Effect of hysteroscopy on the peritoneal dissemination of endometrial cancer cells: a meta-analysis

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1 GYNECOLOGY AND MENOPAUSE Effect of hysteroscopy on the peritoneal dissemination of endometrial cancer cells: a meta-analysis Ya-Nan Chang, M.M., Ying Zhang, M.D., Yong-Jun Wang, M.D., Li-Ping Wang, M.M., and Hua Duan, M.D. Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, People s Republic of China Objective: To determine whether preoperative hysteroscopic examination increases the risk for peritoneal dissemination of endometrial cancer cells and the effect of hysteroscopy on disease prognosis. Design: Meta-analysis. Setting: Literature search conducted via domestic and international databases for studies on preoperative hysteroscopy. Patient(s): A total of 2,944 women with endometrial cancer enrolled in selected studies. Intervention(s): Preoperative hysteroscopic examination for 1,099 patients. Main Outcome Measure(s): Rate of positive peritoneal cytology. Result(s): Of 308 studies retrieved, 19 were included in the meta-analysis. The meta-analysis demonstrated that hysteroscopy resulted in a statistically significantly higher rate of positive peritoneal cytology results compared with no hysteroscopy. In addition, when a liquid medium was used for uterine distention during hysteroscopy, the difference between the two groups remained statistically significant. However, no statistically significant differences were seen when inflation pressure reached or exceeded 100 mm Hg or when the cancer stage was early. Trials that examined long-term outcomes reported no statistically significant differences in disease prognosis between the two groups. Conclusion(s): Hysteroscopic examination before surgery in patients with endometrial cancer may increase the risk of dissemination of malignant cells into the peritoneal cavity. The risk was statistically significantly associated with the use of a liquid medium for uterine cavity distention but not with early-stage disease. There is no evidence to support an association between preoperative hysteroscopic examination and a worse prognosis. There is no reason to avoid diagnostic hysteroscopy before to surgery in patients with endometrial cancer, especially in early stages. (Fertil Steril Ò 2011;96: Ó2011 by American Society for Reproductive Medicine.) Key Words: Endometrial cancer, hysteroscopy, peritoneal dissemination, prognosis Endometrial cancer, one of the most common gynecologic malignancies, has a high diagnostic rate in the early stage, approximately 80% in stage I and 13% in stage II (1, 2). The 5-year overall survival rate is also high; about 90% for patients with stage I disease. However, survival decreases to 60% to 70% after the cancer has spread to the cervix. Hysteroscopy plays an important role in both the early diagnosis and staging of endometrial cancer because of the advantage of visually directed biopsy and the high rate of accuracy in determining cervix invasion, which are necessary for guiding appropriate surgery to avoid over- or undertreatment (3). During the hysteroscopic examination, tissue fragments, blood clots, and even malignant cells may disseminate into the peritoneal cavity under the pressure of the medium used for distention of the uterine cavity. This dissemination of endometrial cancer cells may Received March 25, 2011; revised and accepted July 28, 2011; published online August 26, Y.-N.C. has nothing to disclose. Y.Z. has nothing to disclose. Y.-J.W. has nothing to disclose. L.-P.W. has nothing to disclose. H.D. has nothing to disclose. Supported by the Public Welfare Fund of the Ministry of Health, grant no Reprint requests: Hua Duan, M.D., Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, People s Republic of China ( duanhua_bjfc_edu@163.com). worsen the prognosis of the disease. Positive peritoneal cytology is considered an adverse prognostic factor in endometrial cancer; however, some studies have indicated that it is not an independent prognostic factor (4). Previous studies (5, 6) have confirmed a high association between peritoneal cytology positive for malignant cells and hysteroscopy, but other studies have not shown this association (7). These conflicting results as to whether preoperative hysteroscopy increases the risk for dissemination of malignant endometrial cells into the peritoneal cavity have limited the application of diagnostic hysteroscopy in clinical settings. This meta-analysis integrates the findings of individual studies on the use of preoperative hysteroscopy in an attempt to clarify these conflicting results and guide the clinical use of diagnostic hysteroscopy in the patients with suspected endometrial cancer. MATERIALS AND METHODS Search Strategy A literature search was conducted in December 2009 using MEDLINE (from 1966 to 2009), Embase (from 1974 to 2009), the Chinese Biological Medicine database (CBM) (from 1978 to 2009), Chinese Medical Current Contents (CMCC) (from 1994 to 2009), and China National Knowledge Infrastructure (CNKI) (from 1979 to 2009). The search terms used included endometrial/endometrium cancer, endometrial/endometrium neoplasm, /$36.00 Fertility and Sterility â Vol. 96, No. 4, October doi: /j.fertnstert Copyright ª2011 American Society for Reproductive Medicine, Published by Elsevier Inc.

2 endometrial/endometrium carcinoma, hysteroscop*, dissemination, metastasis, spread, and diffusion, which were combined using the Boolean operators AND or OR. No time or language limits were placed on the searches. References of selected studies were also examined for additional relevant literature not found by the database searches. Study Selection The following inclusion criteria were used for study selection: enrollment of patients with histologically confirmed endometrial cancer; case-control, cohort, or randomized controlled trials; patient allocation to diagnostic hysteroscopy or no hysteroscopy before surgery; and peritoneal cytology as a study outcome. Data Analysis The observation group consisted of patients who underwent hysteroscopy; the control patients were those who did not undergo the procedure. The incidence of positive peritoneal cytology was compared between the two groups, and the statistics extracted from the eligible studies were analyzed using Rev- Man 5.0 software (from the Cochrane library). Subgroup analyses were performed based on the media used to distend the uterine cavity, the inflation pressure (R100 mm Hg), and the disease stage (I or II). Heterogeneity of the odds ratios (ORs) was examined using the I 2 statistic; fixed effects or random effects models were used for the analysis based on the I 2 statistic (where I 2 <50% and P>.1 suggested no statistically significant heterogeneity). A funnel plot was used to detect publication bias and was created using Rev- Man5.0 software. The OR was shown on the horizontal axis, and the vertical axis was the standard error of the natural logarithm of the OR. A balanced funnel plot suggested that publication bias was effectively controlled. RESULTS A total of 308 articles were retrieved from the literature search, and 19 met the inclusion criteria. Eleven papers were published in English and eight in Chinese. Of the 19 studies, 1 was a randomized controlled trial, 1 a prospective trial, and 17 were retrospective trials. The total number of patients included in the studies was 2,944, and 1,099 patients had undergone hysteroscopy (Table 1). The heterogeneity of the 19 included studies was acceptable (P¼.60; I 2 ¼ 0), and a fixed effects model was used; the Mantel- Haenszel test was used for analysis of the ORs. A statistically significant difference in positive peritoneal cytology rates was found between the observation and control groups (OR 1.51; 95% confidence interval [CI], ; P¼.005) (Fig. 1). The funnel plot was balanced, and most of the studies were within the 95% CI, suggesting that publication bias was not present (Fig. 2). Disease Stage The subgroup analysis of studies including patients with early disease (stages I or II) found no statistically significant difference in peritoneal cytology between the groups (OR 2.97; 95% CI, ; P¼.10) (Fig. 3). Distention Media Of the 15 studies where 0.9% sodium chloride or 5% glucose were used to distend the uterine cavity, hysteroscopy resulted in a statistically significantly higher rate of positive peritoneal cytology compared with no hysteroscopy (OR 1.61; 95% CI, ; P¼.004) (Supplemental Fig. 1, available online). Inflation Pressure No statistically significant difference was seen between the groups for peritoneal cytology based on an inflation pressure of at least 100 mm Hg (OR 2.29; 95% CI, ; P¼.08) (Supplemental Fig. 2, available online). TABLE 1 Meta-analysis of hysteroscopy in the peritoneal dissemination of endometrial cancer cells: 19 applicable studies. Study a Study type Scale Number Inflation pressure Peritoneal cytology HSC No HSC Medium (mm Hg) HSC No HSC Ben-Arie et al., 2008 (7) Case control Isotonic sodium chloride Takac et al., 2007 (20) Case control Saline solution Gutman et al., 2005 (21) Case control Saline solution 2 1 Sainz et al., 2004 (22) Randomized Normal saline controlled trial solution Bradley et al., 2004 (23) Cohort Selvaggi et al., 2003 (24) Case control Saline solution Gu et al., 2000 (25) Case control Obermair et al., 2000 (26) Cohort Normal saline Obermair et al., 2000 (27) Case control Normal saline Zerbe et al., 2000 (5) Case control Saline solution Martinez et al., 1996 (28) Case control Gao et al., 2009 (29) Case control % Glucose < Li et al., 2009 (30) Case control % Glucose Li et al., 2009 (31) Case control Shu et al., 2008 (32) Case control % Glucose Gao et al., 2004 (33) Case control % Glucose 2 3 Wang et al., 2002 (34) Case control % Glucose Zhang et al., 2002 (35) Case control % Glucose Wen et al., 2000 (36) Case control % Glucose 3 7 Note: The total number of patients included in the studies was 2,944, with 1,099 patients having undergone hysteroscopy (HSC). a Eleven papers were published in English and eight in Chinese. 958 Chang et al. Hysteroscopy effect on cancer dissemination Vol. 96, No. 4, October 2011

3 FIGURE 1 Effect of hysteroscopy on positive peritoneal cytology in patients with or without hysteroscopy (P¼.005). Prognosis Prognosis, including survival rate and disease recurrence, was reported in six studies, all of which suggested no statistically significant difference for these outcomes. Further analyses were not conducted. DISCUSSION Because of confounding factors such as tumor stage, tumor histology, distention media and pressure, and duration of the hysteroscopic examination, the results of investigations on whether diagnostic hysteroscopy increases the risk for peritoneal dissemination of endometrial cancer cells are conflicting. Our meta-analysis suggests that hysteroscopy results in a statistically significant higher risk for peritoneal dissemination of malignant cells, especially when 0.9% sodium chloride is used as the distention medium. However, the distention pressure does not contribute to the risk. In addition, hysteroscopy does not increase the risk of cancer cell dissemination into the peritoneal cavity when the tumor is localized at the early stage (stages I or II). However, although endometrial cancer cells may disseminate into the peritoneal cavity during hysteroscopy, there is no evidence to suggest that hysteroscopic examination before surgery is correlated with a worse prognosis. Six studies included in the metaanalysis reported follow-up evaluations of 2 months to 5 years. In these studies, the rates of survival and of disease recurrence were not statistically significantly different between the observation and control groups. But the follow-up periods in the research studies included in our analysis may have been too short. Vilos et al. (8) conducted a prospective cohort study of 3,401 patients with follow-up evaluations ranging from 1 to 14 years and concluded that hysteroscopy surgery did not adversely affect the 5-year survival or the long-term prognosis. Other clinical trials have reported similar findings, that preoperative hysteroscopy does not modify recurrence rates, disease-free survival, or overall survival (9, 10). Dissemination of endometrial cancer cells into the peritoneal cavity during hysteroscopic examination is a passive process. There have been no investigations as to whether the dispersal of malignant cells by the distention medium is related to the proliferation, implanting, invasion, or metastatic characteristics of the cancer cells. Biewenga et al. (11) hypothesized that hysteroscopy could result in the peritoneal dissemination of endometrial cancer cells, but that this was a transient effect and that cytology would return to negative after a period of time. The complex molecular mechanisms and the peritoneal microenvironment might allow the malignant cells to remain active in the peritoneal cavity for a long time. However, the cells will eventually die rather than implanting to metastasize or lead to recurrence. Additional studies are needed to confirm this hypothesis. FIGURE 2 Funnel plot of trials on preoperative hysteroscopy. Fertility and Sterility â 959

4 FIGURE 3 Effects of hysteroscopy in patients with localized early (stage I or II) endometrial cancer with and without hysteroscopy (P¼.10). During recent years, the presence of positive peritoneal cytology has not been thought to be an independent prognostic factor for survival of endometrial cancer (12 14). Studies have indicated that the prognosis of patients with only positive peritoneal cytology is better than that of patients with additional high-risk factors for endometrial cancer such as certain histologic types (e.g., clear cell, papillary serous, or poor differentiation), deep myometrial invasion, lymphovascular involvement, or serosal invasion (15, 16). The National Comprehensive Cancer Network (NCCN) recommends that additional treatment should be given to patients with positive peritoneal cytology according to whether there are high-risk factors present (17). The current International Federation of Gynecology and Obstetrics (FIGO) staging has recently been revised. Patients with peritoneal cytology should not be upgraded to stage III A nor to a higher stage in stage I disease (18, 19). Despite the association between hysteroscopy and positive peritoneal cytology, it cannot be determined whether hysteroscopy results in peritoneal metastasis or disease recurrence. The available evidence suggests that preoperative hysteroscopy has no correlation with the prognosis of the disease. Hysteroscopy remains a useful tool either for early diagnosis or for staging of endometrial cancer. REFERENCES 1. Triolo O, Antico F, Palmara V, Benedetto V, Panama S, Nicotina PA. Hysteroscopic findings of endometrial carcinoma: evaluation of 104 cases. Eur J Gynaecol Oncol 2005;26: Purdie DM, Green AC. Epidemiology of endometrial cancer. Best Pract Rec Clin Obstet Gynaecol 2001;6: Duan H, Deng XH. The diagnosis of endometrial cancer and the effect of malignant cells disseminating during hysteroscopy. 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Hysteroscopic surgery does not adversely affect the long-term prognosis of women with endometrial adenocarcinoma. J Minim Invasive Gynecol 2007;14: Cicinelli E, Tinelli R, Colafiglio G, Fortunato F, Fusco A, Mastrolia S, et al. Risk of long-term pelvic recurrences after fluid minihysteroscopy in women with endometrial carcinoma: a controlled randomized study. Menopause 2010;17: Dvorska M, Driak D, Svandova I, Sehnal B, Holy P, Benkovaet K, et al. Significance of hysteroscopic resection in diagnostics of endometrial cancer. Ceska Gynekol 2010;75: Biewenga P, de Blok S, Birnie E. Does diagnostic hysteroscopy in patients with stage I endometrial carcinoma cause positive peritoneal washings? Gynecol Oncol 2004;93: Ren YL, Wang HY, Shi DR, Yang WT, Sun Z, Chen Y. Combined treatment and prognostic factors for stage III and IVendometrial carcinoma. Zhonghua Fu Chan Ke Za Zhi 2008;43: Fadare O, Mariappan MR, Hileeto D, Wang S, McAlpine JN, Rimm DL. 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Gynecologic Cancer Intergroup (GCIG) proposals for changes of the current FIGO staging system. Eur J Obstet Gynaecol Reprod Biol 2009;143: Takac I, Zegura B. Office hysteroscopy and the risk of microscopic extrauterine spread in endometrial cancer. Gynecol Oncol 2007;107: Gutman G, Almog B, Lessing JB, Amiram BA, Grisaru D. Diagnosis of endometrial cancer by hysteroscopy does not increase the risk for microscopic extrauterine spread in early-stage disease. Gynecol Surg 2005;2: Sainz de la Cuesta R, Espinosa JA, Crespo E, Granizo JJ, Rivas F. Does fluid hysteroscopy increase the stage or worsen the prognosis in patients with endometrial cancer? A randomized controlled trial. Eur J Obstet Gynecol Reprod Biol 2004;15: Bradley WH, Boente MP, Brooker D, Argenta PA, Downs LS, Judson PL. Hysteroscopy and cytology in endometrial cancer. Obstet Gynecol 2004;104: Selvaggi L, Cormio G, Ceci O, Loverro G, Cazzolla A, Bettocchi S. Hysteroscopy does not increase the risk of microscopic extrauterine spread in endometrial carcinoma. Int J Gynecol Cancer 2003;13: Gu M, Shi WJ, Huang JT, Barakat RR, Thaler HT, Saigo PE. Association between intitial diagnostic procedure and hysteroscopy and abnormal peritoneal washings in patients with endometrial carcinoma. Cancer 2000;90: Obermair A, Geramou M, Gucer F, Denison U, Graf AH, Kapshammer E, et al. Does hysteroscopy facilitate tumor cell dissemination? Incidence of peritoneal cytology from patients with early stage 960 Chang et al. Hysteroscopy effect on cancer dissemination Vol. 96, No. 4, October 2011

5 endometrial carcinoma following dilatation and curettage (D & C) versus hysteroscopy and D & C. Cancer 2000;88: Obermair A, Geramou M, G ucer F, Denison U, Graf AH, Kapshammer E, et al. Impact of hysteroscopy on disease-free survival in clinically stage I endometrial cancer patients. Int J Gynecol Cancer 2000;10: Martinez CP, Bosch JM, Garcia GE, Lopez TJ, Prats C. Hysteroscopy and endometrial cancer: Does increase the peritoneal positive cytology rate? Progresos en Obstetricia y Ginecologia 1996;39: Gao YH. The relations between hysteroscopy and positive peritoneal cytology with endometrial carcinoma. [D]Medical college Shandong University 2009: Li MJ, Huang H, Wen ZY. Impact of hysteroscopy on peritoneal cytology in patients with endometrial carcinoma. Chin J Min Inv Surg 2009;9: Li YM, Su YY, Chen RH, He HC. Effect of hysteroscopy on the dissemination and prognosis of endometrial cancer. Hainan Medical Journal 2009;20: Shu W, Hu LN. Comparison of hysteroscope assisted dilation and curettage and traditional dilation and curettage in diagnosis of endometrial carcinoma. Progress in Modern Biomedicine 2008;8: Gao WL, Feng LM, Wang WJ, Li JH, Liu XC. Comparison of hysteroscope assisted dilation and curettage and traditional dilation and curettage in diagnosis of endometrial carcinoma. Journal of Capital University of medical Sciences 2004;25: Wang W, Guo YY. Value of hysteroscopy and dilatation and curettage in diagnosis of endometrial carcinoma. Chin J Obstet Gynecol 2002;37: Zhang JW, Hu JH, Peng ZL. The factors by which hysteroscopy facilitates tumor cell dissemination. Journal of Practical Obstetrics and Gynecology 2002;19: Wen HW, Wang J, Liu YM. The value of hysteroscopy in the diagnosis of endometrial cancer. Journal of Beijing medical university 2000;32: Fertility and Sterility â 961

6 SUPPLEMENTAL FIGURE 1 Effect of hysteroscopy on positive peritoneal cytology in patients with hysteroscopy with 0.9% sodium chloride or 5% glucose and without hysteroscopy (P¼.004). 961.e1 Chang et al. Hysteroscopy effect on cancer dissemination Vol. 96, No. 4, October 2011

7 SUPPLEMENTAL FIGURE 2 Effects of hysteroscopy in patients with hysteroscopy and 100 mm Hg distention pressure or greater and without hysteroscopy (P¼.08). Fertility and Sterility â 961.e2