Comparative Mutational Profiling of Multifocal Low Grade Endometrioid Adenocarcinomas Using Oncogene Point Mutation and Loss of Heterozygosity Analysis.
Catalina Amador-Ortiz, Sydney D Finkelstein, Phyllis H Huettner, John D Pfeifer. Washington University in St. Louis, MO; RedPath Integrated Pathology, Pittsburg, PA
Background: Simultaneous endometrial and ovarian adenocarcinomas may represent either independent synchronous tumors or single primary tumors with metastasis. The relatedness of multifocal deposits of adenocarcinoma can be challenging, and discrimination between the two is often difficult based on morphologic features alone. In this study we used comparative mutational profiling guided by microdissection to determine the relatedness of early stage simultaneous endometrioid tumors in clinical settings where the distinction has therapeutic implications (i.e., not widely metastatic).
Design: Departmental records identified 15 patients who presented with simultaneous FIGO grade 1 endometrial and ovarian endometrioid adenocarcinomas diagnosed as independent synchronous stage 1 tumors by established morphologic criteria (i.e., superficial myometrial invasion of endometrial tumors, unilaterality of ovarian tumors, and absence of lymphovascular invasion). DNA was extracted from the tumors, followed by profiling for point mutations in KRAS, as well as quantitative genotyping for a panel of LOH cancer-associated markers targeting 1p, 3p, 5q, 9p, 10q, 17p, 17q, 21q, 22q. Tumor pairs with one or more concordant mutations were classified as metastatic. Clinical records were reviewed to establish disease free and overall survival.
Results: Mutational profiling of 7 control cases (mean age: 61; range 45-86 years) confirmed the ability of the technique to detect relatedness in known metastatic disease. Profiling of the 15 study cases (mean age: 51.5; range 23-70 years) showed 9 to be independent synchronous tumors and 6 to be metastatic (overall survival: 10.6 vs. 13.6 years, p=0.3; disease free survival: 9.6 vs. 9.5 years, p=0.9, respectively). Overall, three mutational signatures emerged which could be classified as 1) highly mutated, 2) minimally mutated with LOH, and 3) MSI. These signatures were equally distributed in the tumors considered to be independent and metastatic by molecular analysis.
Conclusions: By gene mutation and LOH analysis, a significant proportion of patients diagnosed with independent synchronous stage 1 FIGO grade 1 endometrial and ovarian endometrioid adenocarcinomas actually represent cases of metastatic disease. The finding of distinctive mutational signatures in histologically equivalent low grade adenocarcinomas can be used to better understand relatedness in multifocal cancer to potentially predict clinical behavior.
Category: Gynecologic & Obstetrics
Monday, February 28, 2011 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 133, Monday Morning