Molecular Characterization of Undifferentiated Carcinomas That Are Associated with Low-Grade Endometrioid Carcinoma
Elisabetta Kuhn, Asli Bahadirli-Talbott, Ayse Ayhan, Marja Debeljak, James Eshleman, Chenquan Zhao, Ie-Ming Shih. Johns Hopkins Medical Institutions, Baltimore, MD; Seirei Mikatahara General Hospital, Hamamatsu, Japan; Magee-Womens Hospital, Pittsburgh, PA
Background: Uterine and ovarian undifferentiated carcinomas (UC) are often associated with low-grade endometrioid carcinomas (EMC), and are morphologically characterized by a solid growth pattern, and a lack of appreciable features of differentiation. UCs are highly malignant. The molecular pathogenesis that leads to disease aggressiveness remains largely unknown. This study aims to better understand the molecular features of UCs by comparing the molecular alterations in several genes between the UC and the EMC component.
Design: A total of 20 UCs from the uterus (18) and the ovary (2) were collected. Among them, 12 cases contained both UC and EMC components. Immunohistochemistry (IHC) staining was used to determine the expression pattern of ARID1A, β-catenin and PTEN in all specimens. Furthermore, mutation analysis was performed in 11 cases for the following genes that are mutated in endometrioid carcinoma: CTNNB1, FBXW7, KRAS, PIK3CA, PPP2R1A and TP53.
Results: Concordance of IHC pattern for ARID1A, β-catenin and PTEN and gene mutations were recorded in the 12 pairs of samples containing both UC and EMC components, except in three cases of which CTNNB1 mutations and/or nuclear β-catenin staining were detected in the UC but not in the associated EMC. Overall, the most common molecular genetic alterations in UC were mutations in PIK3CA (55%), CTNNB1 (36%), TP53 (27%) and PPP2R1A (18%). No mutations were identified in FBXW7, and KRAS, as well as no loss of ARID1A immunoreactivity, in all cases analyzed. As compared to uterine endometrioid carcinoma without concurrent UC, retained ARID1A expression was significantly associated with endometrial carcinomas containing the UC (p< 0.001).
Conclusions: The above results support a clonal relationship between EMCs and their associated UCs. In some cases, activation of β-catenin may contribute to tumor progression from EMC to UC. Retention of ARID1A expression in all cases with UC suggests a unique molecular mechanism in the development of UC distinct from the classical tumor progression from low-grade to high-grade endometrioid carcinoma, as the latter is frequently associated with loss of ARID1A expression.
Category: Gynecologic & Obstetrics
Monday, March 4, 2013 8:45 AM
Proffered Papers: Section E, Monday Morning