YGYNO-975511; No. of pages: 4; 4C: Gynecologic Oncology xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
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Kyung Hee Han a, Noh Hyun Park a,⁎, Hee Seung Kim a, Hyun Hoon Chung a, Jae Weon Kim a, Yong Sang Song a,b,c
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H I G H L I G H T S
Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul 110-744, Republic of Korea Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea World Class University, Seoul National University, Seoul 151-921, Republic of Korea
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Keywords: Endometrial neoplasms Recurrence Cytology Prognosis Survival
a b s t r a c t
Objective. We compared the impact of positive peritoneal cytology on prognosis between patients with endometrioid and non-endometrioid endometrial carcinoma. Methods. We retrospectively reviewed the medical records of 490 patients diagnosed with endometrial cancer between 2000 and 2012. These patients were divided into two groups: endometrioid and non-endometrioid histologies. We compared the patients' baseline characteristics, tumor recurrence patterns, and survival to determine the prognostic factors and how they differed between the two groups. Results. Of the included patients, 448 had endometrioid histology and 42 had non-endometrioid histology. A total of 27 patients experienced tumor recurrence: 17 with endometrioid histology (4.0%) and 10 with nonendometrioid histology (23.8%). Compared to endometrioid type, non-endometrioid type exhibited higher rates of recurrence (p b 0.01). Recurrence sites of the non-endometrioid group were mainly peritoneal seeding (p b 0.01) and distant organ metastasis (p = 0.02). Risk factors for tumor recurrence included patient age, stage of disease, and adjuvant treatment for endometrioid type. On the other hand, in cases of nonendometrioid endometrial cancer, positive peritoneal cytology was an independent prognostic factor regardless of tumor stage (HR, 15.34; 95% CI, 3.55–66.25; p b 0.01). Among cases with non-endometrioid histology, median recurrence-free survival significantly differed between the negative peritoneal cytology group and the positive peritoneal cytology group (120 months versus 22 months, respectively; p b 0.01). Conclusions. Positive peritoneal cytology is an independent prognostic factor for patients with nonendometrioid endometrial cancer. © 2014 Published by Elsevier Inc.
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Article history: Received 30 January 2014 Accepted 13 May 2014 Available online xxxx
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• We compared the recurrence patterns and survival data for patients with endometrial cancer based on their histology. • Peritoneal recurrence occurred frequently in patients with non-endometrioid endometrial cancer. • Positive peritoneal cytology is a prognostic factor of tumor recurrence for patients with non-endometrioid endometrial cancer.
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Peritoneal cytology: A risk factor of recurrence for non-endometrioid endometrial cancer
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Introduction
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Endometrial cancer is classified into two histological groups: endometrioid and non-endometrioid types. Over 80% of endometrial cancer is of endometrioid type. Endometrioid endometrial cancer (EM) typically arises from atypical complex hyperplasia (e.g., precancerous lesions) and develops in estrogen-rich environments, such as those existing in
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⁎ Corresponding author at: Department of Obstetrics and Gynecology, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-144, Republic of Korea. Fax: +82 2 762 3599. E-mail address: [email protected] (N.H. Park).
cases of obesity, anovulation, and excessive exogenous estrogen [1,2]. Non-endometrioid endometrial cancer (NEM) includes papillary serous, clear cell, mucinous, squamous, undifferentiated, and mixed histological subtypes, and its carcinogenesis is unaffected by hormones. NEM is more frequently detected in older and postmenopausal women, while EM occurs in younger and premenopausal women. P53 mutation is the representative pathogenic aberration of NEM, while PTEN, β-catenin, and K-ras are the candidate molecular alterations of EM [3]. Compared with EM, NEM has different features and worse prognosis. The reported 10-year survival rates with endometrial cancer are 75.9% for EM versus 55.1% for NEM [4]. Although NEM accounts for only 10–15% of all endometrial cancer, it causes more than 45% of all
http://dx.doi.org/10.1016/j.ygyno.2014.05.010 0090-8258/© 2014 Published by Elsevier Inc.
Please cite this article as: Han KH, et al, Peritoneal cytology: A risk factor of recurrence for non-endometrioid endometrial cancer, Gynecol Oncol (2014), http://dx.doi.org/10.1016/j.ygyno.2014.05.010
27 28 29 30 31 Q6 32 33 Q7 34 35 36 37 38 39 40 41 42 43 44
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Materials and methods
8 clear cell (19.0%), 4 undifferentiated (9.5%), 1 small cell (2.4%), and 4 other mixed histologic (9.5%) types. The median follow-up periods were 70 months (range, 12 to 150 months) for EM and 8.5 months (range, 26 to 140 months) for NEM. Table 1 shows the clinical and pathological characteristics according to histological subgroup. Upon diagnosis, patients with NEM showed more advanced disease stage (p b 0.01) and poorer differentiation (p b 0.01) compared to patients with EM. Among the NEM patients, more than half received postoperative adjuvant treatment. Compared to EM patients, those with NEM more frequently exhibited omentum involvement (p = 0.02). Lymphovascular space invasion was found in 33.3% of patients with NEM and 16.5% of patients with EM (p = 0.01). Compared to patients with EM, patients with NEM also more frequently had metastatic pelvic lymph nodes (28.6% versus 12.2%; p = 0.02). However, patients with EM and NEM did not differ regarding myometrial invasion, adnexal extension, cervix stromal involvement, para-aortic lymph node metastasis, and the positivity of estrogen and progesterone receptors (p N 0.05).
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Patients
Recurrence pattern
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Statistical analysis
In total, 27 patients experienced tumor recurrence during the followup period: 17 patients with EM (4.0%) and 10 with NEM (23.8%). Based on RFS, patients with NEM had a higher recurrence rate than patients with EM (p b 0.01). Among NEM patients with positive peritoneal cytology at the staging operation, the recurrence rate was 87.5%. Recurrence sites were classified as local vaginal recurrence, peritoneal seeding, lymph node involvement, and distant metastasis. Multiple sites of metastasis were counted separately. Recurrence sites differed according to the histological subtype of endometrial cancer. Compared to patients with EM, those with NEM more frequently showed peritoneal recurrence (p b 0.01) and distant organ metastasis (p = 0.02). Recurrence rates at the local vaginal stump and the lymph nodes did not significantly differ between patients with EM and NEM (Fig. 1). Patients with positive peritoneal cytology at the staging operation showed a high recurrence rate (p b 0.01). In Table 2, positive peritoneal cytology was found more frequently among patients with advanced stage (p b 0.01) and NEM (p b 0.01). In addition, positive peritoneal cytology was positively correlated with deep myometrial invasion (p = 0.02) and lymph node metastasis (p b 0.01).
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With approval of the Institutional Review Board of Seoul National University Hospital, we reviewed the medical records of patients diagnosed with endometrial adenocarcinoma between January 2000 and June 2012. These recordings included 554 patients, of which 490 underwent a staging operation and were thus eligible for this study. Patients were classified based on the 2009 FIGO staging criteria. In patients with high-risk disease, postoperative adjuvant treatments consisting of radiation therapy and/or chemotherapy were performed. The type of radiation was external beam radiation therapy and/or intravaginal brachytherapy. Platinum-based combination drugs were used for adjuvant chemotherapy. After treatment, adequate follow-up was conducted every three months for the first two years, and then every six months for the subsequent three years. Follow-up investigations included a physical examination, vaginal cytology, and serum CA-125. Computed tomography or magnetic resonance imaging was conducted when clinically indicated.
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Predictors of survival
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To compare the prognostic factors of EM and NEM, we investigated clinical and pathological factors, including age, body mass index (BMI), FIGO stage, histological grade, lymphovascular space invasion, and peritoneal cytology. Patient characteristics were analyzed using Student's t-test, chi-square test, or Fisher's exact test. The Kaplan– Meier method with the log-rank test was utilized to calculate overall survival (OS) and recurrence-free survival (RFS). OS was defined as the time from diagnosis to death, or last follow-up in patients who had been alive at the date. RFS was defined as the time between diagnosis and recurrence, or last follow-up in patients without tumor recurrence. Independent prognostic factors were identified by univariate and multivariate analysis. Hazard ratio (HR) regarding RFS, the ratio of increased hazard for recurrence, was calculated by Cox proportional hazard regression. Statistical analyses were performed with SPSS software (SPSS, Inc., Chicago, IL, USA). Differences with a p value of less than 0.05 were considered significant.
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endometrial cancer deaths [5–9]. Various clinical and pathological factors have been identified as prognostic markers of endometrial cancer; however, most of the relevant studies have focused on EM [6,10]. Few studies have addressed the prognostic factors for NEM [5,11,12]. The prognostic impact of positive peritoneal cytology on endometrial cancer remains controversial. The staging system of the 2009 International Federation of Gynecology and Obstetrics (FIGO) does not include positive peritoneal cytology because of its dependency on extrauterine spread [13,14]. However, recent studies have repeatedly emphasized that positive peritoneal cytology is a predictive factor for endometrial cancer [15,16]. No study has evaluated the impact of positive peritoneal cytology with regard to the histological subtype of endometrial cancer. Therefore, we designed the current study to compare prognostic factors between EM and NEM and to thereby evaluate the impact of positive peritoneal cytology on prognosis based on the histological type of endometrial cancer.
Patient characteristics Among the 490 patients who were diagnosed with endometrioid adenocarcinoma and underwent a staging operation, 448 patients (91.4%) had endometrioid histology. The remaining 42 patients (8.5%) showed non-endometrioid histology: 14 serous (33.3%), 11 mucinous (26.2%),
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Median RFS was 137 months for patients with EM and 100 months 166 for patients with NEM (p b 0.01). RFS was not related to positive 167 Table 1 Baseline characteristics of patients with endometrioid and non-endometrioid endometrial cancer. Characteristics
Endometrioid
Non-endometrioid
All patients, N Age in year at diagnosis Median (range) BMI in kg/m2 at diagnosis Median (range) FIGO stage, N (%) I–II III–IV Histologic grade, N (%) 1–2 3 Adjuvant treatment, N (%) No Chemotherapy only Radiation only Concurrent chemoradiation
448
42
52 (24–93)
55 (36–73)
24.9 (16.9–43.4)
24.0 (17.9–31.9)
377 (84.2) 71 (15.8)
26 (61.9) 16 (38.1)
384 (87.7) 54 (12.3)
19 (65.5) 10 (34.5)
284 (64.0) 16 (3.6) 94 (21.2) 50 (11.3)
20 (47.6) 5 (11.9) 9 (21.4) 8 (19.0)
p value
0.97 0.44 b0.01
b0.01
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BMI, body mass index; FIGO, International Federation of Gynecology and Obstetrics.
Please cite this article as: Han KH, et al, Peritoneal cytology: A risk factor of recurrence for non-endometrioid endometrial cancer, Gynecol Oncol (2014), http://dx.doi.org/10.1016/j.ygyno.2014.05.010
t1:1 t1:2 t1:3 t1:4 t1:5 t1:6 Q3 t1:7 t1:8 t1:9 t1:10 t1:11 t1:12 t1:13 t1:14 t1:15 t1:16 t1:17 t1:18 t1:19 t1:20 t1:21
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Fig. 1. Recurrence rates and recurrence sites for endometrioid and non-endometrioid endometrial cancer. The numbers above the bars indicate the percentage of cases. p values are presented over the numbers of cases, which were calculated by comparing the recurrence rates according to the histology group. The first bar graph indicates recurrence rate regarding RFS between endometrioid and non-endometrioid histologies. The second bar graph means the recurrence rate for each site; local vagina, peritoneum, lymph nodes, or distant organ.
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peritoneal cytology among patients with EM (p = 0.94). However, positive peritoneal cytology was an indicator of RFS in patients with NEM. Among NEM cases, RFS significantly differed between the negative and 171 positive peritoneal cytology groups (120 months versus 22 months, 172 respectively; p b 0.01). 173 Among the included patients with EM, there were insufficient cen174 sored events to calculate the OS during the follow-up period. Peritoneal 175 cytology was not a significant predictive factor for OS in patients with 176 EM or NEM. 177 Peritoneal cytology was associated with RFS among patients with 178 Q10 early NEM (p b 0.01) and those with advanced NEM (p = 0.02). Early 179 stage endometrial cancer (FIGO I–II) refers to disease that is restricted 180 to the uterus, while advanced stage (FIGO III–IV) refers to tumors that 181 have spread beyond the uterus. In all stages, NEM cases with positive 182 peritoneal cytology had shorter RFS than those with negative peritoneal t2:1 t2:2
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Table 2 Clinicopathological characteristics based on peritoneal cytology. Characteristics
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All patients, N (%) FIGO stage, N (%) I II III IV Histology, N (%) Endometrioid Non-endometrioid Serous Mucinous Clear Others Differentiation grade, N (%) 1 2 3
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Number of positive cytology
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14 (3.6) 1 (6.3) 8 (11.6) 9 (50.0)
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b0.01 448 42 14 11 8 9
23 (5.1) 9 (21.4) 5 (35.7) 1 (9.1) 3 (37.5) 0 (0)
264 139 64
11 (4.2) 9 (6.5) 8 (12.5)
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BMI, body mass index; FIGO, International Federation of Gynecology and Obstetrics.
cytology, indicating that positive peritoneal cytology was a poor prognostic factor for NEM regardless of extrauterine disease spread. Multivariate regression analysis supported these findings. Table 3 presents the results of the univariate and multivariate analyses for the prognostic factors of tumor recurrence in EM and NEM. Patient age, FIGO stage, and adjuvant treatment were significantly associated with RFS in patients with EM. On the other hand, positive peritoneal cytology (p b 0.01) and FIGO stage (p = 0.01) were significant independent prognostic factors of recurrence for patients with NEM.
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Discussion
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Most previous studies of endometrial cancer prognostic factors have not considered potential differences according to histological classification. The prognostic factors for endometrial cancer include patient age, disease stage, histological type, grade, myometrial invasion depth, lymphovascular space invasion, and extrauterine spread; however, these factors have been identified from studies focused on EM [10,17]. Endometrial adenocarcinoma is a diverse disease group, and the prognoses vary according to histology. Peritoneal metastasis has previously been reported to be a distinct characteristic of NEM [18]. Uterine papillary serous carcinoma undergoes extrauterine metastasis more frequently than EM [19]. Serous endometrial carcinoma has been found to most often recur as peritoneal seeding [20]. In addition, clear cell type endometrial cancer shows a high risk for peritoneal metastasis [21]. Although mucinous histology has been described as being similar to endometrioid histology, positive peritoneal cytology is reportedly associated with disease recurrence in mucinous endometrial cancer [7,22]. Because the recurrence patterns differ between patients with EM and NEM, the prognostics should be analyzed separately for each histological type. Previous studies of the prognostic factors for NEM have produced controversial results. The traditional risk factors for recurrence and survival are reportedly not applicable for uterine papillary serous carcinoma [23]. A previous study showed that old age was an independent risk factor for tumor recurrence in early stage serous and clear cell
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Please cite this article as: Han KH, et al, Peritoneal cytology: A risk factor of recurrence for non-endometrioid endometrial cancer, Gynecol Oncol (2014), http://dx.doi.org/10.1016/j.ygyno.2014.05.010
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Univariate
p value
4.91 (1.72–13.98) 9.32 (3.54–24.50) 5.68 (2.16–14.95) 2.52 (0.89–7.16) 1.08 (0.14–8.17) 8.49 (2.44–29.57)
b0.01 b0.01 b0.01 0.08 0.94 b0.01
3.40 (1.18–9.74) 3.83 (1.29–11.37) – – – 4.31 (1.06–17.46)
0.02 0.02 – – – 0.04
2.41 (0.51–11.51) 6.73 (1.70–26.64) 5.43 (0.97–30.28) 3.27 (0.92–11.61) 13.90 (3.48–55.49) 3.26 (0.69–15.36)
0.27 b0.01 0.05 0.07 b0.01 0.14
– 6.80 (1.57–29.47) – – 15.34 (3.55–66.25) –
– 0.01 – – b0.01 –
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FIGO, International Federation of Gynecology and Obstetrics.
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[4] Bokhman JV. Two pathogenetic types of endometrial carcinoma. Gynecol Oncol 1983;15:10–7. [5] Vance S, Yechieli R, Cogan C, Hanna R, Munkarah A, Elshaikh MA. The prognostic significance of age in surgically staged patients with type II endometrial carcinoma. Gynecol Oncol 2012;126:16–9. [6] Cirisano Jr FD, Robboy SJ, Dodge RK, Bentley RC, Krigman HR, Synan IS, et al. Epidemiologic and surgicopathologic findings of papillary serous and clear cell endometrial cancers when compared to endometrioid carcinoma. Gynecol Oncol 1999;74:385–94. [7] Mendivil A, Schuler KM, Gehrig PA. Non-endometrioid adenocarcinoma of the uterine corpus: a review of selected histological subtypes. Cancer Control 2009;16:46–52. [8] Wilson TO, Podratz KC, Gaffey TA, Malkasian Jr GD, O'Brien PC, Naessens JM. Evaluation of unfavorable histologic subtypes in endometrial adenocarcinoma. Am J Obstet Gynecol 1990;162:418–23 [discussion 23–6]. [9] Musa F, Huang M, Adams B, Pirog E, Holcomb K. Mucinous histology is a risk factor for nodal metastases in endometrial cancer. Gynecol Oncol 2012;125:541–5. [10] Kosary CL. FIGO stage, histology, histologic grade, age and race as prognostic factors in determining survival for cancers of the female gynecological system: an analysis of 1973–87 SEER cases of cancers of the endometrium, cervix, ovary, vulva, and vagina. Semin Surg Oncol 1994;10:31–46. [11] Faratian D, Stillie A, Busby-Earle RM, Cowie VJ, Monaghan H. A review of the pathology and management of uterine papillary serous carcinoma and correlation with outcome. Int J Gynecol Cancer 2006;16:972–8. [12] Mylonas I, Schindlbeck C. Lymphadenectomy as a prognostic marker in uterine nonendometrioid carcinoma. Arch Gynecol Obstet 2012;285:207–14. [13] Mariani A, Dowdy SC, Podratz KC. New surgical staging of endometrial cancer: 20 years later. Int J Gynaecol Obstet 2009;105:110–1. [14] 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;115:18–25. [15] Garg G, Gao F, Wright JD, Hagemann AR, Zighelboim I, Mutch DG, et al. The risk of lymph node metastasis with positive peritoneal cytology in endometrial cancer. Int J Gynecol Cancer 2013;23:90–7. [16] Milgrom SA, Kollmeier MA, Abu-Rustum NR, Makker V, Gardner GJ, Barakat RR, et al. Positive peritoneal cytology is highly predictive of prognosis and relapse patterns in stage III (FIGO 2009) endometrial cancer. Gynecol Oncol 2013;130:49–53. [17] 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;60:2035–41. [18] Greggi S, Mangili G, Scaffa C, Scala F, Losito S, Iodice F, et al. Uterine papillary serous, clear cell, and poorly differentiated endometrioid carcinomas: a comparative study. Int J Gynecol Cancer 2011;21:661–7. [19] Goff BA, Kato D, Schmidt RA, Ek M, Ferry JA, Muntz HG, et al. Uterine papillary serous carcinoma: patterns of metastatic spread. Gynecol Oncol 1994;54:264–8. [20] Soslow RA, Wethington SL, Cesari M, Chiappetta D, Olvera N, Shia J, et al. Clinicopathologic analysis of matched primary and recurrent endometrial carcinoma. Am J Surg Pathol 2012;36:1771–81. [21] Martinez AA, Weiner S, Podratz K, Armin AR, Stromberg JS, Stanhope R, et al. Improved outcome at 10 years for serous-papillary/clear cell or high-risk endometrial cancer patients treated by adjuvant high-dose whole abdomino-pelvic irradiation. Gynecol Oncol 2003;90:537–46. [22] Havrilesky LJ, Cragun JM, Calingaert B, Alvarez Secord A, Valea FA, Clarke-Pearson DL, et al. The prognostic significance of positive peritoneal cytology and adnexal/serosal metastasis in stage IIIA endometrial cancer. Gynecol Oncol 2007;104:401–5. [23] Fader AN, Starks D, Gehrig PA, Secord AA, Frasure HE, O'Malley DM, et al. An updated clinicopathologic study of early-stage uterine papillary serous carcinoma (UPSC). Gynecol Oncol 2009;115:244–8.
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type endometrial cancer [5]. Lymph node metastasis was reported as a significant predictive factor of mucinous endometrial cancer; however, 219 systemic pelvic and/or para-aortic lymphadenectomy did not improve 220 the survival rate [9,12]. In the present study, we reviewed the clinical 221 data of patients with endometrial adenocarcinoma to identify prognos222 tic factors based on histological subtype. 223 Patients with NEM showed high rates of recurrence and peritoneal 224 tumor dissemination in the pelvic and abdominal cavities in our study, 225 which demonstrated that positive peritoneal cytology, regardless of 226 stage, contributed independently to the predictability of tumor recur227 rence. We found that advanced tumor stage (III–IV) was an adverse var228 iable for patients with both NEM and EM histologies, but for those with 229 EM it seems that the results of peritoneal cytology were not solely pre230 dictive of survival, independent of other unfavorable factors. 231 One limitation of the current study is the small number of patients. 232 However, the patient population size was sufficient to analyze the prog233 nostic factors of NEM compared with those of EM using multivariate 234 methods and a survival analysis. Prognostic factors clearly differed ac235 cording to the histological type of endometrial cancer. In the present 236 study, positive peritoneal cytology was a significant independent pre237 dictor of recurrence-free survival. 238 Our findings suggested that transcoelomic metastasis via the perito239 neum results in treatment failure among patients with NEM. Therefore, 240 peritoneal washing cytology should be considered an essential proce241 dure to include in a staging operation, especially in cases of NEM. Addi242 tionally, a modified staging system should be considered to reflect the 243 different prognostic factors between EM and NEM. 244 Various types of endometrial histology are categorized as NEM. Fur245 ther investigations should be undertaken to evaluate whether positive 246 Q11 peritoneal cytology may also predict tumor recurrence patterns of the 247 several histological types that constitute NEM. For such a study, large 248 numbers of endometrial cancer cases will be needed to garner sufficient 249 cohorts with tumors of these rare histological types.
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Endometrioid Age N 65 years FIGO stage III–IV Tumor grade 3 Positive lymphovascular space invasion Positive peritoneal cytology Adjuvant treatment Non-endometrioid Age N 65 years FIGO stage III–IV Tumor grade 3 Positive lymphovascular space invasion Positive peritoneal cytology Adjuvant treatment
p value
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Table 3 Univariate and multivariate analyses of recurrence-free survival according to endometrial cancer histology.
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Conflict of interest statement
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The authors declare that there are no conflicts of interest.
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References
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[1] Emons G, Fleckenstein G, Hinney B, Huschmand A, Heyl W. Hormonal interactions in endometrial cancer. Endocr Relat Cancer 2000;7:227–42. [2] Mariani A, Webb MJ, Keeney GL, Aletti G, Podratz KC. Endometrial cancer: predictors of peritoneal failure. Gynecol Oncol 2003;89:236–42. [3] Kuhn E, Wu RC, Guan B, Wu G, Zhang J, Wang Y, et al. Identification of molecular pathway aberrations in uterine serous carcinoma by genome-wide analyses. J Natl Cancer Inst 2012;104:1503–13.
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Please cite this article as: Han KH, et al, Peritoneal cytology: A risk factor of recurrence for non-endometrioid endometrial cancer, Gynecol Oncol (2014), http://dx.doi.org/10.1016/j.ygyno.2014.05.010
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Contents lists available at ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
3Q1
Kyung Hee Han a, Noh Hyun Park a,⁎, Hee Seung Kim a, Hyun Hoon Chung a, Jae Weon Kim a, Yong Sang Song a,b,c
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Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul 110-744, Republic of Korea Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea World Class University, Seoul National University, Seoul 151-921, Republic of Korea
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Keywords: Endometrial neoplasms Recurrence Cytology Prognosis Survival
a b s t r a c t
Objective. We compared the impact of positive peritoneal cytology on prognosis between patients with endometrioid and non-endometrioid endometrial carcinoma. Methods. We retrospectively reviewed the medical records of 490 patients diagnosed with endometrial cancer between 2000 and 2012. These patients were divided into two groups: endometrioid and non-endometrioid histologies. We compared the patients' baseline characteristics, tumor recurrence patterns, and survival to determine the prognostic factors and how they differed between the two groups. Results. Of the included patients, 448 had endometrioid histology and 42 had non-endometrioid histology. A total of 27 patients experienced tumor recurrence: 17 with endometrioid histology (4.0%) and 10 with nonendometrioid histology (23.8%). Compared to endometrioid type, non-endometrioid type exhibited higher rates of recurrence (p b 0.01). Recurrence sites of the non-endometrioid group were mainly peritoneal seeding (p b 0.01) and distant organ metastasis (p = 0.02). Risk factors for tumor recurrence included patient age, stage of disease, and adjuvant treatment for endometrioid type. On the other hand, in cases of nonendometrioid endometrial cancer, positive peritoneal cytology was an independent prognostic factor regardless of tumor stage (HR, 15.34; 95% CI, 3.55–66.25; p b 0.01). Among cases with non-endometrioid histology, median recurrence-free survival significantly differed between the negative peritoneal cytology group and the positive peritoneal cytology group (120 months versus 22 months, respectively; p b 0.01). Conclusions. Positive peritoneal cytology is an independent prognostic factor for patients with nonendometrioid endometrial cancer. © 2014 Published by Elsevier Inc.
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Article history: Received 30 January 2014 Accepted 13 May 2014 Available online xxxx
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• We compared the recurrence patterns and survival data for patients with endometrial cancer based on their histology. • Peritoneal recurrence occurred frequently in patients with non-endometrioid endometrial cancer. • Positive peritoneal cytology is a prognostic factor of tumor recurrence for patients with non-endometrioid endometrial cancer.
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Peritoneal cytology: A risk factor of recurrence for non-endometrioid endometrial cancer
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Introduction
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Endometrial cancer is classified into two histological groups: endometrioid and non-endometrioid types. Over 80% of endometrial cancer is of endometrioid type. Endometrioid endometrial cancer (EM) typically arises from atypical complex hyperplasia (e.g., precancerous lesions) and develops in estrogen-rich environments, such as those existing in
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⁎ Corresponding author at: Department of Obstetrics and Gynecology, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-144, Republic of Korea. Fax: +82 2 762 3599. E-mail address: [email protected] (N.H. Park).
cases of obesity, anovulation, and excessive exogenous estrogen [1,2]. Non-endometrioid endometrial cancer (NEM) includes papillary serous, clear cell, mucinous, squamous, undifferentiated, and mixed histological subtypes, and its carcinogenesis is unaffected by hormones. NEM is more frequently detected in older and postmenopausal women, while EM occurs in younger and premenopausal women. P53 mutation is the representative pathogenic aberration of NEM, while PTEN, β-catenin, and K-ras are the candidate molecular alterations of EM [3]. Compared with EM, NEM has different features and worse prognosis. The reported 10-year survival rates with endometrial cancer are 75.9% for EM versus 55.1% for NEM [4]. Although NEM accounts for only 10–15% of all endometrial cancer, it causes more than 45% of all
http://dx.doi.org/10.1016/j.ygyno.2014.05.010 0090-8258/© 2014 Published by Elsevier Inc.
Please cite this article as: Han KH, et al, Peritoneal cytology: A risk factor of recurrence for non-endometrioid endometrial cancer, Gynecol Oncol (2014), http://dx.doi.org/10.1016/j.ygyno.2014.05.010
27 28 29 30 31 Q6 32 33 Q7 34 35 36 37 38 39 40 41 42 43 44
56 57 58 59 60 61 62 63 64 65 66 67
2
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126 127 Q8
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Materials and methods
8 clear cell (19.0%), 4 undifferentiated (9.5%), 1 small cell (2.4%), and 4 other mixed histologic (9.5%) types. The median follow-up periods were 70 months (range, 12 to 150 months) for EM and 8.5 months (range, 26 to 140 months) for NEM. Table 1 shows the clinical and pathological characteristics according to histological subgroup. Upon diagnosis, patients with NEM showed more advanced disease stage (p b 0.01) and poorer differentiation (p b 0.01) compared to patients with EM. Among the NEM patients, more than half received postoperative adjuvant treatment. Compared to EM patients, those with NEM more frequently exhibited omentum involvement (p = 0.02). Lymphovascular space invasion was found in 33.3% of patients with NEM and 16.5% of patients with EM (p = 0.01). Compared to patients with EM, patients with NEM also more frequently had metastatic pelvic lymph nodes (28.6% versus 12.2%; p = 0.02). However, patients with EM and NEM did not differ regarding myometrial invasion, adnexal extension, cervix stromal involvement, para-aortic lymph node metastasis, and the positivity of estrogen and progesterone receptors (p N 0.05).
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Patients
Recurrence pattern
145
87
103
Statistical analysis
In total, 27 patients experienced tumor recurrence during the followup period: 17 patients with EM (4.0%) and 10 with NEM (23.8%). Based on RFS, patients with NEM had a higher recurrence rate than patients with EM (p b 0.01). Among NEM patients with positive peritoneal cytology at the staging operation, the recurrence rate was 87.5%. Recurrence sites were classified as local vaginal recurrence, peritoneal seeding, lymph node involvement, and distant metastasis. Multiple sites of metastasis were counted separately. Recurrence sites differed according to the histological subtype of endometrial cancer. Compared to patients with EM, those with NEM more frequently showed peritoneal recurrence (p b 0.01) and distant organ metastasis (p = 0.02). Recurrence rates at the local vaginal stump and the lymph nodes did not significantly differ between patients with EM and NEM (Fig. 1). Patients with positive peritoneal cytology at the staging operation showed a high recurrence rate (p b 0.01). In Table 2, positive peritoneal cytology was found more frequently among patients with advanced stage (p b 0.01) and NEM (p b 0.01). In addition, positive peritoneal cytology was positively correlated with deep myometrial invasion (p = 0.02) and lymph node metastasis (p b 0.01).
146
101 102
With approval of the Institutional Review Board of Seoul National University Hospital, we reviewed the medical records of patients diagnosed with endometrial adenocarcinoma between January 2000 and June 2012. These recordings included 554 patients, of which 490 underwent a staging operation and were thus eligible for this study. Patients were classified based on the 2009 FIGO staging criteria. In patients with high-risk disease, postoperative adjuvant treatments consisting of radiation therapy and/or chemotherapy were performed. The type of radiation was external beam radiation therapy and/or intravaginal brachytherapy. Platinum-based combination drugs were used for adjuvant chemotherapy. After treatment, adequate follow-up was conducted every three months for the first two years, and then every six months for the subsequent three years. Follow-up investigations included a physical examination, vaginal cytology, and serum CA-125. Computed tomography or magnetic resonance imaging was conducted when clinically indicated.
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Predictors of survival
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118 119
To compare the prognostic factors of EM and NEM, we investigated clinical and pathological factors, including age, body mass index (BMI), FIGO stage, histological grade, lymphovascular space invasion, and peritoneal cytology. Patient characteristics were analyzed using Student's t-test, chi-square test, or Fisher's exact test. The Kaplan– Meier method with the log-rank test was utilized to calculate overall survival (OS) and recurrence-free survival (RFS). OS was defined as the time from diagnosis to death, or last follow-up in patients who had been alive at the date. RFS was defined as the time between diagnosis and recurrence, or last follow-up in patients without tumor recurrence. Independent prognostic factors were identified by univariate and multivariate analysis. Hazard ratio (HR) regarding RFS, the ratio of increased hazard for recurrence, was calculated by Cox proportional hazard regression. Statistical analyses were performed with SPSS software (SPSS, Inc., Chicago, IL, USA). Differences with a p value of less than 0.05 were considered significant.
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Results
95 96 97 98 99 100
105 106 107 108 109 110 111 112 113 114 115 116 117
121 122 123 124 125
O
R O
P
D
93 94
E
92
T
90 91
C
88 89
E
81 82
R
79 80
R
77 78
O
75 76
C
74
N
72 73
U
70 71
F
83 84
endometrial cancer deaths [5–9]. Various clinical and pathological factors have been identified as prognostic markers of endometrial cancer; however, most of the relevant studies have focused on EM [6,10]. Few studies have addressed the prognostic factors for NEM [5,11,12]. The prognostic impact of positive peritoneal cytology on endometrial cancer remains controversial. The staging system of the 2009 International Federation of Gynecology and Obstetrics (FIGO) does not include positive peritoneal cytology because of its dependency on extrauterine spread [13,14]. However, recent studies have repeatedly emphasized that positive peritoneal cytology is a predictive factor for endometrial cancer [15,16]. No study has evaluated the impact of positive peritoneal cytology with regard to the histological subtype of endometrial cancer. Therefore, we designed the current study to compare prognostic factors between EM and NEM and to thereby evaluate the impact of positive peritoneal cytology on prognosis based on the histological type of endometrial cancer.
Patient characteristics Among the 490 patients who were diagnosed with endometrioid adenocarcinoma and underwent a staging operation, 448 patients (91.4%) had endometrioid histology. The remaining 42 patients (8.5%) showed non-endometrioid histology: 14 serous (33.3%), 11 mucinous (26.2%),
128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144
147 148 149 150 151 152 153 154 155 156 157 158 Q9 159 160 161 162 163 164
Median RFS was 137 months for patients with EM and 100 months 166 for patients with NEM (p b 0.01). RFS was not related to positive 167 Table 1 Baseline characteristics of patients with endometrioid and non-endometrioid endometrial cancer. Characteristics
Endometrioid
Non-endometrioid
All patients, N Age in year at diagnosis Median (range) BMI in kg/m2 at diagnosis Median (range) FIGO stage, N (%) I–II III–IV Histologic grade, N (%) 1–2 3 Adjuvant treatment, N (%) No Chemotherapy only Radiation only Concurrent chemoradiation
448
42
52 (24–93)
55 (36–73)
24.9 (16.9–43.4)
24.0 (17.9–31.9)
377 (84.2) 71 (15.8)
26 (61.9) 16 (38.1)
384 (87.7) 54 (12.3)
19 (65.5) 10 (34.5)
284 (64.0) 16 (3.6) 94 (21.2) 50 (11.3)
20 (47.6) 5 (11.9) 9 (21.4) 8 (19.0)
p value
0.97 0.44 b0.01
b0.01
0.02
BMI, body mass index; FIGO, International Federation of Gynecology and Obstetrics.
Please cite this article as: Han KH, et al, Peritoneal cytology: A risk factor of recurrence for non-endometrioid endometrial cancer, Gynecol Oncol (2014), http://dx.doi.org/10.1016/j.ygyno.2014.05.010
t1:1 t1:2 t1:3 t1:4 t1:5 t1:6 Q3 t1:7 t1:8 t1:9 t1:10 t1:11 t1:12 t1:13 t1:14 t1:15 t1:16 t1:17 t1:18 t1:19 t1:20 t1:21
3
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K.H. Han et al. / Gynecologic Oncology xxx (2014) xxx–xxx
D
Fig. 1. Recurrence rates and recurrence sites for endometrioid and non-endometrioid endometrial cancer. The numbers above the bars indicate the percentage of cases. p values are presented over the numbers of cases, which were calculated by comparing the recurrence rates according to the histology group. The first bar graph indicates recurrence rate regarding RFS between endometrioid and non-endometrioid histologies. The second bar graph means the recurrence rate for each site; local vagina, peritoneum, lymph nodes, or distant organ.
168
peritoneal cytology among patients with EM (p = 0.94). However, positive peritoneal cytology was an indicator of RFS in patients with NEM. Among NEM cases, RFS significantly differed between the negative and 171 positive peritoneal cytology groups (120 months versus 22 months, 172 respectively; p b 0.01). 173 Among the included patients with EM, there were insufficient cen174 sored events to calculate the OS during the follow-up period. Peritoneal 175 cytology was not a significant predictive factor for OS in patients with 176 EM or NEM. 177 Peritoneal cytology was associated with RFS among patients with 178 Q10 early NEM (p b 0.01) and those with advanced NEM (p = 0.02). Early 179 stage endometrial cancer (FIGO I–II) refers to disease that is restricted 180 to the uterus, while advanced stage (FIGO III–IV) refers to tumors that 181 have spread beyond the uterus. In all stages, NEM cases with positive 182 peritoneal cytology had shorter RFS than those with negative peritoneal t2:1 t2:2
N C O
R
R
E
C
T
169 170
Table 2 Clinicopathological characteristics based on peritoneal cytology. Characteristics
t2:4 t2:5 t2:6 t2:7 t2:8 t2:9 t2:10 t2:11 t2:12 t2:13 t2:14 t2:15 t2:16 t2:17 t2:18 t2:19 t2:20
All patients, N (%) FIGO stage, N (%) I II III IV Histology, N (%) Endometrioid Non-endometrioid Serous Mucinous Clear Others Differentiation grade, N (%) 1 2 3
U
t2:3
t2:21
E
Q2
Total number of patients
Number of positive cytology
490
32 (6.5)
387 16 69 18
14 (3.6) 1 (6.3) 8 (11.6) 9 (50.0)
p value
b0.01
b0.01 448 42 14 11 8 9
23 (5.1) 9 (21.4) 5 (35.7) 1 (9.1) 3 (37.5) 0 (0)
264 139 64
11 (4.2) 9 (6.5) 8 (12.5)
0.04
BMI, body mass index; FIGO, International Federation of Gynecology and Obstetrics.
cytology, indicating that positive peritoneal cytology was a poor prognostic factor for NEM regardless of extrauterine disease spread. Multivariate regression analysis supported these findings. Table 3 presents the results of the univariate and multivariate analyses for the prognostic factors of tumor recurrence in EM and NEM. Patient age, FIGO stage, and adjuvant treatment were significantly associated with RFS in patients with EM. On the other hand, positive peritoneal cytology (p b 0.01) and FIGO stage (p = 0.01) were significant independent prognostic factors of recurrence for patients with NEM.
183
Discussion
192
Most previous studies of endometrial cancer prognostic factors have not considered potential differences according to histological classification. The prognostic factors for endometrial cancer include patient age, disease stage, histological type, grade, myometrial invasion depth, lymphovascular space invasion, and extrauterine spread; however, these factors have been identified from studies focused on EM [10,17]. Endometrial adenocarcinoma is a diverse disease group, and the prognoses vary according to histology. Peritoneal metastasis has previously been reported to be a distinct characteristic of NEM [18]. Uterine papillary serous carcinoma undergoes extrauterine metastasis more frequently than EM [19]. Serous endometrial carcinoma has been found to most often recur as peritoneal seeding [20]. In addition, clear cell type endometrial cancer shows a high risk for peritoneal metastasis [21]. Although mucinous histology has been described as being similar to endometrioid histology, positive peritoneal cytology is reportedly associated with disease recurrence in mucinous endometrial cancer [7,22]. Because the recurrence patterns differ between patients with EM and NEM, the prognostics should be analyzed separately for each histological type. Previous studies of the prognostic factors for NEM have produced controversial results. The traditional risk factors for recurrence and survival are reportedly not applicable for uterine papillary serous carcinoma [23]. A previous study showed that old age was an independent risk factor for tumor recurrence in early stage serous and clear cell
193
Please cite this article as: Han KH, et al, Peritoneal cytology: A risk factor of recurrence for non-endometrioid endometrial cancer, Gynecol Oncol (2014), http://dx.doi.org/10.1016/j.ygyno.2014.05.010
184 185 186 187 188 189 190 191
194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216
4
Univariate
p value
4.91 (1.72–13.98) 9.32 (3.54–24.50) 5.68 (2.16–14.95) 2.52 (0.89–7.16) 1.08 (0.14–8.17) 8.49 (2.44–29.57)
b0.01 b0.01 b0.01 0.08 0.94 b0.01
3.40 (1.18–9.74) 3.83 (1.29–11.37) – – – 4.31 (1.06–17.46)
0.02 0.02 – – – 0.04
2.41 (0.51–11.51) 6.73 (1.70–26.64) 5.43 (0.97–30.28) 3.27 (0.92–11.61) 13.90 (3.48–55.49) 3.26 (0.69–15.36)
0.27 b0.01 0.05 0.07 b0.01 0.14
– 6.80 (1.57–29.47) – – 15.34 (3.55–66.25) –
– 0.01 – – b0.01 –
F
HR (95% CI)
FIGO, International Federation of Gynecology and Obstetrics.
217 218
[4] Bokhman JV. Two pathogenetic types of endometrial carcinoma. Gynecol Oncol 1983;15:10–7. [5] Vance S, Yechieli R, Cogan C, Hanna R, Munkarah A, Elshaikh MA. The prognostic significance of age in surgically staged patients with type II endometrial carcinoma. Gynecol Oncol 2012;126:16–9. [6] Cirisano Jr FD, Robboy SJ, Dodge RK, Bentley RC, Krigman HR, Synan IS, et al. Epidemiologic and surgicopathologic findings of papillary serous and clear cell endometrial cancers when compared to endometrioid carcinoma. Gynecol Oncol 1999;74:385–94. [7] Mendivil A, Schuler KM, Gehrig PA. Non-endometrioid adenocarcinoma of the uterine corpus: a review of selected histological subtypes. Cancer Control 2009;16:46–52. [8] Wilson TO, Podratz KC, Gaffey TA, Malkasian Jr GD, O'Brien PC, Naessens JM. Evaluation of unfavorable histologic subtypes in endometrial adenocarcinoma. Am J Obstet Gynecol 1990;162:418–23 [discussion 23–6]. [9] Musa F, Huang M, Adams B, Pirog E, Holcomb K. Mucinous histology is a risk factor for nodal metastases in endometrial cancer. Gynecol Oncol 2012;125:541–5. [10] Kosary CL. FIGO stage, histology, histologic grade, age and race as prognostic factors in determining survival for cancers of the female gynecological system: an analysis of 1973–87 SEER cases of cancers of the endometrium, cervix, ovary, vulva, and vagina. Semin Surg Oncol 1994;10:31–46. [11] Faratian D, Stillie A, Busby-Earle RM, Cowie VJ, Monaghan H. A review of the pathology and management of uterine papillary serous carcinoma and correlation with outcome. Int J Gynecol Cancer 2006;16:972–8. [12] Mylonas I, Schindlbeck C. Lymphadenectomy as a prognostic marker in uterine nonendometrioid carcinoma. Arch Gynecol Obstet 2012;285:207–14. [13] Mariani A, Dowdy SC, Podratz KC. New surgical staging of endometrial cancer: 20 years later. Int J Gynaecol Obstet 2009;105:110–1. [14] 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;115:18–25. [15] Garg G, Gao F, Wright JD, Hagemann AR, Zighelboim I, Mutch DG, et al. The risk of lymph node metastasis with positive peritoneal cytology in endometrial cancer. Int J Gynecol Cancer 2013;23:90–7. [16] Milgrom SA, Kollmeier MA, Abu-Rustum NR, Makker V, Gardner GJ, Barakat RR, et al. Positive peritoneal cytology is highly predictive of prognosis and relapse patterns in stage III (FIGO 2009) endometrial cancer. Gynecol Oncol 2013;130:49–53. [17] 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;60:2035–41. [18] Greggi S, Mangili G, Scaffa C, Scala F, Losito S, Iodice F, et al. Uterine papillary serous, clear cell, and poorly differentiated endometrioid carcinomas: a comparative study. Int J Gynecol Cancer 2011;21:661–7. [19] Goff BA, Kato D, Schmidt RA, Ek M, Ferry JA, Muntz HG, et al. Uterine papillary serous carcinoma: patterns of metastatic spread. Gynecol Oncol 1994;54:264–8. [20] Soslow RA, Wethington SL, Cesari M, Chiappetta D, Olvera N, Shia J, et al. Clinicopathologic analysis of matched primary and recurrent endometrial carcinoma. Am J Surg Pathol 2012;36:1771–81. [21] Martinez AA, Weiner S, Podratz K, Armin AR, Stromberg JS, Stanhope R, et al. Improved outcome at 10 years for serous-papillary/clear cell or high-risk endometrial cancer patients treated by adjuvant high-dose whole abdomino-pelvic irradiation. Gynecol Oncol 2003;90:537–46. [22] Havrilesky LJ, Cragun JM, Calingaert B, Alvarez Secord A, Valea FA, Clarke-Pearson DL, et al. The prognostic significance of positive peritoneal cytology and adnexal/serosal metastasis in stage IIIA endometrial cancer. Gynecol Oncol 2007;104:401–5. [23] Fader AN, Starks D, Gehrig PA, Secord AA, Frasure HE, O'Malley DM, et al. An updated clinicopathologic study of early-stage uterine papillary serous carcinoma (UPSC). Gynecol Oncol 2009;115:244–8.
U
N
C
O
R
R
E
C
T
type endometrial cancer [5]. Lymph node metastasis was reported as a significant predictive factor of mucinous endometrial cancer; however, 219 systemic pelvic and/or para-aortic lymphadenectomy did not improve 220 the survival rate [9,12]. In the present study, we reviewed the clinical 221 data of patients with endometrial adenocarcinoma to identify prognos222 tic factors based on histological subtype. 223 Patients with NEM showed high rates of recurrence and peritoneal 224 tumor dissemination in the pelvic and abdominal cavities in our study, 225 which demonstrated that positive peritoneal cytology, regardless of 226 stage, contributed independently to the predictability of tumor recur227 rence. We found that advanced tumor stage (III–IV) was an adverse var228 iable for patients with both NEM and EM histologies, but for those with 229 EM it seems that the results of peritoneal cytology were not solely pre230 dictive of survival, independent of other unfavorable factors. 231 One limitation of the current study is the small number of patients. 232 However, the patient population size was sufficient to analyze the prog233 nostic factors of NEM compared with those of EM using multivariate 234 methods and a survival analysis. Prognostic factors clearly differed ac235 cording to the histological type of endometrial cancer. In the present 236 study, positive peritoneal cytology was a significant independent pre237 dictor of recurrence-free survival. 238 Our findings suggested that transcoelomic metastasis via the perito239 neum results in treatment failure among patients with NEM. Therefore, 240 peritoneal washing cytology should be considered an essential proce241 dure to include in a staging operation, especially in cases of NEM. Addi242 tionally, a modified staging system should be considered to reflect the 243 different prognostic factors between EM and NEM. 244 Various types of endometrial histology are categorized as NEM. Fur245 ther investigations should be undertaken to evaluate whether positive 246 Q11 peritoneal cytology may also predict tumor recurrence patterns of the 247 several histological types that constitute NEM. For such a study, large 248 numbers of endometrial cancer cases will be needed to garner sufficient 249 cohorts with tumors of these rare histological types.
R O
t3:19
Endometrioid Age N 65 years FIGO stage III–IV Tumor grade 3 Positive lymphovascular space invasion Positive peritoneal cytology Adjuvant treatment Non-endometrioid Age N 65 years FIGO stage III–IV Tumor grade 3 Positive lymphovascular space invasion Positive peritoneal cytology Adjuvant treatment
p value
P
t3:5 t3:6 Q4 t3:7 t3:8 t3:9 t3:10 t3:11 t3:12 t3:13 t3:14 t3:15 t3:16 t3:17 t3:18
Multivariate
HR (95% CI)
O
Variables
t3:4
D
t3:3
Table 3 Univariate and multivariate analyses of recurrence-free survival according to endometrial cancer histology.
E
t3:1 t3:2
K.H. Han et al. / Gynecologic Oncology xxx (2014) xxx–xxx
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Conflict of interest statement
251
The authors declare that there are no conflicts of interest.
252
References
253 254 255 256 257 258 259
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Please cite this article as: Han KH, et al, Peritoneal cytology: A risk factor of recurrence for non-endometrioid endometrial cancer, Gynecol Oncol (2014), http://dx.doi.org/10.1016/j.ygyno.2014.05.010
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