1. Introduction:
Ovarian clear cell carcinoma (OCCC)is a distinct subtype of epithelial ovarian cancer (EOC). It is unique in several biological aspects, starting with its significant prevalence variation according to geographic distribution, where it is rare accounting for only 5-10 % of all EOC in the United States and western countries, it has higher prevalence in Asian countries especially Japan where it reaches 25-30%, but the cause of this variation is unclear [
1]. While OCCC is considered to be type 1 ovarian cancer, it does not fit typically for this subtype as it is considered as high grade at presentation, regardless of its stage [
2]. It behaves aggressively especially in advanced stages, unlike other type 1 tumors. OCCC is associated with endometriosis, suggesting that retrograde menstruation is the origin for these tumors [
3]. Both atypical endometriosis and atypical adenofibroma of the ovary have been considered as precancerous lesions [
4,
5]. Another distinctive feature is the association between the presence of thromboembolism and a poor prognosis in OCCC [
6,
7], but the biological mechanism of hypercoagulation in OCCC remains unclear [
8]. CA 125, the standard tumor marker for high grade serous carcinoma, is elevated only in about 57% of OCCC [
9].
OCCC characteristically contains clear or hobnail cells with eccentric, rounded, and bulbous nuclei, multiple complex papillae, densely hyaline basement membrane material, and hyaline bodies. Compared with other types of EOC, the frequency of mitoses is lower (usually < 5 /10 HPFs) [
10]. No single immunohistochemistry marker has been reported to be useful alone in distinguishing between high grade serous and clear cell ovarian carcinoma. A four-marker immunohistochemical panel (WT1/p53/napsin A/PR) can distinguish EOC subtypes with high accuracy, and additional immunohistochemical markers can be used if needed. WT1 is the most important marker that is diffusely expressed in almost all high-grade serous ovarian cancers and low grade serous ovarian cancers and virtually absent in almost all OCCCs and mucinous ovarian cancers [
11]. Fadare et al recommended a panel of immuno-histochemical markers including Napsin-A, HNF-1 β and AMACR to obtain the highest sensitivity and specificity when OCCC is a diagnostic consideration [
12].
Different molecular pathways and genetic alterations have been identified in OCCC, including the most common mutations of AT-rich interaction domain 1A (ARID1A) and phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3) catalytic subunit alpha (PIK3CA). OCCC shows high frequency of PIK3CA mutation (40%), leading to higher activity of the PI3K–AKT–mTOR pathway [
13]. The Standard therapeutic treatment for OCCC according to the NCCN guidelines (version 1.2020) is optimal cytoreduction combined with systemic chemotherapy. Patients with OCCC tend to be less sensitive to conventional platinum-based chemotherapy, where only 11% - 27% of patients with OCCC respond to a platinum-based chemotherapy, resulting in poorer outcome [
14].
The aim of this study is to have a closer insight into the clinic-pathological features and outcome of patients with OCCC, by identifying factors affecting recurrence, progression-free survival (PFS) and OS, through a retrospective review of all OCCC cases diagnosed and treated at Oxford Cancer Centre over a 13-year period.
4. Discussion:
Our study described OCCC medical data- with a total of 49 women- from a single cancer center in UK from January 2009 to December 2021. It was surprising that in our study the mean age at presentation was 62.6 ± 11.04 (range 37-83), with >61% presenting above the age of 60.This is different from previous retrospective studies that showed younger mean age at presentation, as a recent publication [
15] involving 86 patients stated the median age at diagnosis was 49.21 ± 9.91 years (range 25–70 years) with only 12% presenting above the age of 60. A another recently published study [
16], stated the age of onset had 2 peaks, namely 36 years and 77 years, but in our cohort only one woman presented below the age of 40. Both these studies were carried out in China, with different disease prevalence and possible genetic basis may explain the findings. However, the MSK experience [
17] from USA, including 176 OCCC patients, had mean age at diagnosis of 53.
In our study, 36 women (73.4%) were diagnosed at stage I or II. This is in line with prior studies [
17,
18], in which most women with OCCC present with early-stage disease. Part of this may be due to its tendency to present as a large unilateral pelvic mass, compared to the early peritoneal dissemination, which is common in HGSC.
The histopathology protocol followed in our institution for OCCC diagnosis, is based generally on the H&E stain. There are a few well recognized patterns – solid, papillary and tubule-cystic. There can be a mixture of these in the same malignancy. The carcinoma cells can be clear or pink (eosinophilic) and there are characteristic features such a pink globules and hob-nail cells/nuclei seen. If there is a need to differentiate from serous carcinomas or endometrioid carcinomas with secretory changes, then Napsin A is the most widely used immunomarker. ER and PR should be negative as should WT1 unless there is a component of serous carcinoma admixed. We tend to use vimentin to look for endometrioid epithelium. AMACR can also be used for clear cell tumours but Napsin A is the best.
During our 13 years retrospective period, 5 patients have been enrolled into 5 different trials: 1st patient was enrolled in Javelin Ovarian 100, NCT02718417: it was a phase 3 open label study on Avelumab in previously untreated patients with epithelial ovarian cancer. The study was terminated based on the results of a planned interim analysis that showed futility of efficacy [
19]. Another patient was enrolled in OSI trial, Identifier: NCT00889382 a multi-centre, randomized, open-label, phase 1/2 study of continuous weekly paclitaxel and escalating doses of intermittent or continuous OSI-906 in patients with recurrent/relapsed ovarian and other solid tumors [
20]. A 3rd patient was enrolled in Chorus trial Identifier: NCT00075712, Timing of Surgery and Chemotherapy in Treating Patients with Newly Diagnosed Advanced Ovarian Epithelial, Fallopian Tube, or Primary Peritoneal Cavity Cancer [
21]. 4th patient was enrolled in Ovpsch trial, according to her medical notes, but no further details were found either on medical records nor in the trust intranet registered trials. A 5th patient was enrolled in Peacocc trial [
22] ; Phase II, multicenter, single-arm trial in patients with advanced CCGC who had ≥1 prior line of chemotherapy with progression (PD) at study entry.
Since OCCC is a high-risk group, adjuvant chemotherapy is recommended even if the stage is Ia, but the guidelines vary slightly between different gynecologic oncology societies. In our study group, where BSGC guideline is followed, adjuvant chemotherapy was not offered in 10 women (20.4 %), as the guideline states that low stages Ia /Ib OCCC are excluded from offering adjuvant platinum-based chemotherapy. Comparison between different gynecology societies OCCC guidelines is shown is (Table 6). According to GOG 157 trial in which OCCC represented one third of cases (n=130), the benefit of using 6 cycles versus 3 cycles adjuvant paclitaxel and carboplatin chemotherapy in early-stage ovarian cancer in reducing recurrence risk was not evident in OCCC group (RFS HR 0.9, 95%CI 0.43,1.91) [
23,
24]. ACTION study reported similar PFS for patients with early-stage clear-cell carcinoma with or without adjuvant chemotherapy [
25] and two retrospective analyses [
26,
27] reported no benefit from adjuvant chemotherapy after completing surgical staging for stage IA–B clear-cell carcinoma. By contrary, other studies suggest a high level of biological heterogeneity among clear-cell tumours that can sometimes justify an aggressive appearance even among patients with stage I disease [
28]. At present, the true challenge is to predict which patients with early-stage disease are at higher risk of recurrence and would most benefit from additional treatments.
In our study, the mean follow-up time was 105.5 months (range 7-144 months), with 3-year OS 73.4%. The study group showed significant variation in OS for women among stages (p<.001), 3-year OS rate was 92.1% for stage I which is consistent with previous studies [
16,
17,
29], 85.7% in stage II, dropping to 25% in stage III, with the worst prognosis for stage IV with 1-year OS 25%.
In our study group, endometriosis was found in 28 women (57.15%), confirmed in histopathology report, the percentage is in consistent with other studies that reported 18% to 43% of women with OCCC have a history of endometriosis [
30,
31] , and several studies have demonstrated that this benign disease is significantly related to the pathogenesis of OCCC, with 3 fold increased risk of OCCC (OR = 3.05) when endometriosis being reported [
32]. In our study, OS and PFS showed no statistically significant difference when Kaplan Meier analysis stratified by endometriosis. It is unclear in the literature the role of endometriosis on ovarian cancer prognosis. Published studies have generally showed that patients with endometriosis associated ovarian cancer had higher survival rates, but in most series, this finding has been linked to an earlier stage at diagnosis among ovarian cancer cases with endometriosis rather than the association with endometriosis as a prognostic factor or their published data had not statistically significant difference [
33,
34]. Our results agreed with a recent published study that concluded that the presence of endometriosis did not affect neither the OS (87.99 Vs 75.30, p-value=0.25) nor the PFS (111.13 Vs 117.42, p-value=0.48) [
35].
In our study, in a univariant analysis, a statistically significant difference (p<0.001) was found when survival analysis was stratified according to presence of residual disease (suboptimal cytoreduction), showing 3-year OS in no-residual disease group 88.6% (95% CI 108.6-141.8), compared to 12.5% (95% CI 4.48-32.11) in residual disease group, keeping suboptimal cytoreduction a major prognostic predictor for OCCC. The residual disease was linked to advanced stages, and the small number of advanced cases involved in our cohort (13 in total) didn’t allow further analysis. In published data, other studies examined the association between residual disease and prognosis in clear cell carcinoma [
36]. In a retrospective cohort study, examined the association between residual disease and prognosis by histological type of ovarian cancer using data from the National Cancer Database of America, OS differed significantly according to residual disease status not only in patients with high-grade serous carcinoma but also in those with clear cell carcinoma and, while not statistically significantly different, the survival benefit associated with complete cytoreduction was greater in clear cell carcinoma (HR 0.39, 95% CI 0.22 to 0.69) than in high-grade serous carcinoma (HR 0.58, 95% CI 0.49 to 0.68) [
37]. Different studies have elicited the significance of complete cytoreduction and its impact on survival in ovarian cancer patients [
38,
39,
40,
41,
42,
43,
44,
45,
46,
47,
48,
49,
50,
51,
52,
53,
54,
55].
In our study, in multivariant analysis, CA 125, Hb, albumin, endometriosis-association, ascites, residual disease, and FIGO staging were included, only FIGO stage was an independent prognostic indicator of OS with (p<0.05), and none of the remaining factors had statistical significance. A similar analysis in a study published by Park et al [
44], found in the univariate survival analysis, significant prognostic factors for both DFS and OS were coexisting endometriosis, elevated preoperative serum CA-125 levels, advanced FIGO stage (stage I vs stages II-IV), ovarian surface involvement, positive peritoneal cytology, and suboptimal debulking. Coexisting endometriosis and advanced FIGO stage were significant factors for both DFS and OS in the multivariate analysis.
As a mini-review of the literature, we added a table of previous published studies over the last 5 years, involving OCCC in retrospective analysis, and the studies have been summarized as shown [
1,
15,
16,
56,
57,
58,
59].
Author Contributions
All Authors have contributed to the manuscript as following “Conceptualization, Sally EL Tawab, Hooman Soleymani Majd ; Data collection and methodology : Sally EL Tawab, Sanjiv Manek , Kezia Gaitskell ; formal analysis Sally EL Tawab ; resources, Sally EL Tawab, Sabina Nistor, Rene Roux, Ahmed Ashour Ahmed , Sean kehoe , Hooman Soleymani majd, writing—original draft preparation, Sally EL Tawab; writing—review and editing, Sally EL Tawab, Rene Roux; Sanjiv Manek, visualization Ahmed Ashour Ahmed , Sean kehoe, Hooman Soleymani majd ; Supervision, Rene Roux, Ahmed Ashour Ahmed , Sean kehoe, Hooman Soleymani majd ; project administration: Hooman Soleymani Majd. All authors have read and agreed to the published version of the manuscript.