Endometrial Adenocarcinomas With Significant Mucinous Differentiation: A Characterization of Intratumoral Heterogeneity of KRAS Mutations in Mucinous and Endometrioid Histologic Components.

OBJECTIVE: KRAS mutations are frequently seen in malignancies with mucinous morphology. In our previous study, mucinous endometrial carcinomas were associated with a significantly higher frequency of KRAS mutations as compared with matched conventional endometrioid carcinomas. This study expands our previous report by exploring possible intratumoral heterogeneity for KRAS gene mutations in the mucinous components of mucinous carcinomas (MCs) and endometrioid carcinomas with significant mucinous differentiation (ECSMD) versus their associated "usual" endometrioid components. MATERIALS AND METHODS: KRAS-positive cases from our previous report were studied, including 10 MCs and 10 ECSMDs. The specimens were microscopically dissected to separately isolate morphologically mucinous and endometrioid components. Direct DNA sequencing for KRAS mutations at codons 12 and 13 using capillary electrophoresis were performed. RESULTS: KRAS mutations were detected in the endometrioid components of 8 (80%) of 10 MCs and 3 (30%) of 10 ECSMDs. The endometrioid component of the ECSMD group was less frequently associated with KRAS mutation than the endometrioid component of the MC group, even when the mucinous component of the same tumor contained a mutation; the difference is statistically significant (P < 0.05). CONCLUSIONS: Our current study shows that intratumoral heterogeneity for KRAS gene mutation was associated with ECSMD, but less frequently with MC. It is possible that when the mucinous component predominates, qualifying for an MC, KRAS mutations appear to be widespread, irrespective of the mucinous or nonmucinous differentiation of the tumor cells. The findings suggest that multiple samples for KRAS tests may be useful, especially in endometrioid carcinoma with significant mucinous differentiation.

BRAF V600E Mutations in Endometrial Adenocarcinoma.

The BRAF V600E somatic mutation is recognized as an oncogenic driver of many human cancers involving the MAPK/ERK pathway. Colorectal and lung cancers associated with the BRAF V600E mutation often demonstrated mucinous morphology. This study hypothesized that the BRAF V600E mutation may be associated with mucinous morphology in endometrial cancer and aimed to investigate its prevalence in mucinous (endometrial) carcinoma (MC) and endometrioid adenocarcinoma with significant mucinous differentiations (ECMD) (>10% neoplastic cells). Twenty-eight cases of endometrial cancer were selected, including 17 (60.7%) cases of MC or ECMD. All patients were Caucasian with age ranging from 50 to 87 years old (median 65). Genomic DNA was extracted from formalin-fixed paraffin-embedded tumor tissue and subjected to both real-time mutant allele-specific amplification polymerase chain reaction (PCR) and PCR amplification, followed by direct sequencing. Three (3/28, 10.7%) BRAF V600E mutations were detected by real-time mutant allele-specific amplification PCR and confirmed by direct sequencing. Two of 3 cases positive for BRAF V600E mutation were ECMDs with "surface epithelial changes." KRAS mutations were found in 9 cases (32.1%), none with BRAF mutation. This is the first report of BRAF V600E mutation in endometrial cancer, indicating that it may contribute to tumorigenesis of endometrial cancer, although at a low frequency compared with KRAS mutations.