Endometrial cancer is classified into two subtypes: Type I (endometrioid histology) and Type II (ESC, clear cell histology) [1]. Type I cancers are generally estrogen dependent, low grade, have minimal myometrial invasion and carry a good prognosis. Type II cancers including ESC and clear cell carcinomas, are not associated with increased exposure to estrogen, and carry a poor prognosis. In Japan, the incidence of Type II cancers has increased from 2–3% of all uterine cancers in the early 1990’s to 10% in 2008 [2]. ESC accounts for 3% of all endometrial carcinomas in Japan [2]. In Western countries, although ESC only accounts for 10% of all uterine cancers, it is responsible for 40% of uterine cancer deaths [3]. Historically, endometrial cancer treatment has been dictated by grade and stage; however, it is clear that histology-specific treatment algorithms are also required if the prognosis of ESC is to be improved.

Endometrial serous adenocarcinoma (ESC) typically arises in postmenopausal women. The tumor bears histological similarity to ovarian serous adenocarcinoma. ESC has a high propensity for early lymphovascular invasion, as well as intraperitoneal and extra-abdominal spread. It commonly presents at an advanced stage. The overall 5-year survival rate is about 30% for all stages and the recurrence rate after surgery is extremely high (50–80%) [4]. Several groups have reported that 50% of ESC show extra-uterine spread at the time of diagnosis [4,5,6,7]. Interestingly, unlike Type I tumors, in which spread to the regional lymph nodes may be predicted by the depth of myometrial invasion and tumor grade, there are no clear predictive factors of extra-uterine disease for ESC. For example, 37–63% of ESC with no myometrial invasion have extrauterine spread [4,6,8], and 38% of ESC confined to an endometrial polyp have extra-uterine spread [8]. ESC sometimes includes endometrial components [9]. Even if in patients with early-stage disease, a trend toward a worse prognosis was found to exist when ESC comprised even 10% of a tumor [9]. Investigation into the treatment of endometrial carcinoma should include and document tumors with any percentage comprised of ESC [9].

Unlike endometrioid adenocarcinomas which arise directly from atypical endometrial hyperplasia, the precursor lesion for ESC, endometrial glandular dysplasia and endometrial intraepithelial carcinoma (EIC), originates in atrophic endometrium [10,11]. ESC closely resembles serous carcinoma of the ovary and fallopian tube because its papillary growth and cellular features are similar (Figure 1). Contrastingly, endmetrioid carcinoma is the most common form of carcinoma of the endometrium, comprising 75% to 80% of the cases. Grade 1 endometrial carcinomas are well differentiated and are generally associated with a good prognosis (Figure 2).

Recently, Zheng et al. reported a proposed model of ESC carcinogenesis [11]. According to their model, endometrial serous carcinoma arises predominantly in the resting endometrium, manifesting first as p53 immunoreactive, morphologically normal endometrial cells, evolving to endometrial glandular dysplasia, then to serous endometrial intraepithelial carcinoma (EIC), and finally into fully developed serous carcinoma. Furthermore, they showed that a decreasing percentage of diagnosed lesions express ER, ranging from endometrial glandular dysplasia (EmGD) (70–95%) to serous EIC (<30%) and ESC (<30%) [11]. Loss of ER expression occurred after mutation of p53 and is associated with HER2/neu overexpression in ESC [11].

ESCs histologically resemble ovarian serous adenocarcinomas. They contain fibrous stroma and show a papillary pattern of proliferation. Tumor cells are pleomorphic, have prominent nuclear atypia, high N/C ratios, distinctive nucleoli, and frequent nuclear fission. Sixty percent of ESCs contain psammoma bodies. Other pathognomonic cellular features include a ballooned or hobnail-like nucleus and stromal hyalinization.

Type I and Type II endometrial carcinomas also differ on a molecular basis. ESCs are not hormone-sensitive and therefore do not express ER or PR [12]. K-ras, PTEN, β-catenin, which are often mutated in Type I endometrioid adenocarcinomas, are rarely altered in ESCs [13]. Instead, mutation of p53 is often observed [13]. Exomesequencing of ESC identified the frequency of p53 mutation was 81.6% [14]. Amplification of the HER2/neu gene and overexpression of the HER2/neu protein have been shown in many tumors, including ESC [15,16]. Some studies showed that the overexpression of HER2/neu was frequently associated with the advanced stage and poor prognosis in ESC [15,16,17]. Interestingly, mutation of PIK3CA is common in both endometrioid adenocarcinomas and ESCs [18]. Very recently, Kuhn et al. reported that amplification of CCNE1 was 30.4% in ESCs [14]. The novel tumor suppressor gene, ARID1A, which was recently discovered by an exome sequencing study of ovarian clear cell carcinomas [19,20], is rarely mutated in ESCs. In contrast, PPP2R1A, another gene implicated in ovarian clear cell carcinomas, is frequently mutated in ESCs [21,22]. Previously reported clinicopathological and molecular differences between Type I endometrioid adenocarcinomas and Type II ESCs are summarized in Table 1 and Table 2 [23]. Recently, Zhen et al. reported that oncofetal protein IMP3 may be a useful diagnostic marker in the assessment of endometrial cancers and their precursor lesions, particularly when the amount available tissue materials is limited and concern of type II cancer arises [24].

ESC is uncommon, but accounts for a disproportionate number of endometrial cancer deaths. Histology-specific treatment algorithms are needed to improve outcomes; however, the development of standardized protocols through randomized controlled trials has been hampered by the rarity of the subtype. Evaluation of the currently available retrospective and prospective data suggests that ESCs benefit from complete cytoreduction followed by adjuvant chemotherapy, regardless of stage. It is hoped that JGOG2043 will address key questions regarding adjuvant chemotherapy. Additional trials are also required to clarify the role of radiotherapy in ESCs.