Clear Cell Cancer of the Uterine Corpus: The Association of Clinicopathologic Parameters and Treatment on Disease Progression

This paper presents a single-institution experience regarding the clinicopathologic features and treatment strategies used in uterine clear cell cancer (UCC), a rare, aggressive histologic subtype of uterine cancer with poor prognosis and discusses parameters associated with progression-free survival (PFS) and overall survival (OS). A retrospective chart review was performed on all patients (n = 80) diagnosed with UCC and treated between 1994 and 2009 at a single academic institution. Data on demographics, FIGO stage, treatment regimens, and recurrences were collected. Patients with early-stage UCC had an excellent survival regardless of adjuvant therapy. Advanced-stage patients had a worse survival. Vaginal apex brachytherapy was associated with an increased OS (P = 0.02) but not PFS (P = 0.10). The use of platinum-based chemotherapy in combination with vaginal apex brachytherapy did not significantly improve survival. Innovative therapies still need to be identified for this uncommon uterine cancer.


Introduction
Endometrial cancer is the most common gynecologic cancer in the United States, with 43,470 new cases and 7,950 deaths estimated in 2010 [1]. The incidence of endometrial cancer is greater than that of all other female genital tract malignancies combined [1]. Clear cell carcinoma of the uterine corpus (UCC), a rare subtype accounting for 1-6% of uterine cancers, is characterized histologically by the clearing of tumor cell cytoplasm [2][3][4][5]. Patients with UCC are more likely to present with higher-stage disease than those with endometrioid histology, and clear cell histology has been considered a poor prognostic factor [2,6]. Comprehensive surgical staging is recommended in women with UCC, given the high error rate with clinical staging [7]. Aggressive, multimodal treatment (including surgery, chemotherapy, and/or radiation therapy) is usually recommended as compared to type I endometrial cancers.
Due to the rarity of UCC, there are no prospective studies evaluating these treatments solely in women with UCC [4].
Compared with endometrioid and serous carcinomas, little is known about the molecular pathways and immunophenotypic profile involved in UCC. Studies have confirmed that UCC is genetically distinct from endometrioid cancer [8]. Clear cell tumors show similar gene expression profiles regardless of organ of origin [8,9]. Type II endometrial tumors tend to display p53 mutations, compared to Type I cancers [2].
The goal of this paper was to present the clinicopathologic features and treatment strategies used in UCC and determine what parameters are associated with progressionfree survival (PFS) and overall survival (OS).

Materials and Methods
A retrospective chart review was performed on all patients with the diagnosis of UCC from 1994-2009 who were treated 2 Journal of Oncology at the Yale-New Haven Hospital (YNHH). A YNHH Tumor Registry search under the search terms "endometrial cancer" and "clear cell" identified 80 patients with UCC.
Medical charts, including admission and discharge notes, as well as surgical pathology reports and treatment records (chemotherapy and radiation) were reviewed, and epidemiological data (age at diagnosis, ethnicity, gravity, and parity), clinical data (past medical history, menstrual history, smoking history, hormone or tamoxifen use, personal or family history of other malignancies, body mass index (BMI)), and pathologic and histological data (stage, lymphovascular space involvement, positive pelvic washings, involvement of polyps, lymph node metastases, depth of myometrial invasion) as well as survival data (disease-free and overall survival) were extracted. All pathology and cytology specimens had been previously reviewed by gynecologic pathologists at YNHH. Seventy-six patients were staged using the International Federation of Gynecology and Obstetrics (FIGO) 1988 operative staging system for endometrial cancer. The remaining 4 patients had palliative treatment only.
Long-term follow-up data were censored at date of last followup. PFS was calculated from date of diagnosis until date of recurrence, death, or last followup. OS was calculated from date of diagnosis until death or date of last followup. Cox proportional hazards multivariable models and Kaplan-Meier test were used for survival analysis. A P < 0.05 was considered statistically significant. Statistical analyses were performed using SAS 9.2 (SAS Institute, Cary, NC). This research was approved by the Human Investigation Committee at Yale University School of Medicine (HIC#0804003674).
Twelve of the 80 patients (15%) had used hormonereplacement therapy for any duration of time. Eleven patients (13.8%) had a history of oral contraceptive use, and 5 (6.3%) had used tamoxifen. The majority of patients (62.5%, n = 50) had a BMI that classified them as overweight or obese. Twenty-five patients (31.3%) reported that they were past or current smokers.
Radiation was part of the adjuvant treatment for 63 patients (78.8%) ( Table 3). All but one of these patients received vaginal brachytherapy (remote after loading 192 Ir source to a total dose of 21 Gy in 3 fractions or 14 Gy in 2 fractions at 0.5 cm from the vaginal mucosa). One patient was treated only with external beam radiation therapy (EBRT). Five patients received EBRT along with vaginal brachytherapy. One patient received vaginal brachytherapy and whole abdomen radiation treatment with a pelvic boost. Two patients were treated with radiation therapy only at the time of recurrence. Fifty-three patients (66.3%) received chemotherapy (Table 3). Of these, 84.9% (n = 45) were treated with a platinum-based regimen, 35 (66%) of whom received carboplatin (AUC = 6) and paclitaxel (175 mg/m 2 )    Operative notes were available for 72 patients. Of these patients, all but 4 were debulked to no residual disease (n = 65) or residual disease of less than 1 cm (n = 3). All of the patients with residual disease had Stage IV disease. Their progression-free and overall survivals ranged from 1 to 70 months. When considering all patients, the presence of residual disease had a significant impact on OS (P < 0.0001) but not on PFS (P = 0.1). The median overall survival in patients with residual disease, even if optimally debulked to less than 1 cm of disease, was 17.5 months versus 135 months in those patients with no residual disease.
There was a significant relationship between age at diagnosis and OS (P < 0.001; hazard ratio 1.07; 95% CI 1.03-1.12), independent of FIGO stage. Increased age contributed to shorter overall survival. However, there was no significant relationship between age at diagnosis and PFS (P = 0.23; 95% CI 0.98-1.09).
In univariate analysis, vaginal brachytherapy, whether alone or in combination with other radiation therapy, had an impact on OS (median survival with radiation: 140 months versus without radiation: 50 months; P = 0.02), but not on  PFS (P = 0.10). This association was not noted after testing in a multiple regression model. Adjuvant chemotherapy had no significant impact on OS (P = 0.26) or PFS (P = 0.27). When patients treated with vaginal brachytherapy plus carboplatin and paclitaxel (n = 28) were compared to patients who were not treated with this regimen, no significant difference was seen in OS or PFS (P = 0.82 and P = 0.39, resp.).

Discussion
Given the rarity of the diagnosis of UCC, meaningful data is lacking in the form of prospective randomized controlled trials. Historically, Abeler and Kjorstad published a chart review of 97 patients with UCC. Although the patients were treated based on different protocols, they found a 5-year survival rate of 42.3% and 10-year survival at 30.9% [10].
No patient with Stage III or IV survived 5 years. Age did not correlate with survival, implying that UCC histology was the most important prognostic factor. Recently, better survival rates of 79% 5-year survival for early disease and 21% for advanced disease have been reported [7].
Fifty percent of our patients presented with Stage I disease, which is higher than usual as most patients present with metastatic disease [5]. This difference may be because the majority of our patients had mixed histology (clear cell plus serous and/or endometrioid) and not pure clear cell carcinoma. Our findings were consistent with a previous publication reporting LVI to have no effect on survival in endometrial cancer [11].
To our knowledge, there are no published studies on the impact of residual disease on survival in UCC. Previous studies have demonstrated a significant survival benefit with optimal cytoreduction at primary surgery in uterine serous carcinoma [12]. When attempting to look at the role of optimal debulking in survival of UCC patients, only 4 patients (5%) in our present study had residual disease of greater than 1 centimeter. While no conclusions can be drawn regarding clear cell histology because of the small number of advanced stage patients in this study, residual disease may be an important factor to consider in future research on survival in UCC patients.
While surgical staging (total hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymphadenectomy, omentectomy, peritoneal cavity evaluation with washing, smears, and biopsies of suspicious-looking areas) and optimal cytoreduction are the standard of care in patients with UCC, optimal postoperative management is far from being defined. Treatment strategies vary at different stages. Given the small number of women affected with UCC, factors associated with improved survival are difficult to discern. The Society of Gynecologic Oncology reported that although adjuvant radiation is commonly offered to patients with all stages of UCC, no studies have demonstrated improvements in OS, largely because of lack of power [4]. Studies looking exclusively at UCC are limited [2]. Radiotherapy may be justified given that it may provide improved local control. The present study hypothesizes that there may be an impact on OS when patients received vaginal apex brachytherapy. However, more data is needed to confirm this observation.
No studies have been performed regarding adjuvant chemotherapy in an exclusively UCC population [4,5]. Several studies examined the role of postoperative chemotherapy in endometrial cancer. The Gynecologic Oncology Group (GOG) 139 trial prospectively evaluated the largest population of pure UCC patients (n = 44) for chemotherapy response, although UCC patients only comprised 3.7% of the total study population [13]. Clear cell histology was a negative predictor for PFS and OS compared to other histologic subtypes. Carboplatin and paclitaxel have some efficacy in women with UCC with acceptable toxicity [14]. Although other chemotherapeutic regimens have been examined, their efficacy in the UCC subset of patients has yet to be established [15]. A prospective cohort study of 22 patients with Stage I UCC and uterine serous carcinoma concluded that adjuvant therapy may not be necessary in early-stage patients after surgical staging [16]. Given the data available, the authors believe it is reasonable to offer all patients with UCC adjuvant chemotherapy, although the best therapeutic regimen and its true benefit in Stage I patients are still up for discussion.
The potential association of endometrial cancer with other malignancies, particularly carcinomas of the breast and colon, has been investigated previously [17]. A study comparing the rate of breast cancer in patients with uterine serous cancer and that in patients with endometrioid endometrial cancer demonstrated that 19.4% of serous patients had a history of breast cancer compared to 3% of those with endometrioid histology [18]. In our study, 8.8% of our patients had a personal history of breast cancer. This disparity in breast cancer rates between uterine serous cancers and UCC may be due to differences in breast cancer treatment and rates of tamoxifen use or more likely, due to the fact that many of our patients had mixed histology. Women with Lynch syndrome have a 20-60% lifetime risk of developing endometrial cancer [19]. In fact, many women with Lynch syndrome present with endometrial cancer as their first malignancy [20]. There is a higher incidence of nonendometrioid endometrial cancer in patients with Lynch Syndrome (43%) than in those with sporadic uterine tumors, despite younger mean age at diagnosis. In one recent study of patients with endometrial cancer and Lynch syndrome, the authors reported that 21% of the patients had clear cell cancer [19]. Five patients (6.3%) in our study had a personal history of colon cancer, one of whom had a sister with colon cancer. An additional five patients had a first-degree relative with colon cancer, without a personal history of gastrointestinal malignancy. Providers should keep in mind that patients diagnosed with UCC (particularly at a younger age) may carry the Lynch syndrome mutation.

Conclusions
This retrospective, single-institution report of uterine clear cell cancer demonstrates that most patients with UCC have clear cell histology in combination with serous and/or endometrioid histology. In our present study, we show that age and early-stage versus late-stage disease have a significant impact on overall survival. Of particular interest, vaginal brachytherapy also had an impact on overall survival regardless of other aspects of a patient's treatment. When comparing this data with data from patients with uterine serous cancer from the same institution, there does not seem to be a great difference in recurrence rates between clear cell and serous histologies. In a study by Kelly et al., 28% of Stage I serous cancers recurred, and in our study 20% of Stage I UCC patients recurred [21]. As with all research on this aggressive histologic subtype of endometrial cancer, our data is limited by small sample size. However, these results may help guide future prospective research from which we draw more concrete conclusions regarding treatment and followup of patients with UCC.