Recurrence of Endometrial Polyps

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1 Original Article Received: December 19, 2013 Accepted after revision: April 3, 2014 Published online: May 23, 2014 Roberto Paradisi Stefania Rossi Maria Cristina Scifo Francesca Dall O Cesare Battaglia Stefano Venturoli Department of Obstetrics and Gynecology and Reproductive Biology, University Alma Mater Studiorum of Bologna, Bologna, Italy Key Words Endometrial polyps Recurrence Resectoscopic polypectomy Hysteroscopy Abstract Aims: To estimate the recurrence rate of patients with endometrial polyps and to evaluate whether the recurrence can be correlated with the histopathologic features of the polyp. Methods: Two hundred and eighty-two women with endometrial polyps in both pre- or postmenopausal period and suffering from abnormal uterine bleeding or not were treated by resectoscopic surgery in a tertiary university hospital and were subsequently followed to check for polyp recurrence. Results: Polyp recurrence rate after hysteroscopic surgery and correlation between recurrence and main demographic, hysteroscopic and histopathologic characteristics were analyzed. During mean ± SD follow-up period of 26.3 ± 19.7 months, the overall recurrence rate was high (13.3%) and did not vary (p = NS) with age, parity, weight or other demographic characteristics of the patients or with the hysteroscopic appearance. On the contrary, the histopathologic features showed significant differences between patients with and without polyp recurrence. Recurrence rate was higher (p < 0.001) in women with histopathologically hyperplastic polyps without atypia and lower (p < 0.001) in women with benign polyps. Conclusion: The study shows that after resectoscopic polypectomy, the recurrence rate of endometrial polyps is high (13.3%). Moreover, the hyperplastic polyps without atypia recur more frequently than benign ones. karger@karger.com S. Karger AG, Basel /14/ $39.50/ S. Karger AG, Basel Introduction Endometrial polyps are a gynecologic condition commonly encountered in routine clinical practice with a prevalence ranging from 7.8 to 34.9% depending on the population studied [1, 2]. The etiopathogenesis is not yet fully understood [1, 3]. They may be found incidentally in symptom-free women investigated for other indications [4]. Endometrial polyps are generally considered benign proliferations of the endometrium consisting of variable amounts of glands, stroma and blood vessels covered by epithelium [5]. Their morphologic diversity reflects the morphologic spectrum of the background endometrium, and as such may range from atrophic to hyperplastic to carcinomatous without a particular propensity to undergo malignant transformation compared to the normal endometrium [6]. However the detection of intrauterine polyps needs their removal because they are often associated with abnormal uterine bleeding (AUB) [2, 7], and in a variable proportion of cases (0 12.9%) depending on the population studied can develop malignant transformation [2, 4, 7 10]. Hysteroscopic resection is now the gold standard to treat endometrial polyps [2, 5, 7, 11], although hysteroscopic morcellation can offer such a good alternative [12] and has proved clearly superior to previous blind methods where polyp recurrences were much more frequent, because curettage may fail to extract polyps also in 60 87% of the cases [7, 13]. However, even though hysteroscopic resection operates under direct vision in the polyp removal, a low recurrence rate still remains [14 16]. Roberto Paradisi, MD Department of Obstetrics and Gynecology and Reproductive Biology S.Orsola Hospital, University Alma Mater Studiorum of Bologna Massarenti 13, IT Bologna (Italy) unibo.it

2 Until today, the literature has inexplicably devoted very little interest to the study of recurrence of endometrial polyps [14 16]. The paucity of data in this area requires that prospective long-time follow-up studies after hysteroscopic polypectomy are carried out to evaluate recurrence rates of endometrial polyps [2]. The aim of the present study was (a) to estimate the incidence of recurrence in a large series of cases with endometrial polyps that were entirely removed by hysteroscopic resection both in women of pre- and postmenopausal age and in both symptomatic and symptom-free women, and (b) to evaluate whether the recurrence can be correlated with the histopathologic appearance of the polyp. 2 Materials and Methods Subjects From January 2004 to June 2010, 282 women with a diagnosis of endometrial polyps entered into this retrospective cohort study and were treated by resectoscopic surgery. Diagnosis was based on results of consented outpatient diagnostic hysteroscopy. In most cases, transvaginal ultrasonography (TVUS) alone or combined with saline infusion (SIS) was also performed. Diagnosis was thereafter confirmed histologically. Criteria for inclusion were the presence of histologically diagnosed intrauterine single or multiple polyps of various sizes. Criteria for exclusion were various forms of focal and/or diffuse polypoid endometrial hyperplasia. All patients were informed of the risks and benefits of hysteroscopic polypectomy, and written informed consent was obtained. The study was approved by the Institutional Review Board of the Department of Obstetrics, Gynecology and Reproductive Biology of the University of Bologna. Patient data were retrieved from the surgical database of our Department. For all patients, main demographic and clinical characteristics were recorded: age, body mass index (BMI), systemic hypertension, diabetes mellitus, parity, hormone replacement therapy (HRT), tamoxifen treatment, polycystic ovarian syndrome (PCOS) status, number, side and diameter of polyps and histopathologic features. Procedure Hysteroscopic surgery was scheduled in the early follicular phase just after menstruation (days 5 7 of the cycle) in premenopausal women and on a day picked at random in postmenopausal women, and no presurgical medical treatment was given. Operative procedures were carried out under general anesthesia; the cervix was dilated with Hegar dilatators up to size 10 to enable to introduce a 9-mm monopolar resectoscope in the uterine cavity. The resectoscope consisted of a working element with a high-frequency connection for cutting and coagulating, a continuous-flow examination sheath with integrated suction and irrigation channel as well as a 12 telescope (Hopkins II, Storz, Tuttlingen, Germany). Uterine cavity distension was provided by a nonconductive, hyposmolar solution of sorbitol (2.7%) and mannitol (0.54%; Bieffe Medical, Grosseto, Italy). The fluid was introduced by automated hysteroscopic distension pump at an inflow pressure of 100 mm Hg; a precise balancing between infused and collected fluid was recorded during the entire procedure in order to detect eventual intravasation. The polyp resection was performed with a 90 semicircular loop, cutting with monopolar energy (high-cut 80 W; Storz). Data on polyp diameter previously obtained by diagnostic hysteroscopy, TVUS and SIS were thereafter confirmed during hysteroscopic resection comparing the length of the 1.0-cm-long yellow tip of the electronic knife to the size of the polyp to be resected. Full removal of intrauterine polyps including the stalks and bases for a depth of at least 5 mm up to the border with myometrium was carried out in all patients, and no endometrial ablation was associated with polyp resection. No complications worthy of note occurred during the operation. All the patients were discharged on the same day after the procedure. All surgical procedures took min and were made by the same surgeon (R.P.) with more than 20 years of experience in hysteroscopic surgery to avoid interoperator variability. As initial follow-up, all patients were subjected to TVUS and SIS, and, in the case of subjects with endometrial thickness greater than 5 mm, which is suspicious for polyp [17], even to a consented outpatient diagnostic hysteroscopy by well-trained sonographers and clinicians (S.R. and C.B.), after approximately 1 3 months to evaluate uterine cavity. Subsequently, similar annual checkups to assess polyp recurrence were performed for the following 2 years. S t a t i s t i c s Statistical analysis was performed using SPSS 13.0 software (SPSS Inc., Chicago, Ill., USA). Mean ± SD and 95% CI were used to describe continuous data. Differences in demographic and clinical characteristics between women in pre- or postmenopausal age and in those with or without recurrence were investigated by the χ 2 test or Fisher s exact test as appropriate and by Student s t test and the Mann-Whitney U test for quantitative variables (absence of normality distribution of quantitative variables was assessed using Kolmogorov-Smirnov test). A p value of <0.05 was accepted as statistically significant. Cox regression analysis was also performed to evaluate risk factors associated with recurrence. Independent predictors entering in the initial model were: age, BMI, history of hypertension, history of diabetes, tamoxifen use, polyp diameter and histopathologic type of polyp. Time from surgery and recurrence (last follow-up) was expressed in months. A value of p < 0.05 was assumed as significant to enter variables in the final model. R e s u l t s Of the 282 study patients, 101 (35.8%) and 181 (64.2%) were pre- and postmenopausal, respectively. Patients were considered postmenopausal if they experienced amenorrhea for at least 12 months. The demographic characteristics and hysteroscopic and histopathologic features of the whole study population and divided on the basis of pre- or postmenopausal age are detailed in table 1. All demographic characteristics between women in the pre- and postmenopausal age were significantly different (p < 0.001), except for PCOS status (p = NS). In Paradisi/Rossi/Scifo/Dall O /Battaglia/ Venturoli

3 Table 1. Main demographic characteristics and hysteroscopic and histopathologic features of the entire study population and divided on the basis of pre- or postmenopausal age Whole study population (n = 282) Premenopausal age (n = 101) Postmenopausal age (n = 181) p Demographic characteristics Age, years 53.7± ± ±7.8 Parity 1.1± ± ± BMI, kg/m ± ± ± History of hypertension 80 (28.4) 7 (7.0) 73 (40.3) History of diabetes 13 (4.6) 0 13 (7.2) HRT use 35 (12.4) 0 35 (19.3) Tamoxifen use 38 (13.5) 4 (4.0) 34 (18.8) PCOS status 11 (3.9) 4 (4.0) 7 (3.9) a NS Symptomatic women 115 (40.8) 56 (55.4) 59 (32.6) Syptom-free women 167 (59.2) 45 (44.6) 122 (67.4) Hysteroscopic features Polyp diameter, mm 16.5± ± ± Polyp number 1.4± ± ±0.7 NS Solitary 224 (79.4) 75 (74.3) 149 (82.3) NS Multiple 58 (20.6) 26 (25.7) 32 (17.7) NS Polyp site Anterior wall 70 (24.8) 25 (24.8) 45 (24.9) NS Posterior wall 85 (30.1) 31 (30.7) 54 (29.8) NS Right lateral wall 37 (13.2) 13 (12.9) 24 (13.3) NS Left lateral wall 39 (13.8) 15 (14.9) 24 (13.3) NS Fundal 51 (18.1) 17 (16.8) 34 (18.8) NS Histopathologic features Benign polyp 240 (85.1) 85 (84.2) 155 (85.6) NS Hyperplastic polyps without atypia 39 (13.8) 13 (12.9) 26 (14.4) NS Hyperplastic polyps with atypia 3 (1.1) 1 (1.0) 2 (1.1) NS Cancerous polyps 0 (0) 0 (0) 0 (0) NS Values are presented as mean ± SD or n (%). p values refer to differences between premenopausal and postmenopausal women. a Previous PCOS history. particular, the presence of AUB was significantly higher (p < 0.001) in premenopausal than postmenopausal women. In contrast, the main hysteroscopic features between women in pre- and postmenopausal age were similar (p = NS). No difference between polyp number and site in the two groups of patients was evidenced. Only polyp mean diameter was significantly larger (p < 0.001) in postmenopausal women. Among the main histopathologic features, we showed that approximately 85% of the women had benign polyps, while 13.8% had hyperplastic polyps without atypia. Only 3 (1.1%) women had hyperplastic polyps with atypia and were hysterectomized. No cancerous polyps were observed. No significant differences (p = NS) concerning the histopathologic features between women of pre- and postmenopausal age were observed. Of the 279 (98.9%) women remaining in the followup, 244 were followed in our clinic directly, while for the remaining 35, who were not able to come to our center, data on recurrence of pathology were obtained through telephone interviews. In these interviews, specific data to investigate any polyp recurrence were recovered according to a design in all respects similar to that of our clinic, including, in particular, detailed data on the timing for carrying out follow-up, on diagnostic methods used for follow-up (TVUS, SIS and diagnostic hysteroscopy) and on the quality and validity of the medical centers employed. Of these 279 patients, 37 (13.3%) had a recurrence. The mean ± SD period of follow-up was 26.3 ± 19.7 months ( ; 95% CI). The demographic characteristics and hysteroscopic and histopathologic features of patients with polyp recurrence compared to 3

4 Table 2. Main demographic characteristics and hysteroscopic and histopathologic features of remaining study population in the follow-up and divided on the basis of polyp recurrence Whole study population (n = 279) Recurrence (n = 37) No recurrence (n = 242) p Demographic characteristics Age, years 53.7± ± ±12.6 NS Parity 1.1± ± ±1.0 NS BMI, kg/m ± ± ±5.6 NS History of hypertension 78 (28.0) 8 (21.6) 70 (28.9) NS History of diabetes 13 (4.6) 2 (5.4) 11 (4.5) NS HRT use 35 (12.5) 5 (13.5) 30 (12.4) NS Tamoxifen use 38 (13.6) 4 (10.8) 34 (14.0) NS PCOS status 11 (3.9) 2 (5.4) 9 (3.7) NS Symptomatic women 115 (41.2) 18 (48.6) 97 (40.1) NS Syptom-free women 164 (58.8) 19 (51.4) 145 (59.9) NS Premenopausal women 100 (35.8) 15 (40.6) 85 (35.1) NS Postmenopausal women 179 (64.2) 22 (59.5) 157 (64.9) NS Hysteroscopic features Polyp number 1.4± ± ±0.8 NS Solitary 222 (79.6) 29 (78.4) 193 (79.8) NS Multiple 57 (20.4) 8 (21.6) 49 (20.2) NS Polyp diameter, mm 16.5± ± ±10.2 NS Histopathologic features Benign polyp 240 (86.0) 20 (54.1) 220 (90.9) Hyperplastic polyps without atypia 39 (14.0) 17 (45.9) 22 (9.1) Values are presented as mean ± SD or n (%). p values refer to differences between women with and without recurrence. 4 patients with no recurrence are detailed in table 2. No significant differences (p = NS) were found in some potential predictive parameters such as age, parity, weight and other demographic characteristics between patients with and without polyp recurrence. Moreover, similar percentages of polyp recurrence were found in both patients with or without AUB and also in patients of preand postmenopausal age. Presence of polyp recurrence was not correlated with main hysteroscopic features, such as polyp number and diameter. In contrast, the histopathologic features showed significant differences between patients with and without polyp recurrence. Benign polyps in particular were more frequent (p < 0.001) in patients with no recurrence, and hyperplastic polyps without atypia were more frequent (p < 0.001) in those with recurrence. Moreover, the final model of Cox multivariate regression analysis showed that only the histopathologic type of polyp was an independent predictor of recurrence (p < 0.001) with a hazard ratio of 4.99 ( fig. 1 ), different from the other risk factors, such as age, BMI, history of hypertension, history of diabetes, tamoxifen use and polyp diameter, which were all nonsignificant (p = NS). Only age was close to the significance limit (p = 0.096). The 37 women with recurrence underwent a subsequent surgical procedure. In particular, a total of 31 women (20 and 11 with benign and hyperplastic polyps, respectively, at the first procedure) required a single repeated hysteroscopic polypectomy with a new benign histological outcome. Fourteen of these 31 women were still symptomatic with AUB, with a percentage similar to that of the first procedure. Three further women with previous AUB and hyperplastic polyp without atypia had more than once recurrences with hyperplastic polyp without atypia and recurrent AUB and underwent hysterectomy to guarantee no more recurrences. Moreover, 3 additional hysterectomies were performed in women with previous hyperplastic polyp without atypia for a recurrence associated with symptomatic hyperplastic polyp with atypia in 2 cases and cancerous polyp in one. Paradisi/Rossi/Scifo/Dall O /Battaglia/ Venturoli

5 Tamoxifen use Polyp diameter D i s c u s s i o n Diabetes Hypertension Hyperplastic polyps BMI Age Fig. 1. Risk factors associated with polyp recurrence. Odds ratio (95% CI) of some demographic characteristics and hysteroscopic and histopathologic features in women with and without polyp recurrence during the follow-up period. OR >1 indicates higher risk in women with polyp recurrence. Endometrial polyp is a prevalently benign focal lesion protruding into the uterine cavity and is easily diagnosed during diagnostic hysteroscopy, TVUS and SIS. The increasing use of TVUS has resulted in many more asymptomatic polyps being diagnosed [4]. The advent of SIS allowed further refinement of endometrial details and intracavitary masses [18]. Hysteroscopic surgery has become the first-line therapeutic option in the treatment of patients with endometrial polyps [7, 11] if we consider that it leads to a satisfaction that is similar to more invasive surgical procedures, such as hysterectomy, as regards AUB [5]. Recently, appropriate practice guidelines for the diagnosis and management of endometrial polyps have been skilfully defined [1, 2]. The study confirms that in a large unselected population of women with endometrial polyps, the rate of malignancy is low, and the frequency of hyperplastic polyps with atypia is consistent with that reported in the literature [2, 4, 7 10, 19]. Our numbers, however, both at the first procedure and in the progression of recurrences are too low to draw any conclusions. The frequency of hyperplastic polyps without atypia is lower than that observed by Savelli et al. [7], higher than that observed by Preutthipan and Herabutya [14] and similar to that of many other studies [4, 20, 21]. Moreover, no difference in the histopathologic features was observed between pre- and postmenopausal women in agreement with others [10, 14]. Hysteroscopic features also showed similar outcomes between pre- and postmenopausal women, except polyp mean diameter, which was greater in postmenopausal women in disagreement with Preutthipan and Herabutya [14]. Worthy of note among the demographic characteristics is the prevalence of AUB in premenopausal women in agreement with others [14]. Concerning recurrences, our primary efficacy end point, we investigated for the first time in a large series of cases the frequency and management of any recurrence of endometrial polyps in women treated with resectoscopic hysteroscopy, and we found a fairly high recurrence rate of 13.3% on a mean follow-up of 2 years. To date, the literature has greatly underrated this topic, and only 3 papers [14 16] give scanty and even contradictory data despite recent guidelines of AAGL [2] that advocate prospective follow-up studies in this regard. Preutthipan and Herabutya [14] showed among the various instruments used that the resectoscope has a 0% recurrence rate, whereas microscissors, grasping forceps or electric probe have a recurrence rate varying from 2 to 15%, even if the duration of follow-up is uncertain. Henriquez et al. [15] observed during a follow-up of one year that a total of 14 women out of 78 (18.3%) required surgical reintervention after the first hysteroscopic polypectomy; 2 of them underwent a second polypectomy, while the others underwent endometrial ablation or hysterectomy. Gao et al. [16] found during a long follow-up (more than 3 years) a recurrence rate of 5.3% in a small series of tamoxifen-associated endometrial polyps treated with hysteroscopic polypectomy and endometrial ablation. Our data are more consistent with those of Henriquez et al. [15] and Gao et al. [16], who used the latter, in particular, a surgical technique (hysteroscopic polypectomy with endometrial ablation) more resistant to recurrences, while our data disagree with those of Preutthipan and Herabutya [14], who found no recurrences with the resectoscope. Hence, the statement resectoscope is a more preferable instrument to prevent the recurrence of the intrauterine polyps [14] should be cor- 5

6 rected to resectoscope is a more preferable instrument to limit the recurrence of the intrauterine polyps. Regarding potential predictive clinical risk factors that may influence the incidence of recurrences, age, parity, BMI, history of hypertension or diabetes mellitus, tamoxifen treatment, HRT and PCOS status seem to be unaffected. Moreover, the risk of recurrence appears to be independent of the presence of AUB and the menopausal status, and also seems uninfluenced by main hysteroscopic features (number and diameter of the polyps). In truth, the age, hypertension and menopausal status have been indicated as risk factors for malignant polyps [7], and polyp diameter was regarded as the only variable associated with a potential malignancy of the polyp [21]. Resectoscopic surgery gives the opportunity under direct vision of removing completely the polyp with its stalk and base leaving intact the adjacent endometrium. In this context then, a recurrence should be considered as a new polyp, although it is difficult to determine retrospectively if recurrence develops in a location near or far from the previous polyp. On the contrary, blind methods, as simple curettage, can fail in extracting the entire polyp also in 60 87% of the cases [13] and lead to a fragmentation and facilitate its reconstitution, which cannot be considered a real recurrence. Our data thus show certainly a marked difference in the histopathologic features and demonstrate how only the histopathologic type represents an independent predictive risk factor of recurrence. Indeed, the risk of recurrence is significantly higher in hyperplastic polyps without atypia compared with benign polyps, since nearly half of hyperplastic polyps without atypia recurred, while less than 10% of benign ones did the same. There is also more frequent progression of the hyperplastic polyps without atypia towards forms of symptomatic recurrences or precancerous or cancerous forms that require more radical surgery, such as hysterectomy. However, even benign polyps, and among them also those that are asymptomatic, have a certain ability to recur, and therefore it is recommended that these also are removed, as has been reported already [10]. It is nevertheless difficult to explain why some women have a tendency to experience recurrence and others do not. It is possible that some of them have a polypoid background in the endometrium resulting from proliferative processes arising from genetic aberrations [22]. In conclusion, our study has some limitations such as the retrospective nature of the study, the heterogeneity of the follow-up, and its limited duration (2 years). Nevertheless, the correlation between recurrence and hyperplastic appearance of the polyp cannot be underestimated, and therefore we must emphasize the importance and the need for further validation by prospective and multicenter long-term follow-up studies. If we consider that the recurrence rate is high enough, it is recommendable in any case to remove all verified endometrial polyps, benign ones, because they may sometimes recur and, a fortiori, hyperplastic ones without atypia as they have an even higher propensity to recur. Acknowledgements We thank Dr. Elisa Rossi, statistician, for the assistance in statistical analysis, and all patients for their cooperation in the followup done by phone. References 1 Salim S, Won H, Nesbitt-Hawes E, Campbell N, Abbott J: Diagnosis and management of endometrial polyps: a critical review of the literature. 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