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  Do clear cell ovarian carcinomas have poorer prognosis compared to other epithelial cell types? A study of 1411 clear cell ovarian cancers John K. Chan  a, ⁎ , Deanna Teoh  a  , Jessica M. Hu  a  , Jacob Y. Shin  a  ,Kathryn Osann  c , Daniel S. Kapp  b a   Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco School of Medicine,UCSF Helen Diller Family Comprehensive Cancer Center, 1600 Divisadero Street Box 1702, San Francisco, CA 94143-1702, USA  b  Department of Radiation Oncology, Stanford University School of Medicine, Stanford Cancer Center, 300 Pasteur Drive, HH333, Stanford, CA 94305, USA c  Division of Hematology/Oncology, Department of Medicine, Chao Family Comprehensive Cancer Center, University of California, Irvine  –   Medical Center,101 The City Drive, Orange, California 92868, USA Received 12 December 2007Available online 18 April 2008 Abstract Objective.  To compare the clinico-pathologic characteristics and survival of women with clear cell versus other epithelial ovarian cancers.  Methods.  Data were obtained from the Surveillance, Epidemiology and End Results Program between 1988 and 2001 and analyzed usingKaplan – Meier and Cox proportional hazards models.  Results.  Of 28,082 women with epithelial ovarian cancer, 1411 (5%) had clear cell, 13,835 (49.3%) papillary serous, 3655 (13%) endometrioid,2711 (9.7%) mucinous, and 6470 (23%) had unspecified histologies. The median age of overall patients was 64 years; with clear cell patients presenting at younger age (55 years). The proportion of clear cell histology was significantly higher in Asians versus Whites, Blacks, and others(11.1% versus 4.8%, 3.1%, and 5.5%;  p b 0.001). Clear cell carcinoma is more likely to be diagnosed at early-stage (67.3%) compared to 19.2% inserous, 61.6% endometrioid, and 61.3% in mucinous carcinomas (  p b 0.005). Retroperitoneal lymph node metastases were found in 13.6% of serous carcinomas, 7.9% clear cell, 7.3% endometrioid, and 3.8% of mucinous (  p b 0.001). Adjusted for stage, the 5-year disease-specific survivalof patients with clear cell carcinoma is worse compared to serous: 85.3% vs. 86.4% for stage I, 60.3% vs. 66.4% stage II, 31.5% vs. 35.0% stageIII, and 17.5% vs. 22.2% for stage IV, respectively (  p b 0.001). On multivariate analysis, age, stage, grade, histology, and surgical treatment wereindependent predictors of disease-specific survival. Conclusions.  Our data suggest that women with clear cell ovarian cancer present at a younger age, are more likely to be Asian, and have a poorer prognosis compared to serous cancers.© 2008 Elsevier Inc. All rights reserved.  Keywords:  Ovarian cancer; Clear cell; Epithelial carcinomas; Prognosis Introduction Ovarian cancer is the fourth most common gynecologiccancer in the United States, but accounts for the leading causeof gynecologic cancer deaths. It is estimated that 22,430 newcases will be diagnosed in 2007, with 15,280 deaths [1]. Themajority of epithelial ovarian cancers will be of seroushistology and diagnosed in advanced stages. Histologic celltype has been recognized as an important prognostic factor inovarian cancer.Prior reports have shown that clear cell cancers compriseapproximately 5% of all epithelial ovarian cancers. In contrast to serous cancers, the majority of clear cell adenocarcinomas arediagnosed at an early stage; however, the prognostic advantageof this remains unclear. Although a number of reports haveshown similar survival rates for serous compared to clear cellovarian carcinomas [2 – 5], others have found that clear cellcarcinomas are a more aggressive histologic subtype [6 – 8].  Available online at www.sciencedirect.com Gynecologic Oncology 109 (2008) 370 – 376www.elsevier.com/locate/ygyno ⁎ Corresponding author. Fax: +1 415 885 3586.  E-mail address:  chanjohn@obgyn.ucsf.edu (J.K. Chan).0090-8258/$ - see front matter © 2008 Elsevier Inc. All rights reserved.doi:10.1016/j.ygyno.2008.02.006  These reports have revealed that clear cell cancers have adistinct, aggressive biologic behavior with poor response to platinum-based therapy compared to their other epithelialcounterparts. However, most of these studies srcinate fromsingle-institutions and are limited by a small sample size. In thiscurrentpopulation-basedstudyof1411clearcellcancerpatients,we propose to evaluate whether clear cell ovarian carcinomashave a poorer prognosis compared to other epithelial ovariancarcinomas. Materials and methods Women diagnosedwith clear cell ovariancarcinoma between 1988and 2001were identified from the Surveillance, Epidemiology and End Results (SEER)database. During this time period, 26,671 patients with serous, endometrioid,mucinous or other type of epithelial ovarian carcinoma were used for comparison. Data are reported from twelve population-based registries that represent approximately 26% of the U.S. population: San Francisco – Oakland,Connecticut, metropolitan Detroit, Hawaii, Iowa, New Mexico, Seattle (Puget Sound), Utah, metropolitan Atlanta, Alaska, San Jose – Monterey, and LosAngeles. To better characterize our patient population, the race classifications of the SEER program were categorized into four groups: Whites, Blacks, Asiansand Others. Asians were arbitrarily defined as Chinese, Japanese, Korean,Vietnamese, and Filipina. All other race and ethnicity classifications weredefined as Others. The ICD-O-3 histology codes used were serous (8441 – 8442,8460 – 8462), clear cell (8310 – 8313), endometrioid (8380 – 8383), and mucinous(8470 – 8482). Ovarian clear cell cancers were compared to serous, endome-trioid, and mucinous tumors. Uterus-sparing surgeries were defined as minimalsurgeries that did not include a hysterectomy. Standard surgeries were classifiedas those including a hysterectomy and/or debulking. The Institutional ReviewBoard by Stanford University approved this study. Data including age at diagnosis, race, extent of surgery, stage of disease, histology, and survival wereTable 1Characteristics of epithelial ovarian cancer by cell typeCharacteristics Total ( n =28,082) No. (%)Serous ( n =13,835) No. (%)Endometrioid ( n =3655) No. (%)Mucinous ( n =2711) No. (%)Clear cell ( n =1411) No. (%)  p -valueAge at diagnosisMedian 64 64.0 56.0 58.0 55.0Range (12 – 101) (12 – 101) (18 – 94) (14 – 97) (12 – 94)Median year of diagnosis 1995 1995 1995 1994 1996Race a  White 24,357 (86.7%) 12,219 (88.3%) 3162 (86.5%) 2268 (83.7%) 1164 (82.5%)  p b 0.001Black 1631 (5.8%) 730 (5.3%) 158 (4.3%) 193 (7.1%) 50 (3.5%)Asian 1488 (5.3%) 605 (4.4%) 244 (6.7%) 177 (6.5%) 165 (11.7%)Other 546 (1.9%) 250 (1.8%) 82 (2.2%) 68 (2.5%) 30 (2.1%)Stage at diagnosis a  Stage I 6257 (22.3%) 1659 (12.0%) 1718 (47.0%) 1483 (54.7%) 795 (56.3%)  p b 0.001Stage IA 3710 (13.2%) 812 (5.9%) 1042 (28.5%) 1090 (40.2%) 484 (34.3%)  p b 0.001Stage IB 396 (1.4%) 179 (1.3%) 123 (3.4%) 53 (2.0%) 21 (1.5%)Stage IC 1831 (6.5%) 587 (4.2%) 474 (13.0%) 274 (10.1%) 262 (18.6%)Stage II a  2296 (8.2%) 990 (7.2%) 532 (14.6%) 179 (6.6%) 155 (11.0%)Stage IIA 605 (2.2%) 250 (1.8%) 183 (5.0%) 52 (1.9%) 47 (3.3%)Stage IIB 735 (2.6%) 273 (2.0%) 205 (5.6%) 66 (2.4%) 49 (3.5%)Stage IIC 868 (3.1%) 425 (3.1%) 130 (3.6%) 54 (2.0%) 56 (4.0%)Stage III a  10,082 (35.9%) 6320 (45.7%) 869 (23.8%) 574 (21.2%) 295 (20.9%)Stage IIIA 534 (1.9%) 294 (2.1%) 83 (2.3%) 48 (1.8%) 21 (1.5%)Stage IIIB 761 (2.7%) 461 (3.3%) 103 (2.8%) 65 (2.4%) 23 (1.6%)Stage IIIC 5434 (19.4%) 3627 (26.2%) 476 (13.0%) 246 (9.1%) 184 (13.0%)Stage IV 9447 (33.6%) 4866 (35.2%) 536 (14.7%) 475 (17.5%) 166 (11.8%)GradeGrade 1 2395 (8.5%) 747 (5.4%) 710 (19.4%) 803 (29.6%) 31 (2.2%)  p b 0.001Grade 2 5114 (18.2%) 2625 (19.0%) 1217 (33.3%) 715 (26.4%) 183 (13.0%)Grade 3 12,344 (44.0%) 7250 (52.4%) 1277 (34.9%) 426 (15.7%) 455 (32.2%)Unknown grade 8229 (29.3%) 3213 (23.2%) 451 (12.3%) 767 (28.3%) 742 (52.6%)Surgery a   No surgery 5145 (18.3%) 1384 (10.0%) 53 (1.5%) 255 (9.4%) 34 (2.4%)  p b 0.001Uterus-sparing  b 4272 (15.2%) 2111 (15.3%) 569 (15.6%) 654 (24.1%) 165 (11.7%)Standard c 18,649 (66.4%) 10,336 (74.7%) 3033 (83.0%) 1802 (66.5%) 1212 (85.9%)LymphadenectomyYes 7718 (27.5%) 3771 (27.3%) 1638 (44.8%) 856 (31.6%) 659 (46.7%)  p b 0.001 No 18,541 (66.0%) 9161 (66.2%) 1742 (47.7%) 1689 (62.3%) 611 (43.3%)Unknown 1823 (6.5%) 903 (6.5%) 275 (7.5%) 166 (6.1%) 141 (10.0%)Median no. nodes resected 7 6 9 7 8Presence of positive nodesYes 2754 (9.8%) 1886 (13.6%) 267 (7.3%) 104 (3.8%) 112 (7.9%)  p b 0.001 No 6048 (21.5%) 2379 (17.2%) 1608 (44.0%) 886 (32.7%) 669 (47.4%)Unknown 19,280 (68.7%) 9570 (69.2%) 1780 (48.7%) 1721 (63.5%) 630 (44.6%) a   Numbers do not add up to 100% due to small numbers of patients with unknown status.  b Uterus-sparing surgeries, including minimal surgery or surgeries that did not include a hysterectomy. c Standard surgeries, including surgeries including a hysterectomy and/or debulking.371  J.K. Chan et al. / Gynecologic Oncology 109 (2008) 370  –  376   recorded for analysis. Disease-specific survival probability was calculated usingthe Kaplan – Meier method. Differences between groups were calculated usingthe log-rank test. The Cox proportional hazards model was used to assess thesignificance of multiple variables simultaneously.  P  -values b 0.05 wereconsidered statistically significant. Results From 1988 to 2001, 28,082 women were diagnosed withepithelial ovarian cancer. The largest subgroup, 13,835 (49.3%)of patients had serous histology. 1411 (5%) were of clear cellhistology; of the remainder, 3655 (13%) were endometrioid,2711 (9.7%) mucinous, and for 6470 (23%) histology wasnot specified. Demographics of the study population are assummarized in Table 1. Compared to serous cancer patients, themedian age at diagnosis was significantly younger for thosewith clear cell carcinoma: 55 years vs. 64 years (  p b 0.001).Patients with clear cell carcinoma were more likely to be Asian;in fact, the proportion of Asians, Whites, and Blacks withclear cell histology was 11.1%, 4.8%, and 3.1%, respectively(  p b 0.001).Women with clear cell carcinoma were significantly morelikelytobediagnosedwithstageI – IIdiseasecomparedtoserouscancers (67.3% for clear cell and 19.2% for serous;  p b 0.001).More specifically, over half (56.3%) of clear cell cancers werefound with stage I disease (Table 1). Patients with clear cellcarcinoma were more likely to undergo primary surgery, 85.9%compared to 66.5%, 74.7%, and 83% of mucinous, serous, andendometrioid cancer patients (  p b 0.001). Of the entire studygroup,27.5%underwentlymph nodedissection, andthe mediannumberofresectednodeswas7(range:1 – 90).Ofthosepatients,9.8% ( n =2,754) had nodal involvement. Retroperitoneal lymphnode involvement was present in 7.9% of clear cell carcinomas,13.6% serous carcinomas, 7.3% endometrioid carcinomas, and3.8% mucinous carcinomas (  p b 0.001). Of all patients whounderwent a lymphadenectomy, 35.7% had positive lymphnodes. In women with serous, endometrioid, mucinous, andclear cell histologies, 50.0%, 16.3%, 12.1%, and 17.0% hadnodal involvement, respectively.In the overall study group, the 5-year disease-specificsurvival of women  ≤ 64 years versus  N 64 years was 56.7%versus 31.8% (  p b 0.001). Whites, Blacks, and Asians hadcorresponding disease-specific survivals of 44.6%, 40.7%, and54.6%, respectively (  p b 0.001). Women with stage I, II, III, andIV disease had 5-year disease-specific survivals of 88.3%,65.0%, 34.1%, and 19.7% (  p b 0.001). Those with grade 1 haddisease-specific survivals of 83.5% compared to 56.4% and36.5% in grade 2 and 3 disease (  p b 0.001). The number of lymph node metastases (1, 2 – 5,  N 5 nodes) was associated witha worsened disease-specific survival of 41.4%, 37.1%, and36.0%, though not statistically significant (  p =0.062).Across all stages, the overall 5-year disease-specific survivalof clear cell cancer patients was higher at 64.5% compared to39.4% for serous, 72.5% for endometrioid, and 68.1% for mucinous cancers (  p b 0.001); however, after adjusting for stageof disease, clear cell carcinomas had a poorer overall prognosis(  p b 0.001 for stages I – IV) (Table 2; Figs. 1A – D). Adjusted for stage, the 5-year disease-specific survival of patients with clear cell carcinoma is worse compared to serous: 85.3% vs. 86.4%for stage I, 60.3% vs. 66.4% for stage II, 31.5% vs. 35.0% stageIII, and 17.5% vs. 22.2% stage IV, respectively (  p b 0.001).On multivariate analysis, older age at diagnosis (  p b 0.001),advanced stage (  p b 0.001), higher grade of disease (  p b 0.001),lack of surgery (  p b 0.001), and clear cell histology (  p b 0.001)were all independent predictors for poorer survival (Table 3). Discussion Since 1973, clear cell ovarian carcinoma has been recog-nized by the World Health Organization as a distinct histologicsubtype of ovarian cancer. Unlike other epithelial ovariancancers, clear cell carcinomas have a greater tendency to present with a large, unilateral pelvic mass in early stage, be associatedwith thromboembolic complications and paraneoplastic syn-dromes [2 – 8]. Given that clear cell cancers are more likely to present at early stage but display aggressive behavior, it isunclear if these tumors portend for a poorer prognosis.A prior study of 44 women with clear cell cancers showedthat these patients have a poorer survival compared to serous Table 2Five-year disease-specific survival by cell typeCharacteristics Total Serous Endometrioid Mucinous Clear cellLog-rank Overall 45.1% 39.4% 72.5% 68.1% 64.5%  p b 0.001Age at diagnosisAge ≤ 64 56.7% 48.1% 78.2% 77.4% 66.5%  p b 0.001Age N 64 31.8% 29.8% 59.3% 52.8% 59.4%  p b 0.001RaceWhite 44.6% 39.0% 72.8% 68.5% 64.8%  p b 0.001Black 40.7% 41.1% 58.9% 58.0% 41.7%  p b 0.001Asian 54.6% 43.0% 74.0% 78.1% 60.2%  p b 0.001Other 49.5% 33.9% 82.1% 66.8% 41.2%  p b 0.001Stage at diagnosisStage I 88.3% 86.4% 92.7% 93.1% 85.3%  p b 0.001Stage IA 93.2% 91.0% 94.8% 94.9% 91.6%  p =0.001Stage IB 90.0% 93.7% 91.2% 91.3% 56.3%  p b 0.001Stage IC 78.4% 77.7% 89.2% 86.7% 77.3%  p b 0.001Stage II 65.0% 66.4% 81.9% 61.3% 60.3%  p b 0.001Stage IIA 76.5% 77.0% 80.7% 76.6% 66.9%  p =0.104Stage IIB 66.9% 66.0% 82.1% 57.9% 69.5%  p =0.003Stage IIC 55.6% 61.1% 82.9% 54.3% 45.6%  p b 0.001Stage III 34.1% 35.0% 50.6% 34.5% 31.5%  p b 0.001Stage IIIA 44.7% 48.7% 60.0% 47.0% 43.9%  p =0.093Stage IIIB 41.9% 41.6% 57.8% 38.8% 20.4%  p =0.004Stage IIIC 35.9% 35.5% 49.7% 34.8% 31.4%  p b 0.001Stage IV 19.7% 22.2% 34.6% 21.6% 17.5%  p b 0.001GradeGrade 1 83.5% 75.7% 93.4% 85.6% 75.4%  p b 0.001Grade 2 56.4% 43.6% 79.2% 70.7% 75.6%  p b 0.001Grade 3 36.5% 34.6% 55.5% 37.0% 51.0%  p b 0.001Surgery No surgery 9.2% 11.8% 40.6% 8.1% 27.8%  p =0.007Uterus-sparing a  50.5% 38.4% 79.1% 76.6% 66.2%  p b 0.001Standard  b 51.6% 42.7% 71.7% 71.3% 65.2%  p b 0.001 a  Uterus-sparing surgeries, including minimal surgery or surgeries that did not include a hysterectomy.  b Standard surgeries, including surgeries including a hysterectomy and/or debulking.372  J.K. Chan et al. / Gynecologic Oncology 109 (2008) 370  –  376   cancers, despite the fact that clear cell tumors are more likely to present at early stage (51% vs. 31%) [6]. This report also foundthat clear cell tumor recurrences were more likely to involvelymph nodes and parenchymal organs. However, this studyincluded only 44 women and extended from 1944 to 1981.Moreover, others have also shown that advanced clear celltumors are more platinum-resistant. These investigators foundthat only 45% of patients with clear cell cancers respond to platinum-based chemotherapy versus 81% in other epithelialcell types [9]. Similarly, another study showed that of 24 women with stage III clear cell ovarian cancer treated with platinum-based chemotherapy, 70% had progression of disease Fig. 1. A. Kaplan – Meier analysis of stage I patients based on histology. B. Kaplan – Meier analysis of stage II patients based on histology. C. Kaplan – Meier analysis of stage III patients based on histology. D. Kaplan – Meier analysis of stage IV patients based on histology.373  J.K. Chan et al. / Gynecologic Oncology 109 (2008) 370  –  376 

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Jul 23, 2017
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