JJCO. Original Article. Banghyun Lee 1, Dong Hoon Suh 2, Kidong Kim 2, Jae Hong No 2, and Yong Beom Kim 2,3, * Abstract

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1 JJCO Japanese Journal of Clinical Oncology Japanese Journal of Clinical Oncology, 2016, 46(8) doi: /jjco/hyw063 Advance Access Publication Date: 20 May 2016 Original Article Original Article Influence of positive peritoneal cytology on prognostic factors and survival in early-stage endometrial cancer: a systematic review and meta-analysis Banghyun Lee 1, Dong Hoon Suh 2, Kidong Kim 2, Jae Hong No 2, and Yong Beom Kim 2,3, * 1 Department of Obstetrics and Gynecology, Hallym University Kangdong Sacred Heart Hospital, Seoul, 2 Department Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do, and 3 School of Medicine, Seoul National University, Seoul, Republic of Korea *For reprints and all correspondence: Yong Beom Kim, Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, 82, Gumi-ro 173 beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, Republic of Korea. ybkimlh@snubh.org Received 26 February 2016; Accepted 17 April 2016 Abstract Objective: The prognostic significance of positive peritoneal cytology in patients with early-stage endometrial cancer (Stage 1 or 2) is controversial and perhaps depends on the presence of other factors. The relationship of other prognostic factors with positive peritoneal cytology remains unclear. This study aimed to investigate the association between positive peritoneal cytology and prognostic factors and the influence of positive peritoneal cytology on survival in patients with early-stage endometrial cancer. Methods: We identified 351 articles on the PubMed, Cochrane and Embase databases using a combination of the following search terms: endometrial cancer, endometrial carcinoma, positive peritoneal cytology and positive peritoneal washing. When filtered for studies comparing positive peritoneal cytology with negative peritoneal cytology in early-stage endometrial cancer, 11 retrospective studies met the selection criteria. Meta-analyses were performed using Review Manager 5.3 software. Results: In patients with surgical stage 1 or 2 early-stage endometrial cancer, the incidence of Grade 3 was higher and 5-year overall survival was worse in patients with positive peritoneal cytology compared with negative peritoneal cytology. However, the incidence of Grade 1 was lower in those with positive peritoneal cytology compared with negative peritoneal cytology. In patients with surgical stage 1 early-stage endometrial cancer, the incidence of myometrial invasion 1/2 tended to be higher and 5-year progression-free survival was worse in the positive peritoneal cytology group than the negative peritoneal cytology group. However, the incidence of myometrial invasion <1/2 was lower in the positive peritoneal cytology group than the negative peritoneal cytology group. Conclusion: This study demonstrates that positive peritoneal cytology in patients with early-stage endometrial cancer is significantly associated with other prognostic factors and survival, suggesting its potential as a prognostic factor. Key words: cytology, endometrial neoplasm, grade, prognosis, survival The Author Published by Oxford University Press. All rights reserved. For Permissions, please journals.permissions@oup.com 711

2 712 Prognostic significance of peritoneal cytology Introduction Although peritoneal cytology has no effect on staging, it is a mandatory component of the 2009 International Federation of Gynecology and Obstetrics (FIGO) staging system. Positive peritoneal cytology (PPC) is of prognostic significance in patients with advanced-stage endometrial cancer that spreads to the adnexa, lymph nodes (LN) or peritoneum (1). However, the prognostic significance of isolated PPC in patients with early-stage endometrial cancer (EEC, Stage 1 or 2) is controversial (2 6). Inasystemicreviewofcompletely surgically staged endometrial cancer with PPC, patients with low-risk uterine factors [Grade 1 or 2, myometrial invasion (MI) <1/2, no cervical involvement and no lymphovascular space invasion (LVSI)] had a significantly lower rate of recurrence than patients with high-risk uterine factors (4.1% vs. 32%) (2,6). Although this finding suggests that the prognostic significance of PPC depends on the presence of other risk factors (7,8), other studies have reported that PPC is an independent factor for survival in patients with surgically staged EEC (3,5,9,10). Additional studies have addressed the prognostic significance of PPC in terms of its relation to other factors such as grade, MI and LVSI, and the results are conflicting (4 7,11 14). A large-scale study using the Surveillance, Epidemiology and End Results (SEER) database found that the incidence of PPC increased in surgically staged EEC with highrisk factors such as Grade 3, clear cell or serous carcinoma and carcinosarcoma (9). Owing to the shift in the staging method of endometrial cancer from clinical to surgical in 1988, patients with PPC without extrauterine extension of the cancer were upstaged to FIGO Stage 3A1. Debates about the prognostic significance of upstaging and the need for routine peritoneal cytology subsequently ensued because a small fraction of patients with endometrial cancer were upstaged without clear benefits of survival (4,6 8,11,15). The need for peritoneal cytology is still controversial given the lack of effect of PPC on staging. Therefore, via a systemic review and meta-analysis of the literature, our study assessed the association between PPC and other prognostic factors and the influence of PPC on the survival of patients with EEC towards the overall goal of clarifying the clinical significance of PPC in EEC. Materials and methods Search strategy In June 2015, we searched the PubMed, Cochrane library and Embase databases for all pertinent studies without restriction on the year of publication. A combination of the following keywords was used in the search: endometrial cancer, endometrial carcinoma, PPC and positive peritoneal washing. References of selected clinical studies and review articles were also examined for additional relevant literature not covered by the database searches. Selection criteria The inclusion criteria for study selection were as follows: endometrial carcinoma confirmed via permanent pathology; total or radical hysterectomy and/or retroperitoneal pelvic or paraaortic LN sampling or dissection; comparison of PPC with negative peritoneal cytology (NPC) in patients in which peritoneal cytology was performed; and Stage 1 or 2 endometrial carcinoma. The exclusion criteria were as follows: Stage 1 or 2 endometrial carcinoma according to the 1971 FIGO clinical staging system; studies that were not case-match controlled; uterine cancers other than endometrial cancers; articles not in English; review articles; editorials; case reports; letters and non-human studies. Therefore, our study included the patients who were diagnosed as Stage 1 or 2 endometrial carcinoma according to the 2009 FIGO surgical staging system or Stage 1, 2 or 3A1 according to the 1988 FIGO surgical staging system. When multiple studies reported overlapping groups of patients, only one study with largest number of events was included in the metaanalysis to avoid duplication of information. Data extraction and outcomes of interest Two investigators independently extracted the data of interest from studies using a checklist for data recording. Any discrepancies between investigators were resolved via discussion. Data retrieved from studies included the name of the first author, year of publication, design of study, stage, histologic type, post-operative adjuvant therapy, number of patients with PPC or NPC, grade, LVSI, MI and survival rates. Stage 3A1 was included in surgical Stage 1 or 2 or Stage 1. The primary outcome in the meta-analysis was the incidence of the prognostic factors of endometrial cancer including grade, LVSI and MI. The secondary outcome was survival rate; for example, 5- year overall survival and 5-year progression-free survival. Overall survival was defined as the time from surgery to death from any cause. Progression-free survival was defined as the time from the first day of treatment to the date on which the disease progressed or the date on which the patient died from any cause. Statistics and publication bias The eligible population was classified as patients with Stage 1 or 2 or Stage 1 according to the surgical staging systems. Case and control groups consisted of patients with PPC and NPC, respectively. To evaluate the primary outcome, the incidence of each variable was compared between the two groups. For survival analyses, the observed events, the log-rank expected events, the variance of the log-rank statistic and hazard ratio (HR) were calculated based on a previous report (16). The heterogeneity of the odds ratio (OR) or HR was assessed using the I 2 statistic. The random-effect model using the Mantel Haenszel method was used for analysis of prognostic factors. Survival analyses were also performed with the fixedeffect model using the Mantel Haenszel method. Funnel plots were used to identify publication bias. The OR or HR of each study was plotted on the horizontal axis and the corresponding standard error of the log of the OR or HR was plotted on the vertical axis to generate a scatter plot. The meta-analyses were performed using Review Manager Version 5.3 software (The Nordic Cochrane Centre, Copenhagen, Denmark). P < 0.05 was considered statistically significant. Results Our literature search identified 351 studies and 11 retrospective studies met the selection criteria (Fig. 1). Papanicolaou smear was mainly performed to assess PPC status. Seven studies of surgical stage 1 or 2 and four of surgical stage 1 were identified, including patients (722 PPC; NPC; , Stage 1 or 2; 1193, Stage 1). Endometrioid adenocarcinoma was the most common histologic type in both the PPC and NPC groups. Serous, clear cell

3 Jpn J Clin Oncol, 2016, Vol. 46, No Figure 1. Flow chart showing study selection. EEC, early-stage endometrial cancer. and carcinosarcoma histologies were frequently noted in the PPC group. Most of the studies used radiotherapy as adjuvant therapy. Chemotherapy, combined therapy of radiotherapy and chemotherapy and progestin were also performed. Adjuvant therapies were more frequently done in the PPC group than the NPC group (Table 1). In patients with surgical stage 1 or 2 EEC, the incidence of Grade 3 was significantly higher in patients with PPC compared with NPC, whereas the incidence of Grade 1 was significantly lower in those with PPC compared with NPC. However, there was no difference between the incidence of Grade 2, LVSI or MI between the two groups. A large-scale study (485 PPC; NPC) was included in our analysis of grade. Exclusion of this study did not affect our results (Grade 1: OR = 0.55, 95% confidence interval = , p = 0.01, heterogeneity I 2 = 0%; Grade 2: OR = 0.96, 95% confidence interval = , p = 0.94, heterogeneity I 2 = 55%; Grade 3: OR = 2.95, 95% confidence interval = , p = 0.06, heterogeneity I 2 = 46%) (Table 2 and Fig. 2A). In patients with surgical stage 1 EEC, grade distribution and the incidence of MI 1/2 were not significantly different in the PPC and NPC groups. However, the incidence of MI 1/2 tended to be higher in patients with PPC compared with NPC, whereas MI < 1/2 was significantly lower in those with PPC compared with NPC (Table 2 and Fig. 2B). Five-year overall survival in patients with surgical stage 1 or 2 EEC was significantly worse in the PPC group than the NPC group, but was not significantly different between the groups in patients with surgical stage 1 EEC. Compared with NPC, PPC was significantly associated with worse 5-year progression-free survival in patients with surgical stage 1 EEC (Table 3). The funnel plots were balanced suggesting the absence of publication bias. Discussion Via meta-analysis, we demonstrate a positive and significant correlation between PPC in patients with EEC, and Grade 3 and deep MI suggesting the possibility of PPC as a prognostic factor. Based on surgical stage, PPC was associated with a higher incidence of Grade 3 and MI 1/2 and a lower incidence of Grade 1 and MI < 1/2. We further demonstrate that PPC in patients with EEC correlates significantly with poor survival. The incidence of PPC ranges from 4.9% to 21.2% in EEC (6,14). A randomized controlled trial (GOG 33), showed that for clinical stage 1 endometrial carcinoma the incidence of outer-third MI, Grade 3 and LVSI was 22%, 25%, and 15%, respectively, and the incidence of pelvic and paraaortic lymphadenopathy was 9% and 6%, respectively (22,23). In surgically staged EEC, another randomized controlled trial (GOG 99) identified factors associated with high-intermediate risk for recurrence (including Grades 2 and 3, outer-third MI and LVSI) with prognostic benefits when patients were managed via adjuvant therapies (24). Therefore, evaluation of the relation between PPC and these prognostic factors in EEC is

4 714 Prognostic significance of peritoneal cytology Table 1. Characteristics of included studies (n = 11) according to surgical stages Study Year Design of study Stage Methods assessing PPC Histologic types Adjuvant therapy Number of patients PPC NPC PPC NPC PPC NPC Turner et al. (10) Grimshaw et al. (17) Kennedy et al. (18) Kasamatsu et al. (15) Tebeu et al. (19) Tebeu et al. (20) Fadare et al. (4) 1989 Case control 1 Papanicolaou smear Adenocarcinoma (94%) Adenoacanthoma (2%) Adenosquamous (2%) Mucinous (0.5%) Clear cell (0.5%) Other (1%) 1990 Case control 1 Papanicolaou smear In all stages, Adenocarcinoma (81.9%) Adenoacanthoma (8.4%) Adenosquamous (7.1%) Serous (1.8%) Clear cell (0.8%) 1993 Case control 1, 2 Papanicolaou smear Endometrioid (92.2%) 2003 Case control 1, 2 Papanicolaou smear and alcian blue stain Adenosquamous (3.7%) Serous (1.5%) Clear cell (2.2%) Other (0.4%) Endometrioid (96%) Adenosquamous (4%) 10 (71.4%) 2 (14.3%) 2 (14.3%) 249 (97.3%) 10 (3.9%) 4 (1.6%) 6 (2.3%) 1 (0.4%) EBRT &/or Brachy (78.8%) 23 (89.3%) 444 (78.6%) EBRT (9.3%) 1 (14.3%) 27 (9.2%) Progestin (3%) Radiotherapy (Moderate risk - Brachy and high risk - EBRT) (data: not available) Preoperative radiotherapy [EBRT (1.9%), Brachy (4.1%)] 2003 Case control 1, 2 Adenocarcinoma (100%) 17 (100%) 126 (100%) Radiotherapy (100%); EBRT & Brachy (47.6%) EBRT (7.7%) Brachy (42%) Unknown (2.8%) 2004 Case control 1, 2 Adenocarcinoma (95%) Serous (2.6%) Clear cell (2.3%) 2005 Case control 1, 2 Papanicolaou smear Endometrioid (82.8%) Serous (10.3%) Mixed (3.4%) Carcinosarcoma (3.4%) 8 (80%) 1 (10%) 1 (10%) 16 (84.2%) 2 (10.5%) 1 (5.3%) Adjuvant therapy: 14 (100%) EBRT (1.1%) Radiotherapy (50.2%); EBRT & Brachy (19.3%) EBRT (6.1%) Brachy (24.4%) Unknown (0.3%) Chemotherapy (13.8%) EBRT &/or Brachy (48.3%) Chemotherapy/EBRT or Brachy (13.8%) Progestin (3.4%) 100% 11 (64.7%) 3 (17.6%) 3 (17.6%) 81.8% 14 (42.4%) 9 (27.3%) 4 (12.1%) 3 (30%) 3 (30%) 2 (20%) 1 (10%) 100% 57 (45.2%) 8 (6.3%) 57 (45.2%) 4 (3.2%) 46.4% 46 (16.5%) 10 (3.6%) 72 (25.9%) 1 (0.4%) 1 (5.3%) 11 (57.9%) 2 (10.5%)

5 Jpn J Clin Oncol, 2016, Vol. 46, No (100%) Case control 1, 2 Endometrioid (100%) 32 (100%) 275 (100%) Chemotherapy (Platinum based) (10.4%) EBRT in 1C-2 (data: not available) Saga et al. (5) 259 (53.4%) 4216 (29.7%) Radiotherapy (30.4%) Chemotherapy (data: not available) (86.9%) 1068 (7.5%) 797 (5.6%) 355 (73.2%) 85 (17.5%) 45 (9.3%) 2013 Cohort 1, 2 Endometrioid/mucinous (86.4%) Serous/clear cell (7.8%) Carcinosarcoma (5.8%) Garg et al. (9) (1.5%) 64 (46.7%) 2 (1.5%) 2 (40%) 2 (40%) Chemotherapy (platinum and/or taxane based) (1.4%) EBRT &/or Brachy (46.5%) Chemotherapy/EBRT &/or Brachy (2.8%) 3 (60%) 2 (40%) 2013 Case control 1 In all stages, Endometrioid (68.5%) Serous Clear cell Carcinosarcoma Kyrgiou et al. (21) (46.6%) 1 (0.4%) 21 (77.8%) 1 (3.7%) Chemotherapy (49.8%) Radiotherapy (0.8%) 222 (93.3%) 5 (2.1%) 4 (1.7%) 7 (2.9%) 20 (74.1%) 3 (11.1%) 4 (14.8%) 2014 Case control 1 Papanicolaou smear Endometrioid (91.3%) Serous (1.5%) Carcinosarcoma (3.0%) Other (4.2%) Shiozaki et al. (3) PPC, positive peritoneal cytology; NPC, negative peritoneal cytology; EBRT, external beam radiotherapy. necessary to clarify the prognostic significance of peritoneal cytology, which is still required in the current staging system. Many studies found no association between PPC and other prognostic factors in EEC (4,5,7,13). However, others reported a positive correlation between PPC and Grade 3, deep MI and LVSI (11,12). In the study by Kadar et al. (11) of clinical stage 1 and 2 endometrial cancer, the incidence of Grade 3 and LVSI was higher in patients with PPC than in those with NPC. In the study by Kashimura et al. (12) of clinical stage 1 endometrial cancer, the incidence of MI 1/2 was higher in the PPC group than in the NPC group. Supporting these studies, our meta-analysis demonstrated that PPC positively correlated with Grade 3 in patients with surgical stage 1 or 2. In our data, PPC also positively correlated with deep MI in patients with surgical stage 1 EEC. This finding suggests that discrepancy of the association between MI and PPC in patients with surgical stage 1 or 2 and one may depend on whether patients with Stage 2 were included in population because MI is a prognostic factor in Stage 1. Uncommon histologic types such as serous, clear cell, carcinosarcoma and undifferentiated in endometrial cancer are associated with a poor prognosis (9,22). In our study, serous, clear cell and carcinosarcoma types were in a small portion of histologies and frequently noted in PPC. These findings support the previous study that reported the significant associations between PPC and these rare histologic types (9). Some studies have shown a significant association between PPC and survival in patients with surgically staged EEC (3,5,9,10). In a recent study including patients extracted from SEER database, PPC was an independent predictor of poor 5-year disease-specific survival in patients diagnosed with Stage 1 or 2 EEC regardless of histologic type (9). In retrospective studies, it was also an independent predictor of poor 5-year disease-specific survival in patients with Stage 1 or 2 EEC (5) and of poor 5-year overall survival in patients with Stage 1 EEC (10). Compared with NPC, it was independently associated with worse 5-year progression-free survival in patients with Stage 1 EEC (3,10), and our meta-analysis data agree with this finding. Although our metaanalyses were unable to include all heterogeneous previous studies that analysed survival according to different staging systems, our data suggest that PPC may be a prognostic factor for survival in patients with EEC. Additionally, in our study, PPC had a significant association with overall survival in patients with surgical stage 1 or 2 but not those with in surgical stage 1. This discrepancy of the association between survival and PPC in patients with surgicalstage1or2andonemaydependonwhetherpatients with Stage 2 were included in population suggesting that PPC may be of prognostic significance for survival in patients with Stage 2 EEC. Analysis of SEER data suggested that more frequent administration of adjuvant radiation in PPC (PPC vs. NPC, 53.4% vs. 29.7%) might have a more significant influence on survival in PPC than NPC (9). Similarly, in our data, adjuvant therapies especially radiation were more frequently done in PPC than NPC suggesting that it might make a more significant contribution to survival of PPC. Our meta-analyses had following limitations. One, all included studies were retrospective trials. We could not find any randomized or prospective trials that evaluated the significance of peritoneal cytology in EEC. Two, because of the lack of studies providing adequate data, LVSI was analysed in surgical stage 1 or 2 EEC but not in surgical stage 1 EEC. In our study, the incidence of LVSI was not dependent on PPC supporting prior studies (4,6,14).

6 716 Prognostic significance of peritoneal cytology Table 2. Associations between PPC and prognostic factors in patients with EEC Studies (n) Number of patients a OR 95% CI P value Heterogeneity (I 2 ) PPC NPC Stage 1 or 2 Grade 1 5 (4,5,9,18,20) 111/ / , 0.49 < % Grade 2 4 (4,9,18,20) 187/ / , % Grade 3 4 (4,9,18,20) 208/ / , % LVSI 3 (4,5,15) 29/90 144/ , % MI < 1/2 2 (5,19) 31/49 271/ , % MI 1/2 2 (5,19) 18/49 130/ , % Stage 1 Grade 1 2 (10,21) 8/33 201/ , % Grade 2 2 (10,21) 14/33 314/ , % Grade 3 3 (10,18,21) 11/38 167/ , % MI < 1/2 3 (3,10,17) 48/62 981/ , % MI 1/2 3 (3,10,17) 14/62 111/ , % PPC, positive peritoneal cytology; NPC, negative peritoneal cytology; OR, odds ratio; CI, confidence interval; LVSI, lymphovascular space invasion; MI, myometrial invasion. a Number of events/number entered. Figure 2. Associations between Grade 3 cancer and PPC in patients with EEC: (A) surgical stage 1 or 2 and (B) surgical stage 1. PPC, positive peritoneal cytology; EEC, early-stage endometrial cancer; NPC, negative peritoneal cytology; M H, Mantel Haenszel; CI, confidence interval. Table 3. Survival rates according to PPC in patients with EEC Studies (n) Number of patients a HR (95% CI) Effect Heterogeneity PPC NPC P value P value Surgical stage 1 or 2 5-year OS 2 (5,15) 8/80 20/ (1.24, 6.66) Surgical stage 1 5-year OS 2 (10,17) 2/24 54/ (0.17, 2.94) year PFS 2 (3,10) 14/50 54/ (2.34, 7.61) < PPC, positive peritoneal cytology; NPC, negative peritoneal cytology; HR, hazard ratio; CI, confidence interval; OS, overall survival; PFS, progression-free survival. a Number of events/number entered.

7 Jpn J Clin Oncol, 2016, Vol. 46, No Conclusion On the basis of a systemic review and meta-analysis, we suggest that PPC may be a potential prognostic factor in EEC owing to its significant association with other prognostic factors and its significant influence on survival. Although only retrospective studies were included in our meta-analyses, our study is of importance because it systemically analysed the clinical significance of PPC in EEC (an ongoing issue of contention). Large-scale prospective randomized studies are needed to clarify the prognostic significance of PPC in EEC. Conflicts of interest statement None declared. References 1. Mehasseb MK, Latimer JA. Controversies in the management of endometrial carcinoma: an update. Obstet Gynecol Int 2012;2012: del Carmen MG. Positive peritoneal cytology in patients with endometrial cancer: continued controversy despite shift in staging. Cancer Cytopathol 2014;122: Shiozaki T, Tabata T, Yamada T, Yamamoto Y, Yamawaki T, Ikeda T. Does positive peritoneal cytology not affect the prognosis for stage I uterine endometrial cancer? The remaining controversy and review of the literature. Int J Gynecol Cancer 2014;24: Fadare O, Mariappan MR, Hileeto D, Wang S, McAlpine JN, Rimm DL. Upstaging based solely on positive peritoneal washing does not affect outcome in endometrial cancer. Mod Pathol 2005;18: Saga Y, Imai M, Jobo T, et al. Is peritoneal cytology a prognostic factor of endometrial cancer confined to the uterus? Gynecol Oncol 2006;103: Wethington SL, Barrena Medel NI, Wright JD, Herzog TJ. Prognostic significance and treatment implications of positive peritoneal cytology in endometrial adenocarcinoma: unraveling a mystery. Gynecol Oncol 2009;115: Takeshima N, Nishida H, Tabata T, Hirai Y, Hasumi K. Positive peritoneal cytology in endometrial cancer: enhancement of other prognostic indicators. Gynecol Oncol 2001;82: Mariani A, Webb MJ, Keeney GL, Aletti G, Podratz KC. Assessment of prognostic factors in stage IIIA endometrial cancer. Gynecol Oncol 2002;86: Garg G, Gao F, Wright JD, Hagemann AR, Mutch DG, Powell MA. Positive peritoneal cytology is an independent risk-factor in early stage endometrial cancer. Gynecol Oncol 2013;128: Turner DA, Gershenson DM, Atkinson N, Sneige N, Wharton AT. The prognostic significance of peritoneal cytology for stage I endometrial cancer. Obstet Gynecol 1989;74: Kadar N, Homesley HD, Malfetano JH. Positive peritoneal cytology is an adverse factor in endometrial carcinoma only if there is other evidence of extrauterine disease. Gynecol Oncol 1992;46: Kashimura M, Sugihara K, Toki N, et al. The significance of peritoneal cytology in uterine cervix and endometrial cancer. Gynecol Oncol 1997;67: Obermair A, Geramou M, Tripcony L, Nicklin JL, Perrin L, Crandon AJ. Peritoneal cytology: impact on disease-free survival in clinical stage I endometrioid adenocarcinoma of the uterus. Cancer Lett 2001;164: Gu M, Shi W, Barakat RR, Thaler HT, Saigo PE. Peritoneal washings in endometrial carcinoma. A study of 298 patients with histopathologic correlation. Acta Cytol 2000;44: Kasamatsu T, Onda T, Katsumata N, et al. Prognostic significance of positive peritoneal cytology in endometrial carcinoma confined to the uterus. Br J Cancer 2003;88: Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials 2007;8: Grimshaw RN, Tupper WC, Fraser RC, Tompkins MG, Jeffrey JF. Prognostic value of peritoneal cytology in endometrial carcinoma. Gynecol Oncol 1990;36: Kennedy AW, Webster KD, Nunez C, Bauer LJ. Pelvic washings for cytologic analysis in endometrial adenocarcinoma. J Reprod Med 1993;38: Tebeu PM, Popowski GY, Verkooijen HM, et al. Impact of peritoneal cytology on survival of endometrial cancer patients treated with surgery and radiotherapy. Br J Cancer 2003;89: Tebeu PM, Popowski Y, Verkooijen HM, et al. Positive peritoneal cytology in early-stage endometrial cancer does not influence prognosis. Br J Cancer 2004;91: Kyrgiou M, Chatterjee J, Lyus R, Amin T, Ghaem-Maghami S. The role of cytology and other prognostic factors in endometrial cancer. J Obstet Gynaecol 2013;33: Rungruang B, Olawaiye AB. Comprehensive surgical staging for endometrial cancer. Rev Obstet Gynecol 2012;5: Creasman WT, Morrow CP, Bundy BN, Homesley HD, Graham JE, Heller PB. Surgical pathologic spread patterns of endometrial cancer. A Gynecologic Oncology Group Study. Cancer 1987;60: Keys HM, Roberts JA, Brunetto VL, et al. A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 2004;92: