 and 20 of PIK3CA were amplified and directly sequenced. In addition, 20 UMMMT cases were analyzed for PTEN mutations and MSI (10 of which were included in the 35 cases used in the IHC analysis).
Results: P16 expression was seen in 23 of 34 (68%) of CC and 30 of 33 (91%) of SC. 12 of 35 (34%) UMMMT showed significantly less p16 expression in CC (score = 3.33) than SC (score = 9.83) (P = < 0.0001), compared to LMS (7.8) and LGSS (3.38). P53 expression was seen in 19 of 35 (54%) of CC and 18 of 33 (55%) of SC in UMMMT with no difference between the two components. Out of the 12 cases with loss of p16 in CC, 9 (75%) had low p53 expression. 12 out of 35 cases (34%) showed complete loss of p53 expression in both CC and SC. 5 of 35 UMMMT (14%) showed loss of MLH1 and PMS2 expression, and no loss was seen in LMS or LGSS. 8 out of 20 (40%) cases showed PTEN mutations that were identical in CC and SC. Currently, no mutations have been identified in PIK3CA, but these studies are ongoing.
Conclusions: The high concordance rate between CC and SC with regards to PTEN mutations, p53 expression, MSI, and DNA MMR immunostaining provide further evidence that the two components are of monoclonal origin. Although previous studies have found concordance of p16 expression in the two components we found a statistically significant difference in p16 expression. This finding suggests that specific biomarkers may provide insight into the divergent nature of the two components and the molecular underpinnings of this aggressive malignancy.
Category: Gynecologic & Obstetrics
Wednesday, March 2, 2011 1:00 PM
Poster Session VI # 177, Wednesday Afternoon