Clear-cell cancers are more varied, often characterized by tubulocystic, solid, and papillary patterns. The name clear cell is given due to the increased percentage of glycogen within the cell. Because of the varied histology of clear-cell carcinoma, diagnosis requires at least 25 % of the tumor to illustrate a clear-cell component [5]. Clear-cell endometrial adenocarcinomas are histologically similar to those arising from the ovary, vagina, and the cervix [4]. As in UPSC, clear-cell carcinomas are high grade and tend to be deeply invasive (Fig. 23.2).

If the serous component of a tumor is greater than 10 % but less than 90 %, the tumor is considered mixed serous histology. Typically, the other fraction of the tumor is endometrioid histology. Once thought to have similar survival, a multi-institutional review compared patients with UPSC to those with mixed UPSC and found that the pure UPSC group had an almost threefold risk of recurrence and death than the mixed-cell histology [5]. This holds true for pure clear-cell versus mixed clear-cell histology. These patients historically do relatively the same with regard to survival [6].

While type I tumors are associated with mutations in PTEN, K-ras, and microsatellite instability [7], type II are most commonly found to have p53 mutations and/or Her-2/neu overexpression [8, 9]. P53 is a tumor suppressor gene that regulates transcription and initiates apoptosis in the event of DNA damage. When a mutation or defect in p53 occurs, proliferation of tumor cells occurs. It is thought that approximately 50 % of cancers arise from this defect. It is still currently scrutinized whether BRCA1/2 mutation carriers have an increased risk for UPSC; however a recent study by Pennington et al. did demonstrate a higher than expected BRCA1 mutation rate at 2 % [10]. Given this finding, it has been suggested that women with a diagnosis of UPSC be offered genetic counseling and testing. Additional data suggests that epidermal growth factor receptor (EGFR) expression correlates with a poorer prognosis in both type I and II endometrial carcinoma, reducing survival in UPSC and clear-cell carcinomas from 86 % to 27 % [11]. While Her-2/neu is thought to play a role in UPSC, Herceptin use has not been studied extensively in recurrent or metastatic disease, and successful treatments have only been reported in case reports [12]. Current studies are underway, particularly a phase II study of carboplatin/paclitaxel with or without trastuzumab for advanced or recurrent UPSC patients with 3+ IHC for Her2/neu. Other molecular targets include PPP2R1A, FBXW7, and PIK3CA. Mutations in the regulatory unit of PPP2R1A’s serine-threonine protein phosphatase 2 are reported in as high as 32 % of UPSC [10]. This enzyme is responsible for control of cell growth and division and is located downstream of Her2/neu, which may prove a potential target for treatment of UPSC. FBXW7 is an F-box protein important in targeting tumor-promoting proteins, including cyclin E. Cyclin E upregulates the cell cycle, particularly in the transition from G1 to S phase, in a dose-dependent manner that increases oncogenic potential [13]. A genome-wide analysis of UPSC by Kuhn et al. demonstrated that PIK3CA was mutated and/or amplified in 48 % of the sequenced patients, supporting the PIK3CA/AKT/mTOR pathway is one from which USC arises. Therefore, findings to support this notion will likely lead to adjuvant treatment with mTOR inhibitors such as rapamycin.