Inactivation of the PTEN tumor-suppressor gene is one of the earliest aberrations observed in endometrial cancer precursors and is the most common genetic defect in type I cancers, observed in up to 83% of tumors (206). Tumors with PTEN mutations tend to be well differentiated and minimally invasive (220–222). Approximately 20% of sporadic endometrioid cancers demonstrate a molecular phenotype referred to as microsatellite instability (MSI) (223–225). Microsatellites are short segments of repetitive DNA bases scattered throughout the genome. MSI describes the accumulation of sequence changes in these DNA segments that occur because of the inactivation of intranuclear proteins that comprise the mismatch repair system (226). Inactivation of MLH1, a component of the mismatch repair system, is a common event in type I endometrial cancer. This alteration occurs through hypermethylation of CpG islands in the gene promoter, a process known as epigenetic silencing (227). This is in contrast to colon cancer, in which MSI and inactivation of the mismatch repair genes occurs through mutations in mismatch repair genes, including hMSH2, hMLH1, PMS1, PMS2, or hMSH6 (44–46). MSI and abnormal methylation of MLH1 are early events in endometrial carcinogenesis and are described in precancerous lesions (196,224). Mutations in codons 12 or 13 of the K-ras oncogene are reported in 10% to 20% of endometrial adenocarcinomas (228). The presence of mutations of K-ras appears to be an independent unfavorable prognostic factor (229,230).
Chromosomal instability with extensive genomic derangements is commonly found in type II endometrial cancers (231). The most frequent genetic alteration is TP53 mutation, present in about 90% of serous carcinomas (205,227,232,233). In contrast to endometrioid carcinoma, MSI is rare (<5%), as are K-ras and PTEN mutations (210,234,235). Other genetic alterations that occur more frequently in serous compared to endometrioid carcinomas are inactivation of  Exploratory Iaparotomy  Biopsy of any suspicious Iesions  TAH-BSO  Peritoneal cytology  Resect any enlarged Iymph nodes  Selective pelvic and para-aortic Iymphadenectomy (see Table 30.8)  Grade 1,2  No or minimal myometrial invasion Pelvic RT & vaginal boost (extended field if positive para-aortic nodes) Whole abdominal radiation or chemotherapy  G2, superficial myometrial invasion  G3, no myometrial   invasion  G3, any myometrial invasion  Deep myometrial invasion  Cervix spread  Positive Iymph nodes  Adnexal spread  Intraperitoneal disease completely resected Positive peritoneal cytology
Figure 35.6 Surgical management of patients with stage I–II endometrial carcinoma.
p16 (45%) and overexpression and gene amplification of HER2/neu oncogene (45% and 70%, respectively) (232,236,237). HER-2/neu overexpression is related to diminished, progression-free survival (238–240). E-cadherin, an oncogene responsible for cell-to-cell adhesion that seems to play a critical role in initiation and progression of endometrial neoplasia, is absent or reduced in 62% to 87% of cases. Loss of E-cadherin is often associated with advanced stage and LOH in both serous and clear cell carcinomas (214,241,242).