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ORIGINAL ARTICLE
Year : 2016  |  Volume : 53  |  Issue : 2  |  Page : 288-291
 

Clinical characteristics with patterns of relapse and survival analysis of ovarian clear cell carcinoma


1 Depatment of Gynecological Oncology, Tata Memorial Hospital, Mumbai, India
2 Depatment of Medical Oncology, Tata Memorial Hospital, Mumbai, India
3 Depatment of Pathology, Tata Memorial Hospital, Mumbai, India

Date of Web Publication6-Jan-2017

Correspondence Address:
R A Kerkar
Depatment of Gynecological Oncology, Tata Memorial Hospital, Mumbai
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.197719

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 » Abstract 

Aims: To analyze clinical characteristics, patterns of relapse, and treatment outcomes of clearcell carcinoma of the ovary (CCO). Materials and Methods: Case files of 51 patients diagnosed with CCO between 2003 and 2010 were reviewed. Results: The median age at diagnosis was 48 years (27-64 years). Fifty percent presented with nonspecific gastrointestinal symptoms. The median serum Ca125 was 74 IU/ml (6-1567 U/ml). Optimal cytoreduction was achieved in 32 (62.7%) patients. Of the 51 patients in this series, 34 (66.6%) had Stage I disease; Stage Ia in 12 (23.6%), Stage Ib in 1(1.9%), and Stage Ic in 21 (41.1%). Thirteen (25.6%) presented with Stage III and 4 (7.8%) with Stage IV. No patient had Stage II disease. All patients received 4-6 cycles of platinum-based combination chemotherapy. There were 18 relapses (35.2%), with disease-free intervals <6 months in 9, 6-12 months in 4, and >12 months in 5, respectively. Of them 33.3% had a recurrent pelvic mass. The median survival after relapse was 14 months. There were 13 deaths, 11 due to disease progression, 1 due to chemo toxicity, and 1 unrelated to disease. At a median follow up of 28 months, disease-free survival (DFS) and overall survival (OS) of patients with Stage I-Stage II (early) disease was 64% and 80%, respectively. In patients with advanced disease, that is, Stages III and IV, DFS and OS were 35% and 38%, respectively. Conclusion: CCO generally presents at an early stage but has a high propensity for relapse. Patients with early-stage disease have a relatively good prognosis as compared with those with advanced-stage disease.


Keywords: Clear cell, ovary, relapse


How to cite this article:
Kaur S, Kerkar R A, Maheshwari A, Shylasree T S, Gupta S, Deodhar K. Clinical characteristics with patterns of relapse and survival analysis of ovarian clear cell carcinoma. Indian J Cancer 2016;53:288-91

How to cite this URL:
Kaur S, Kerkar R A, Maheshwari A, Shylasree T S, Gupta S, Deodhar K. Clinical characteristics with patterns of relapse and survival analysis of ovarian clear cell carcinoma. Indian J Cancer [serial online] 2016 [cited 2020 Mar 31];53:288-91. Available from: http://www.indianjcancer.com/text.asp?2016/53/2/288/197719



 » Introduction Top


Clear cell carcinomas of the ovary (CCO) have distinct clinical and histopathological characteristics and poor treatment outcomes as compared to other epithelial cancers of the ovary.[1] CCO has been defined by World Health Organization as an ovarian carcinoma characterized by clear cells growing in solid/tubular or glandular pattern.[2] The diagnosis proves challenging to both, pathologists and clinicians because it is relatively uncommon, consensus guidelines are lacking and management is controversial. International Federation of Gynecology and Obstetrics FIGO recommends comprehensive surgical staging as essential.[3] Combination chemotherapy with paclitaxel and platinum analogues is accepted as the standard regimen for epithelial ovarian cancers but treatment outcomes in patients with clear cell histology are difficult to assess due to the confounding effects of low numbers of patients within any one clinical trial and heterogeneous stages of disease.[4],[5]

CCO is a rare disease accounting for <5% of all ovarian malignancies and studies have shown various geographical variations with higher incidence in Asian population.[6] Most of the available data is from the Western population and to the best of our knowledge there is no report from India. Therefore this study was planned with an aim to analyze clinical characteristics, patterns of relapse, and treatment outcomes of patients with CCO presenting to a tertiary care cancer center.


 » Materials and Methods Top


All patients diagnosed with clear cell carcinoma of the ovary in our center between 2003 and 2010 were analyzed. All pathological specimens were reviewed by trained gynecologic oncopathologists at our center. Clinical characteristics, surgical and chemotherapy details and patterns of relapse for these patients were studied. Primary cytoreduction included intraperitoneal cytology, total abdominal hysterectomy with bilateral adnexal resection, and infracolic omentectomy. Comprehensive pelvic and para-aortic lymphadenectomy was done only in patients with enlarged nodes. Patients who had undergone surgery at other hospitals prior to referral were staged and managed as per the intraoperative details provided and postoperative imaging. Majority of patients received paclitaxel (175 mg/m 2 over 3 hours) and carboplatin (AUC 5 or 6). Some received a combination of cyclophosphamide, doxorubicin, and cisplatin (CAP) as follows: Each cycle consisted of an infusion of 50 mg/m 2 cisplatin for 1 hour accompanied by an i.v. injection of 50 mg/m 2 doxorubicin and 500 mg/m 2

cyclophosphamide. Chemotherapy was given at 3-weekly intervals for 6 cycles. None of our patients underwent radiotherapy. After completion of treatment, patients who had achieved clinical remission (CR) were then followed up 3-monthly for the first 2 years, 6-monthly for the next 3 years, and annually thereafter. Detailed history, clinical examination, and serum Ca-125 were done at every visit.

Kaplan–Meier curves were constructed for median follow-up and survival data. A log-rank test was performed to compare time-to-event distributions and prognostic factor analysis. Overall survival was determined as the time from date of diagnosis to death or the date of the last follow-up or contact. Disease-free survival (DFS) was defined as the time from date of surgery to the time of relapse or last follow-up. Statistical analysis was performed with a Statistical Package for Social Sciences (SPSS) software, version 18.0 (SPSS, Chicago, IL, USA).


 » Results Top


Patient characteristics

The characteristics of the study population are identified in [Table 1]. Median age at diagnosis was 48 (27-64 years). Of them 26 (50%) presented with nonspecific gastrointestinal symptoms, 20 (39.2%) had an abdomino-pelvic mass. A total of 44 (86.2%) had an Eastern Cooperative Oncology Group ECOG performance status of 0 or 1. All had baseline contrast-enhanced computed tomography (CT) scans/ultrasound and serum Ca125 assessments. Median serum Ca125 was 74 (6-1567 U/ml). Serum CA125 was normal (<35 U/ml) in 18 patients. Seven (13.7%) patients were associated with ovarian endometriosis on histopathology.
Table 1: Patient characteristics

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Primary cytoreduction was done in all except two who received neoadjuvant chemotherapy followed by interval cytoreduction. These two patients received three cycles of paclitaxel and platinum doublet initially (extensive, probably nonresectable disease in one and massive ascites with pleural effusion in one) followed by three cycles of adjuvant chemotherapy after surgery. Pelvic lymphadenectomy was performed in 14. None of the patients underwent para-aortic lymph node dissection as there were no enlarged nodes on imaging. Optimal cytoreduction (defined as residual tumor ≤1 cm) was achieved in 32 (62.7%) patients. Out of 51, 34 (66.6%) had Stage I disease: 12 Stage Ia (23.6%), 1 Stage Ib (1.9%), and 21 Stage Ic (41.1%). Thirteen (25.6%) had Stage III disease and four (7.8%) had Stage IV. No patient had Stage II disease.

All patients received six cycles of adjuvant chemotherapy with taxane and platinum except three who received only four cycles and two who received CAP. Of the three who received only four cycles, one had disease progression on chemotherapy, one died of chemotoxicity and the third had received chemotherapy outside our institute and presented to us with relapsed disease. Two patients registered with our institute in the year 2003 received CAP as the taxane-platinum doublet was not considered a standard regimen at that time. Three patients with stage IV had chemorefractory disease and died of disease progression while on adjuvant therapy.

Relapse patterns

There were 18 (35.2%) relapses, 4 in patients with initial Stage Ia, 8 with Stage Ic, and 6 with Stage III. Disease-free interval (DFI) was less than 6 months, 6-12 months, and more than 12 months in 9, 4, and 5 patients, respectively. At first relapse, six patients presented with a pelvic mass, four had omental deposits, four para-aortic nodal relapse, and two had liver metastasis. One patient each presented with ascites alone and isolated supraclavicular lymph node metastasis. Seven of 18 patients were treated with secondary cytoreductive surgery and adjuvant chemotherapy. Three of 7 are alive in complete remission (CR), 3/7 lost to follow up in CR, and 1/7 died of second relapse after a DFI of 2 years. Eight of 18 received only chemotherapy of which three are alive in CR, 2 were lost to follow up with disease and 3 died of disease progression. Three of 18 patients with DFI less than 6 months, who presented in poor general condition, were given supportive care and eventually died. Median survival after relapse was 14 months.

Outcomes

The outcomes of the study population are identified in [Table 2]. Majority of the patients (33/51) were in CR at their last follow-up. There were 13 deaths and of these 11 were due to disease progression, one due to chemotoxicity and one unrelated to disease. Three patients were lost to follow-up with disease and two were still on treatment at the time of analysis. At a median follow-up of 28 months, DFS of early stage (Stage I/II) and advanced stage (Stage III/IV) was 64% and 35%, respectively [Figure 1]a. Overall survival (OS) of patients with early-stage was 80% and advanced-stage was 38% [Figure 1]b. A univariate analysis was done in order to recognize following prognostic factors for overall survival; age (<50 vs > 50 years), baseline serum Ca-125 (<35 vs >35 U/ml), (stage I/II vs stage III/IV), and primary cytoreduction (optimal <1 cm vs suboptimal >1 cm). Statistically significant predictor for survival was stage (early vs advances; P = 0.01). There was a suggestion that baseline serum Ca125 (<35 vs> 35 U/ml; P = 0.06) may affect survival.
Table 2: Results

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Figure 1: (a) Disease free survival of early versus advanced stage. (b) Overall survival of early versus advanced stage

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 » Discussion Top


CCO has little in common with other epithelial ovarian carcinoma than sharing the site of origin. These tumors demonstrate a distinct clinical behavior and are frequently diagnosed at an early stage, rarely occur bilaterally, and are more often accompanied by thromboembolic events, malignant hypercalcemia, and the coincident presence of endometriosis than the other common epithelial cancers of the ovary. Median age (48 years) in the present study supports the fact that CCO is a disease of young women. This is in concordance with the Surveillance, Epidemiology and End Results (SEER) data reported by Chan et al., where women with clear cell histology were younger than patients with serous cancers (55 vs 64 years; median age).[6] CCO presents predominantly as a pelvic mass, which leads to the diagnosis of the disease at an early-stage. Data from large institutional cohorts comparing early-stage to advanced-stage ovarian cancers (I/II vs III/IV) have shown that 57-81% of CCO were diagnosed as stage I/II.[7],[8] The percentage of patients with early-stage disease in the current study was 66.6%. Two-third of these patients were Stage Ic further inciting queries about the disease biology. In our series 13.7% of women were associated with endometriosis as confirmed by histopathological evaluation. Similar association has been well documented in the past by many authors, varying from as low as 14% by Valenzuela et al. to as high as 49% by Orezzoli et al.[9],[10]

Based on series of early-stage epithelial ovarian cancers, relapses are more frequent than expected in clear cell carcinoma. Of the 18 relapses in the present study, 12 (66.6%) were of Stage I. Included in the Stage I recurrences, 8/12 were Stage Ic. Similar relapse patterns among Stage I CCO particularly Stage Ic have been reported by other authors such as Behbakht et al. (10/27 relapses in Stage I; 7/13 of these relapses from Stage Ic) and Sugiyama et al. (14/38, i.e., 37% of patients with Stage Ic clear cell carcinoma relapsed) in their series.[7],[8] In spite of all patients receiving adjuvant chemotherapy in Stage I the recurrence rate is high in our study, which may be due to chemoresistance of the tumor. This further fuels the controversy of impact of chemotherapy on survival in early-stage CCO. Among Stage III patients 6/13 relapsed. Of these 6 relapses only one could be salvaged with secondary cytoreduction and chemotherapy whereas all others either died or had progressive disease at last follow up. Three of four Stage IV patients also died of primary progressive disease. The poor prognosis and aggressive nature of advanced stage CCO was also reported by Behbakht et al. (3/13 alive in stage III/IV at last follow up) and Goff et al. (3/24 alive in stage III at last follow up).[1],[7]

At a median follow-up of 28 months, DFS and OS in patients with early-stage disease (Stage I/II) was 64% and 80%, respectively. Several authors in the past have discussed and compared the survival outcomes of CCO with high-grade serous ovarian carcinoma. This finding was also replicated in a large report on Stage I patients with 5-year survivals of 76% and 73% for Stage I CCO and serous cell ovary (SCO), respectively.[11] Another population-based study of ovarian cancers conducted in British Columbia found that the 10-year disease-specific survival of 87% for 35 patients with Stage Ia/Ib CCO compared with 68% for those with high grade serous carcinoma.[12] Chih-ming et al. evaluated 20 patients with Stage I pure clear cell carcinoma and reported 4-year survival of 76%.[13] Patients with advanced-stage (Stage III/IV) had a DFS and OS of 64% and 35%, respectively. Unlike early stage CCO the prognosis of advanced-stage carcinoma is worse when compared with other epithelial ovarian cancers. A meta-analysis of over 8704 women with Stage III/IV epithelial ovarian cancer from 7 randomized trials analyzed 221 women with Stage III/IV CCO. Estimated median OS was 21.3 months (95% CI 17.8-28.1 months) for patients with CCO when compared with median OS of 40.8 months (95% CI: 39.7-42.2) for serous ovarian cancer.[14] The experience of the Hellenic Cooperative Oncology Group (5 year OS of 32%) and Kennedy et al. (5 year OS for stage III 26%, stage IV 0%) further substantiate the findings of this study.[15],[16]

The above discussion depicts the lack of our current knowledge in understanding the biology of the disease and paucity of the reported literature when compared with serous epithelial ovarian carcinoma. This study has its limitation of a retrospective design with small number of patients. The current study suggests that CCO is a disease of young females with good prognosis when diagnosed in early stages. The poor survival of advanced-stage disease further emphasizes the aggressive nature of the disease with an unmet need to develop novel chemotherapeutic strategies for primary as well as recurrent disease.

 
 » References Top

1.
Goff BA, Sainz de la Cuesta R, Muntz HG, Fleischhacker D, Ek M, Rice LW, et al. Clear cell carcinoma of the ovary: A distinct histologic type with poor prognosis and resistance to platinum-based chemotherapy in stage III disease. Gynecol Oncol 1996;60:412-7.  Back to cited text no. 1
    
2.
Serov S, Scully R, Sobin L. International Histological Classification of Tumors, Number 9. Histologic Typing of Ovarian Tumors. Geneva: World Health Organization; 1973. p. 1-7.  Back to cited text no. 2
    
3.
F.I.G.O. Cancer Committee. Staging announcement. Gynecol Oncol 1986;25:383-5.  Back to cited text no. 3
    
4.
McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 1996;334:1-6.  Back to cited text no. 4
    
5.
Anglesio MS, Carey MS, Köbel M, Mackay H, Huntsman DG; Vancouver Ovarian Clear Cell Symposium Speakers. Clear cell carcinoma of the ovary: A report from the first Ovarian Clear Cell Symposium, June 24th, 2010. Gynec oncol 2011;121:407-15.  Back to cited text no. 5
    
6.
Chan JK, Teoh D, Hu JM, Shin JY, Osann K, Kapp DS. Do clear cell ovarian carcinomas have poorer prognosis compared to other epithelial cell types? A study of 1411 clear cell ovarian cancers. Gynecol Oncol 2008;109:370-6.  Back to cited text no. 6
    
7.
Behbakht K, Randall TC, Benjamin I, Morgan AM, King S, Rubin CS. Clinical characteristics of clear cell carcinoma of the ovary. Gynecol Oncol 1998;70:255-8.  Back to cited text no. 7
    
8.
Sugiyama T, Kamura T, Kigawa J, Terakawa N, Kikuchi Y, Kita T, et al. Clinical characteristics of clear cell carcinoma of the ovary. a distinct histologic type with poor prognosis and resistance to platinum-based chemotherapy. Cancer 2000;88:2584-9.  Back to cited text no. 8
    
9.
Valenzuela P, Ramos P, Redondo S, Cabrera Y, Alvarez I, Ruiz A. Endometrioid adenocarcinoma of the ovary and endometriosis. Eur J Obstet Gynecol Reprod Biol 2007;134:83-6.  Back to cited text no. 9
    
10.
Orezzoli PJ, Russell AH, Oliva E, Del Carmen MG, Eichhorn J, Fuller AF. Prognostic implication of endometriosis in clear cell carcinoma of the ovary. Gynecol Oncol 2008;110:336-44.  Back to cited text no. 10
    
11.
Vergote I, De Brabanter J, Fyles A, Bertelsen K, Einhorn N, Sevelda P, et al. Prognostic importance of degree of differentiation and cyst rupture in stage I invasive epithelial ovarian carcinoma. Lancet 2001;357:176-82.  Back to cited text no. 11
    
12.
Kobel M, Kalloger SE, Santos JL, Huntsman DG, Gilks CB, Swenerton KD. Tumor type and substage predict survival in stage I and II ovarian carcinoma: Insights and implications. Gynecol Oncol 2010;116:50-6.  Back to cited text no. 12
    
13.
Ho CM, Chien TY, Shih BY, Huang SH. Evaluation of complete surgical staging with pelvic and para-aortic lymphadenectomy and paclitaxel plus carboplatin chemotherapy for improvement of survival in stage I ovarian clear cell carcinoma. Gynecol Oncol 2003;88:394-9.  Back to cited text no. 13
    
14.
Mackay HJ, Brady MF, Oza AM, Reuss A, Pujade-Lauraine E, Swart AM, et al. Gynecologic Cancer InterGroup. Prognostic relevance of uncommon ovarian histology in women with stage III/IV epithelial ovarian cancer. Int J Gynecol Cancer 2010;20:945-52.  Back to cited text no. 14
    
15.
Pectasides D, Fountzilas G, Aravantinos G, Kalofonos C, Efstathiou H, Farmakis D. Advanced stage clear-cell epithelial ovarian cancer: The Hellenic Cooperative Oncology Group experience. Gynecol Oncol 2006;102:285-91.  Back to cited text no. 15
    
16.
Kennedy AW, Markman M, Biscotti CV, Emery JD, Rybicki LA. Survival probability in ovarian clear cell adenocarcinoma. Gynecol Oncol 1999;74:108-14.  Back to cited text no. 16
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2]

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