Gynecologic Oncology 133 (2014) 56–62

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Endometrial polyps in obese asymptomatic pre and postmenopausal patients with breast cancer: Is screening necessary? Daniel Mª. Lubián López ⁎, Francisco Orihuela López, Lucía García-Berbel Molina, Patricia Boza Novo, Estrella Pozuelo Solís, David Menor Almagro, Rafael Comino Delgado Department of Obstetrics and Gynecology, University Hospital of Puerto Real, Faculty of Medicine, University of Cádiz, Spain

H I G H L I G H T S • Obese asymptomatic postmenopausal women with breast cancer have a very high prevalence of subclinical endometrial polyps. • In premenopausal women with estrogen receptor positive breast cancer, obesity is not a risk factor for endometrial polyps. • Pre-tamoxifen endometrial assessment could be a rational option in postmenopausal ER(+) breast cancer, obese and elderly patients.

a r t i c l e

i n f o

Article history: Received 24 September 2013 Accepted 18 December 2013 Keywords: Breast cancer Endometrial polyp Obesity Hysteroscopy Menopausal status Body mass index

a b s t r a c t Objective. To evaluate the prevalence of endometrial polyps in obese asymptomatic pre and postmenopausal patients with breast cancer and to know if a baseline pretamoxifen endometrial assessment should be taken into consideration in these women at high risk. Methods. A cross-sectional study was carried out with 201 women with breast cancer. A diagnostic hysteroscopy was performed in all women. All formations suspected as polyps were removed. The prevalence of endometrial polyps was analyzed in all patients (n = 182) and in premenopausal (n = 49) and postmenopausal (n = 118) women with estrogen receptor (ER) positive breast cancer (BC) according to their body mass index (BMI) and other risk factors. Results. Hysteroscopic evaluation was possible in 182 cases (90.5%). Of the total of women, 160 (87.9%) were ER(+)BC patients, 133 (73.1%) postmenopausal women and 41.5% were obese (BMI ≥ 30 kg/m2). Endometrial polyps were found in 52 cases (28.5%) (3 cases of simple hyperplasia harbored within a polyp). In premenopausal patients with ER(+)BC, there were no statistical differences in endometrial polyps according to their BMI (22.3% in non-obese women vs 31.7% in obese) while in all patients (26.4% in non-obese vs 44.0% in obese) and in postmenopausal women with ER(+)BC (25.9% in non-obese vs 48.6% in obese) there were statistical differences. In all women the relative risk (RR) of endometrial polyps in obese patients was 2.24 (1.01–4.83), in obese postmenopausal women with ER(+)BC was 2.75 (1.01–7.40) and in obese premenopausal patients with ER(+) BC was 1.42 (0.80–3.29). Conclusions. Asymptomatic women with breast cancer have a high prevalence of baseline subclinical endometrial polyps and it is very high in obese postmenopausal patients with estrogen receptor positive breast cancer. Therefore, there may be a future role for baseline pretamoxifen screening of some sort for the obese asymptomatic postmenopausal patient, especially if they are elderly and ER positive. © 2014 Elsevier Inc. All rights reserved.

Introduction Breast cancer patients also have a higher risk of endometrial pathology [1] because many individual and environmental risk factors (nulliparity, early onset of menarche, late age at menopause, obesity,

⁎ Corresponding author at: Department of Obstetrics and Gynecology, University Hospital of Puerto Real, Faculty of Medicine, University of Cádiz, Spain, Cta. Nacional IV, Km. 665, Puerto Real, Cádiz, Spain. E-mail address: [email protected] (D.Mª. Lubián López). 0090-8258/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ygyno.2013.12.029

etc.) are shared in both endometrial pathology and breast cancer promotion [2,3]. Although the American College of Obstetricians and Gynecologists [4] in 2006 stated that in asymptomatic women using tamoxifen (TAM), screening for endometrial cancer has not been shown to be effective; emerging evidence based on the presence of benign endometrial polyps before therapy suggests the existence of high and low-risk groups for the development of atypical hyperplasias with tamoxifen treatment in postmenopausal women [5,6]. Cancer risk in an endometrial polyp is low (3–10.7%) but the risk of these polyps becoming malignant after tamoxifen treatment, even in asymptomatic patients, is considerably

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higher than the risk observed in the general population [7]. Moreover, in premenopausal women, tamoxifen has no known increased risk of uterine cancer [4] but probably does increase the risk of uterine bleeding [8–11]. Obesity is a very well known important risk factor for endometrial polyps in pre and postmenopausal women [12,13]. Few studies provide a reliable systematic pretreatment endometrial assessment both in the general and in the obese population [14–22]. In all studies, transvaginal ultrasonography (TVUS) has been used as a screening method and most of them used an endometrial thickness (ET) N4 mm to indicate a hysteroscopic evaluation in postmenopausal patients. Hysteroscopy is the most reliable method of endometrial disease diagnosis and the available hysteroscopes have made it possible to remove polyps as outpatient surgery with few complications and a high degree of user satisfaction. This has made hysteroscopy the gold standard for diagnosing and the treatment of endometrial polyps [23]. On the other hand, a new option in postmenopausal women with ER positive breast cancer is third generation aromatase inhibitors (AIs) (letrozole, anastrozole and exemestane). Current studies found less rate of emerging endometrial pathology during AIs therapy [24] than tamoxifen use. To the best of our knowledge, no other study has investigated the prevalence of endometrial polyps by systematic hysteroscopy in all these patients, regardless of hormonal status, hormonal receptor positivity and BMI. It is very important to know if there are endometrial polyps not only in postmenopausal women with ER-positive breast cancer (potential endometrial side effects of tamoxifen use), but also in premenopausal women because of increased uterine bleeding risk, which creates a consequent need for many diagnostic tests, subsequent treatment and a high burden of anxiety in women with cancer. Therefore, the diagnosis and resection of endometrial polyps prior to hormonal treatment would be a very reasonable option in these patients, especially those at high risk for them. The goal of our study was to estimate the true prevalence of endometrial polyps in obese asymptomatic pre and postmenopausal patients with breast cancer, before any treatment at the moment of their diagnoses.

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Methods Anthropometric parameters were measured in all women. Obesity was defined as a BMI ≥ 30 kg/m2. A detailed gynecologic history and a TVUS evaluation of the endometrium were performed. In premenopausal women, the endometrial thickness was measured in the early follicular phase. In women with amenorrhea ≥1 year FSH levels were determined. A diagnostic hysteroscopy without anesthesia was done in each woman before any treatment for their breast cancer, independent of the ultrasonography findings. Hysteroscopic evaluation was done in the outpatient clinic by two experienced gynecologists (DLL and RCD) using a 5-mm sheathed hysteroscope (Bettocchi Office Hysteroscope, Karl Storz, Tuttlingen, Germany) and physiological saline as the distension medium. At the hysteroscopic finding of polyps and, based on the hysteroscopist's judgment, an immediate outpatient polypectomy was done with scissors or with a bipolar electrode (Versapoint Bipolar Electrosurgery System, Ethicon, Somerville, NJ, USA). In the cases of polyps larger than 3 cm in diameter, severe endocervical stenosis or when the patient was unable to tolerate the procedure, a deferred inpatient resectoscopic polypectomy under general anesthesia was accomplished. In all cases, polyps were sent for histological examination. The findings were classified according to the WHO histopathological criteria [26]. This classification is based on the morphological features of glands and stroma in the polyps. Size was estimated by the hysteroscopist using the largest polyp as the reference. The gold standard for calling something a true endometrial polyp was the histology report. Endometrial polyp prevalence was analyzed in all patients (Group 1), in premenopausal ER(+) breast cancer patients (Group 2) and in postmenopausal ER(+) breast cancer patients (Group 3) according to their body mass index (BMI) and other risk factors. Analyses were performed only in pre and postmenopausal ER(+) breast cancer patients because these are the potential users of adjuvant hormonal treatment.

Statistical analysis Patients and methods Inclusion criteria A cross-sectional study was carried out on 294 pre and postmenopausal women suffering infiltrating breast cancer who were treated in the Unit of Gynecologic Oncology of the Puerto Real University Hospital from January 2008 to January 2012. Before surgical treatment, patients were eligible for the hysteroscopic endometrial assessment if they had an intact uterus (no previous hysterectomy, no previous TAM, and no previous endometrial ablation), in the case of premenopausal women had not reported genital bleeding or hormonal therapy use (including contraceptives) during the previous year and in the case of postmenopausal women had not received, from the previous year, or were not receiving any hormonal therapy (HT), had no postmenopausal genital bleeding, or had not been submitted to an endometrial biopsy or to a diagnostic– therapeutic curettage in their post-menopausal period. Patients were defined as postmenopausal by amenorrhea ≥1 year and had FSH ≥ 40 mIU/mL. Women must be asymptomatic from a gynecologic standpoint and informed consent was obtained from each patient after the nature of the study was fully explained. Inclusion criteria were carried-out by 201 women. An approved protocol was obtained from the local ethics committee, and this study was conducted according to the guidelines of the Helsinki Declaration and resolution 196/96 of the National Health Council on Research Involving Human Subjects [25].

The data were collected and analyzed using SPSS 15.0 for Windows (version 11.5, SPSS Inc., USA). Clinical and demographic variables of patients (age, parity, breast feeding, age at menarche and menopause, time since menopause, body mass index, previous hormone replacement therapy, breast tumor size, and endometrial thickness) were compared in all groups of women. Prevalence of endometrial polyps in the different groups was calculated. Statistical analysis was carried out by calculating frequencies, means and standard deviations. A Chi-square test was adopted for comparison of frequencies and Student's t test was used for means comparisons. In a second time, obesity and other risk factors associated with endometrial polyps were analyzed. In order to evaluate these risk factors, prevalence ratios with their respective 95% confidence intervals were calculated using Pearson's Chisquare or Fisher's exact test. Statistical significance was set at p b 0.05.

Results Principal demographic and clinical characteristics of patients in all groups are shown in Table 1. Among the initial 294 women who had been diagnosed with breast cancer and before any treatment, 201 were eligible for the endometrial hysteroscopic evaluation and finally, it was possible in 182 patients (90.5%). In 9 cases (4.4%), after being informed about the procedure, the patient refused the consent and in 10/182 cases (5.4%) hysteroscopy was not possible because a firm endocervical stenosis was present or the patient was unable to tolerate the procedure.

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Table 1 Demographic and clinical characteristics of patients. Variable

Premenopausal patients n: 49 (26.9%)

Postmenopausal patients n: 133 (73.1%)

All patients n: 182 (100%)

Age (years) Age ≥ 60 (years) (%) Body mass index (kg/m2) Obesity prevalence (%) Pregnancy Parity Age at menarche (years) Age at menopause (years) Time since menopause (years) Endometrial thickness (mm) Endometrial thickness ≥ 4 mm (%) Previous HTa (%) History of breastfeeding (%) Breast tumor size (mm) Estrogen-receptor positive breast cancer (%): Progesterone-receptor positive breast cancerb (%)

45.1 ± 4.9 (34–54) 0 25.3 ± 3.6 (19.9–34.6) 18.2 2.2 ± 0.9 (1–5) 1.5 ± 1.0 (0–3) 12.5 ± 1.2 (10–14) – – 4.7 ± 3.0 (1–14) 61.2 – 56.3 23.2 ± 18.1 (6–10) 42/49 (85.7) 30/43 (69.7)

64.3 ± 7.2 (46–84) 68.2 30.2 ± 5.3 (18.7–43.7) 51.1 3.5 ± 2.2 (0–11) 3.1 ± 1.5 (0–9) 12.6 ± 1.4 (9–17) 49.7 ± 4.9 (34–60) 14.8 ± 7.6 (1–37) 4.0 ± 2.2 (0–15) 30.2 11.7 70.2 21.8 ± 12.5 (5–90) 118/133 (88.7%) 82/107 (76.6)

58.9 ± 11.8 (34–84) 48.4 28.9 ± 5.8 (17.2–43.7) 41.7 3.2 ± 1.9 (0–11) 2.7 ± 1.7 (0–9) 12.6 ± 1.5 (9–17) 49.7 ± 4.9 (34–60) 14.8 ± 7.6 (1–37) 4.5 ± 3.0 (0–15) 41.7 11.7 62.1 22.8 ± 14.8 (5–90) 160/182 (87.9) 112/150 (74.2)

Data of variables are expressed as mean ± standard deviation (range) and absolute number and its frequencies. a HT = hormonal replacement therapy (use before 1 year). b Only if data is available.

patient's age (68.8 ± 7.6 years vs 62.3 ± 8.0 years, p b 0.001), weight (78.6 ± 15.9 kg vs 72.2 ± 13.0 kg, p = 0.04), and BMI (32.0 ± 5.5 kg/m2 vs 29.5 ± 5.6 kg/m2, p = 0.04) were significantly associated with the finding of endometrial polyps. These results are similar in all patients (group 1), but not found in premenopausal women with ER(+) breast cancer (group 2) (Table 3). In all patients (pre and postmenopausal women), the relative risk (RR) of endometrial polyps in obese patients was 2.24 (1.01–4.83) and in postmenopausal women with ER(+) breast cancer was 2.75 (1.01–7.40) while in premenopausal women with ER(+)BC, there were no statistical differences in endometrial polyp prevalence according to their BMI (31.7% in obese women vs 22.3% in non-obese women) (RR = 1.42 (0.80–3.29)) (Table 4). In all patients, other inherent risk factors for endometrial polyps and others related with breast tumors, analyzed by calculating the prevalence ratios, showed that of all analyzed parameters (age, menopausal status, time since menopause, pregnancy, age at menarche, age at menopause, previous use of hormone therapy, endometrial thickness, breast estrogen receptor, breast progesterone-receptor, and breast tumor size) only age and time since menopause had a significant association. Patients over 60 years of age had a 2.93 fold increase of endometrial polyps compared to younger patients (95% CI: 1.52–5.64) and those with b15 years since menopause had a 0.32-fold decrease of endometrial polyps compared to patients with more years since menopause (95% CI: 0.14–0.69) (Table 5). In all patients, 51.3% of women over 60 years and BMI ≥ 30 kg/m2 showed endometrial polyps vs only 23.5% in women b60 years and BMI b 30 kg/m2; p = 0.002. In group 3, women over 60 years and

Resectoscopic polypectomy under general anesthesia was required in 19/52 (36.5%) of hysteroscopic diagnoses of endometrial polyps, which represent 10.4% of the total (19/182). Hysteroscopic and histological diagnoses of endometrial polyps in pre and postmenopausal women according to hormone receptors are shown in Table 2. Among all women (pre and postmenopausal), hysteroscopic diagnosis of endometrial polyps was performed in 61 patients. Pathologic investigations that were performed led to the detection of endometrial polyps in 52 (85.2%) of these 61 patients (3 cases of simple hyperplasia harbored within a polyp). Complex atypical hyperplasia or endometrial cancers were not found. In premenopausal women (49 patients), 13 of 16 (81.2%) hysteroscopic diagnoses of endometrial polyps were confirmed by pathologic investigations. In the postmenopausal breast cancer group (118 patients), of the 45 polyps detected by hysteroscopy (1 case of simple hyperplasia harbored within a polyp), 39 (86.6%) were histologically confirmed. Thus, the overall prevalence of histological endometrial polyps was 28.5% in group 1, 26.1% in group 2, and 29.6% in group 3 (Table 2). General hysteroscopic characteristics of histologically tested polyps (52/182) include the following: Average number and range: 1.31 ± 0.66 (1–5); size (of the largest): 16.89 ± 8.01 mm (2–30); proportion of polyps with size b 5 mm: 17/52 (32.6%); outpatient polypectomy: 33/52 (63.4%) and deferred inpatient resectoscopic polypectomy: 19/52 (36.5%). No differences between groups in the size, number, location and method of resection of polyps were found. In postmenopausal women with ER(+) breast cancer (group 3), when we compared the anthropometric parameters of patients suffering from endometrial polyps and patients with normal endometrium,

Table 2 Hysteroscopic and histological diagnosis of endometrial polyps in pre and postmenopausal patients according to estrogen receptor status of the breast cancer. Premenopausal patients n (49) Diagnostic method of endometrial polyp/s

Hysteroscopy Histology

ER(+)a (42)

Postmenopausal patients n (133)

ER(−)a (7)

ER(+)a (118)

Total

All patients n (182)

ER(−)a (15)

Total

n

%

n

%

n

%

n

%

n

%

n

%

n

%

14 11

33.3 26.1

2 2

28.5 28.5

16 13

32.6 26.5

40 35

33.8 29.6

5 4

33.3 26.6

45 39

33.8 29.3

61 52

33.5 28.5

Data of variables are expressed as absolute number and its frequencies. a ER: Estrogen receptors.

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Table 3 Correlation between anthropometric variables and endometrial polyps in the different groups. Group/clinical variables

Endometrial polyps

a

Premenopausal ER(+)BC (42) Age (years) Weight (kg) Height (cm) Body mass index (kg/m2) Postmenopausal ER(+)BCb (118) Age (years) Weight (kg) Height (cm) Body mass index (kg/m2) All breast cancer patients (182) Age (years) Weight (kg) Height (cm) Body mass index (kg/m2) a b c

p-Valuec

No endometrial polyps

n

%

n

%

11 48.5 ± 5.4 67.7 ± 8.9 161.3 ± 3.7 25.8 ± 3.2 35 68.8 ± 7.6 78.6 ± 15.9 156.2 ± 6.0 32.0 ± 5.5 52 63.3 ± 12.0 77.3 ± 15.5 157.7 ± 6.8 30.8 ± 6.6

26.1

31 45.3.1 ± 2.2 64.1 ± 8.3 161.1 ± 6.9 25.2 ± 3.7 83 62.3 ± 8.0 72.2 ± 13.0 156.6 ± 6.2 29.5 ± 5.6 130 56.7 ± 11.0 69.8 ± 13,4 158.6 ± 6.5 27.9 ± 5.6

73.9

29.6

28.5

0.09 0.41 0.90 0.73 70.3 b0.001 0.046 0.77 0.04 71.4 b0.001 0.009 0.51 0.01

Premenopausal ER(+)BC: Premenopausal and estrogen receptor positive breast cancer patients. Postmenopausal ER(+)BC: Postmenopausal and estrogen receptor positive breast cancer patients. The significance of bold values was established as p b 0.05.

BMI ≥ 30 kg/m2 had endometrial polyps in 54.9% vs only 12.3% in women b 60 years and BMI b 30 kg/m2; p b 0.001. In Tables 4 and 5, it is observed that both variables in all patients (age and BMI) are similar predictors of the presence of endometrial polyps (BMI kg/m2 ≥ 30: 44% of endometrial polyps vs 56% of non endometrial polyps; Age ≥ 60 years: 44.5% of endometrial polyps vs 55.5% of non endometrial polyps). Discussion Endometrial polyps are a common pathology, occurring in more than 25% of the general population (symptomatic and asymptomatic, pre and postmenopausal women), most frequently in peri and postmenopausal women [27]. In gynecological asymptomatic patients with breast cancer, we found a hysteroscopic diagnosis of polyps in 28.5% of all patients, in 26.5% of premenopausal women and in 29.3% of postmenopausal women, higher than reported in 2009 by Dreisler et al. [28], who found polyps in 13% (22/169) of asymptomatic postmenopausal women diagnosed by saline contrast sonohysterography (SCHS), but their patients did not have breast cancer, were younger than ours (mean age 45 years [20–75] vs. 58.9 [34–84]) and as they recognized “our threshold of 5 mm, however, could have led to an incorrect, low estimate of the prevalence of uterine polyps”. In the same way, all the other authors [20,29–31] found a much lower incidence of endometrial polyps, and we believe it is because they did not perform hysteroscopy on patients with endometrial thickness less than 4 mm and their patients were younger and less obese than those in our study. Thus, in postmenopausal women, we detect endometrial polyps b 5 mm in 22.8% of polyps. This is the main reason why we found a higher

prevalence than in all previous studies. In premenopausal women, polyps less than 5 mm were even more frequent (32.6% of all polyps). In 52/61 (85.2%) of hysteroscopic diagnoses of endometrial polyps in our women, diagnosis was histologically confirmed, representing an acceptable down rate of false-positive findings in the hysteroscopic screening. This compares favorably with another study with a rate of 62–75% [20], and this could be due to the realization of the study by a single observer and a single laboratory. In premenopausal women, we found a high prevalence of ER(+) breast cancer (85.7%) while Bakkum-Gamez and cols [31] report a prevalence of 64%. In these patients, tamoxifen does not seem to increase the risk of developing polyps, but 50% of these patients will be symptomatic and their removal could avoid anxiety and subsequent diagnostic tests and treatments in the case of abnormal bleeding due to polyps. From a diagnostic point of view, saline contrast sonohysterography (SCHS) is as capable as office hysteroscopy at excluding endometrial polyps and it could be cheaper, easier and less painful for patients. In screening, SCHS has a similar level of performance to diagnostic hysteroscopy for the detection of focal intrauterine pathology [32] and depending on operator and patient preference procedures are virtually interchangeable. Gumus et al. [33] reported than SCHS showed very good agreement with hysteroscopy for the diagnosis of endometrial abnormalities in asymptomatic postmenopausal women (sensitivity of 88.8% and a specificity of 84.4% vs 91% and 82% of the hysteroscopy). Although hysteroscopy is the most effective method in the diagnosis and treatment of endometrial polyps [20], gynecological asymptomatic women could find it too invasive. However, it was found that women recently diagnosed with breast cancer were very willing and often grateful to

Table 4 Obesity as a risk factor associated with endometrial polyps in different groups of asymptomatic breast cancer patients: Prevalence ratio (PR). Group

BMI (kg/m2)

Endometrial polyps (%)

No endometrial polyps (%)

Premenopausal ER(+)BCa n = 42 Postmenopausal ER(+)BCb n = 118 All breast cancer patients N = 182

b30 ≥30 b30 ≥30 b30 ≥30

22.3 31.7 25.9 48.6 26.4 44.0

77.7 68.3 74.1 51.4 73.6 56.0

Pearson's Chi-square or Fisher's exact test. PR: prevalence ratio; 95% CI: 95% confidence interval. a Premenopausal ER(+)BC: Premenopausal and estrogen receptor positive breast cancer patients. b Postmenopausal ER(+)BC: Postmenopausal and estrogen receptor positive breast cancer patients. c The significance of bold values was established as p b 0.05.

p-Valuec

0.110 0.046 0.042

Gross PR (relative risk) 1.00 1.42 1.00 2.75 1.00 2.24

95% CI

(0.80–3.29) (1.01–7.40) (1.01–4.83)

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Table 5 Other risk factors associated with endometrial polyps in asymptomatic breast cancer patients (182): Prevalence ratio (PR). Factor Age (n = 182) b60 ≥60 Menopausal status (n = 182) Premenopausal Postmenopausal Time since menopause (n = 133)a b15 years ≥15 years Pregnancy (n = 182) b3.5 ≥3.5 Age at menarche (years) (n = 182) b12.5 ≥12.5 Age at menopause (years) (n = 133)a b50 ≥50 Endometrial thickness (n = 164) b4 mm ≥4 mm Endometrial thickness (n = 164) b5 mm ≥5 mm Previous HT use (n = 72)a No Yes Breast estrogen receptor: (n = 182) ER(−) ER(+) Breast progesterone receptor (n = 182) PR(−) PR(+) Breast tumor size (n = 150) b25 mm ≥25 mm

Endometrial polyps (%)

No endometrial polyps (%)

p-Valueb

Gross PR (relative risk)

21.2 44.5

78.8 55.5

0.001

1.00 2.93

(1.52–5.64)

26.7 34.3

73.3 65.7

0.301

1.00 1.44

(0.70–3.02)

25.8 50.6

74.2 49.4

0.003

0.34 1.00

(0.14–0.69)

31.5 34.0

68.5 66.0

0.661

0.81 1.00

(0.44–1.66)

34.5 31.7

65.5 68.3

0.750

1.00 0.92

(0.49–1.70)

37.9 33.6

62.1 66.4

0.661

1.00 0.82

(0.41–1.79)

28.9 39.5

71.1 60.5

0.143

1.00 1.61

(0.80–3.20)

29.5 45.1

70.5 54.9

0.06

1.00 2.01

(0.95–4.18)

31.5 20.0

68.5 80.0

0.591

1.00 0.54

(0.07–5.22)

36.4 31.9

63.6 68.1

0.673

1.00 0.81

(0.32–2.07)

39.5 29.5

60.5 70.5

0.253

1.00 0.64

(0.29–1.37)

30.8 35.1

69.2 64.9

0.575

0.82 1.00

95% CI

(0.41–1.63)

Pearson's Chi-square or Fisher's exact test. PR: prevalence ratio; 95% CI: 95% confidence interval. a Only in postmenopausal women. b The significance of bold values was established as p b 0.05.

be thoroughly examined. In this way, 90.5% of women had a successful screening with hysteroscopy and biopsy, and outpatient screening was well tolerated with a failure rate of only 5.3%, similar to Duffy et al. [20] with a successful rate of 91% and failure rate of 4% in the Yorkshire region. This would suggest that hysteroscopy is successful as a technique and that patient acceptability is high, even in postmenopausal asymptomatic women. Obesity is a well know risk factor for developing endometrial polyps [12,13] in pre and postmenopausal women, but we had demonstrated it in postmenopausal women only. In premenopausal women, age is more important than BMI as risk factor for endometrial polyps (Table 4). When we analyzed the risk factors for baseline endometrial polyps (Table 5), we found that only time since menopause ≥ 15 years and age above 60 years are predictors of endometrial polyps; these findings are in accordance with those observed in the general population [7]. These results, along with a much higher prevalence of endometrial polyps in ER(+) menopausal women above 60 years who are obese (54.9%) vs women younger than 60 years who are not obese (12.3%), lead us to conclude that in those patients, pretreatment screening is especially necessary. Various risk factors have been identified for endometrial polyps in patients with tamoxifen treatment, such as older age at menopause, longer duration of breast disease, long-term tamoxifen therapy (N 48 consecutive months), heavier body weight and thicker endometrium measured by transvaginal ultrasonography (TVS) [7], but to our

knowledge, there is no study similar to ours that analyzes these risk factors previous to using tamoxifen. Only age, menopausal status and postmenopausal bleeding have been identified as associated factors with malignancy in endometrial polyps [34]. With respect to age, Antunes et al. [34] and more recently, Costa-Paiva et al. [35], from the same group, confirmed that women above 60 years of age have a prevalence of premalignant or malignant polyps 5.31 times greater than women 40–59 years of age, and Hileeto et al. [36] also found a strong association between age and malignancy in endometrial polyps, reporting a rate of 32% of malignant polyps in a group of women over 65 years of age compared to 7.2% in women 25–65 years of age. Advanced age and menopausal status have also been identified in other studies as predictors of malignancy in endometrial polyps [37,38]. It is important to note that the presence of abnormal bleeding, either in menopause or in perimenopause, was not found to be a risk factor for premalignancy or malignancy in the studies carried out by Savelli et al. [37] and Ben-Arie et al. [39], although Costa-Paiva et al. [35] found a higher prevalence of malignancy in endometrial polyps in women with postmenopausal bleeding (PR: 3.67 (95% CI; 1.69–7.97)). Contrary to results published in previous reports [2,15,16,40], where the incidence of baseline atypical lesions was between 0.7 and 3.8%, we did not find any cases of atypical lesion in this current study of asymptomatic women. There were no endometrial malignancies, and this is in accordance with the most important previous study [20].

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In relation to the effect of tamoxifen, endometrial polyps are the most common endometrial pathology described in association with postmenopausal use, with an incidence of 8–36% [7], and Bergman et al. [41] observed that in users of this drug, as well as a higher incidence of endometrial polyps, there was also a greater association of these polyps with carcinomas of a more aggressive histological type and grade. Cohen [42] summarizes that the rate of malignancy reported in endometrial polyps recovered from postmenopausal breast cancer tamoxifen-treated patients is much higher than in the general population (from 2.0 up to 10.7%) and that no specific clinical features (including patient's age and the frequency of postmenopausal bleeding) are associated with these malignant polyps. Up to the present moment, the indication of polypectomy has not been agreed upon, especially for premenopausal and asymptomatic women [7]. In tamoxifen-treated patients, risk factors for the development of atypical endometrial lesion are obesity, prior exposure to unopposed estrogens, and endometrial polyps diagnosed at the basal screening (11.7% vs 0.7% without previous polyps) [6,16]. In the Intergroup Exemestane Study (IES) [43], in the Breast International Group (BIG) 1–98 trial [44] and in the TEAM study [45], in postmenopausal women, treatment with third-generation aromatase inhibitors (AIs) (exemestane or letrozole) was associated with the lower incidence of endometrial abnormalities than sequential treatment (tamoxifen followed by AIs). Thus, as many authors have cited [18,40], we believe that there may be a future role for baseline pretreatment screening of endometrial polyps in postmenopausal women with ER-positive breast cancer, and probably also in premenopausal women, but it is necessary that the cost of this screening should be carefully analyzed to determine if there is a cost effective approach to this issue. If appropriate, we would recommend this to be done by transvaginal ultrasonography (TVUS), saline contrast sonohysterography (SCHS) in all patients or progesterone challenge test (PCT) [46] in menopausal patients, and probably, by outpatient hysteroscopy in high risk women (postmenopausal with ER(+) breast cancer, obese and above 60 years old women), because it would be beneficial to diagnose and treat endometrial polyps before starting the treatment with tamoxifen or to evaluate aromatase inhibitor treatment in these patients with a lesser effect on the endometrium.

Conclusion In summary, our results demonstrate a high prevalence of occult endometrial polyps in asymptomatic women with breast cancer prior to any treatment. This prevalence is especially very high in obese postmenopausal patients. This finding is higher than previous reports based on nonhysteroscopic systematic endometrial investigation. Therefore, from these results, we believe that endometrial assessment before starting hormonal therapy in obese asymptomatic patients with BC at high risk (postmenopausal, ER-positive and elderly) should be taken into account for future investigations.

Conflict of interest statement The authors report no conflicts of interest.

Financial disclosure None reported.

Funding sources None.

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References [1] Curtis RE, Boice JD, Shriner DA, Hankey BF, Fraumeni JF. Second cancers after adjuvant therapy for breast cancer. J Natl Cancer Inst 1996;88:332–4. [2] Willet WC, Rockhill B, Hankinson SE, Hunter DJ, Colditz GA. Epidemiology and non genetic causes of breast cancer. In: Harris JR, Lippman ME, Morrow M, Osborne CK, editors. Diseases of the breast. 2nd ed. Philadelphia, PA, USA: Lippincott Williams and Wilkins; 2000. p. 175–220. [3] Brinton LA, Hoover RN. Epidemiology of gynecological cancers. In: Hoskins WJ, Perez CA, Young RC, editors. Principles and practice of gynecologic oncology. 3rd ed. Philadelphia, PA, USA: Lippincott Williams and Wilkins; 2000. p. 3–27. [4] Tamoxifen and uterine cancer. ACOG Committee Opinion No. 336. American College of Obstetricians and Gynecologists. Obstet Gynecol 2006;107:1475–8. [5] Vosse M, Renard F, Coibion M, Neven P, Nogaret JM, Hertens D. Endometrial disorders in 406 breast cancer patients on tamoxifen: the case for less intensive monitoring. Eur J Obstet Gynecol Reprod Biol 2002;101:58–63. [6] Berliere M, Radikov G, Galant C, Piette P, Marbaix E, Donnez J. Identification of women at high risk of developing endometrial cancer on tamoxifen. Eur J Cancer 2000;36:S35–6. [7] Biron-Shental T, Tepper R, Fishman A, Shapira J, Cohen I. Recurrent endometrial polyps in postmenopausal breast cancer patients on tamoxifen. Gynecol Oncol 2003;90:382–6. [8] Buijs C, Willemse PH, de Vries EG, et al. Effect of tamoxifen on the endometrium and the menstrual cycle of premenopausal breast cancer patients. Int J Gynecol Cancer 2009;19:677–81. [9] McGonigle KF, Lantry SA, Odom-Maryon TL, Chai A, Vasilev SA, Simpson JF. Histopathologic effects of tamoxifen on the uterine epithelium of breast cancer patients: analysis by menopausal status. Cancer Lett 1996;101:59–66. [10] Cheng WF, Lin HH, Torng PL, Huang SC. Comparison of endometrial changes among symptomatic tamoxifen-treated and nontreated premenopausal and postmenopausal breast cancer patients. Gynecol Oncol 1997;66:233–7. [11] Chang J, Powles TJ, Ashley SE, Iveson T, Gregory RK, Dowsett M. Variation in endometrial thickening in women with amenorrhea on tamoxifen. Breast Cancer Res Treat 1998;48:81–5. [12] Onalan R, Onalan G, Tonguc E, Ozdener T, Dogan M, Mollamahmutoglu L. Body mass index is an independent risk factor for the development of endometrial polyps in patients undergoing in vitro fertilization. Fertil Steril 2009;91(4):1056–60. [13] Indraccolo U, Di Iorio R, Matteo M, Corona G, Greco P, Indraccolo SR. The pathogenesis of endometrial polyps: a systematic semi-quantitative review. Eur J Gynaecol Oncol 2013;34(1):5–22. [14] Lahti E, Blanco G, Kauppila A, Apaja-Sarkkinen J, Taskinen PJ, Laatikainen T. Endometrial changes in postmenopausal breast cancer patients receiving tamoxifen. Obstet Gynecol 1993;81:660–4. [15] Willen R, Lindahl B, Andolf E, Ingvar C, Liedman R, Ranstam J. Histopathologic findings in thickened endometria, as measured by ultrasound in asymptomatic, postmenopausal breast cancer patients on various adjuvant treatment including tamoxifen. Anticancer Res 1998;18:667–76. [16] Berliere M, Charles A, Galant C, Donnez J. Uterine side effects of tamoxifen: a need for systematic pretreatment screening. Obstet Gynecol 1998;91:40–4. [17] Gerber B, Krouse A, Muller H, et al. Effects of adjuvant tamoxifen on the endometrium in postmenopausal women with breast cancer: a prospective long-term study using transvaginal ultrasound. J Clin Oncol 2000;18:3464–70. [18] Neven P, DeMuyider X, VanBelle Y, VanHooff I, Vanderick G. 66 G. Garuti et al./Gynecologic Oncology 98 (2005) 63–67 Longitudinal hysteroscopic follow-up during tamoxifen treatment. The Lancet 1998;351:36. [19] Goncalves MAG, Goncalves NJ, Matias MM, Nazario ACP, Rodrigues DeLima G, Baracat EC. Hysteroscopic evaluation of the endometrium of postmenopausal patients with breast cancer before and after tamoxifen use. Int J Gynecol Obstet 1999;66:273–9. [20] Duffy S, Jackson TL, Lansdown M, Philips K, Wells M, Pollard S, et al. The ATAC adjuvant breast cancer trial in postmenopausal women: baseline endometrial subprotocol data. BJOG 2003;110:1099–2006. [21] Garuti G, Cellani F, Centinaio G, Sita G, Nalli G, Luerti M. Baseline endometrial assessment before tamoxifen for breast cancer in asymptomatic menopausal women. Gynecol Oncol 2005;98:63–7. [22] Garuti G, Grossi F, Centinaio G, Sita G, Nalli G, Luerti M. Pretreatment and prospective assessment of endometrium in menopausal women taking tamoxifen for breast cancer. Eur J Obstet Gynecol Reprod Biol 2007;132:101–6. [23] Bettocchi S, Ceci O, Di Venere R, Pansini MV, Pellegrino A, Marello F, et al. Advanced operative office hysteroscopy without anaesthesia: analysis of 501 cases treated with a 5 Fr. bipolar electrode. Hum Reprod 2002;17:2435–8. [24] Garuti G, Cellani F, Centinaio G, Montanari G, Nalli G, Luerti M. Prospective endometrial assessment of breast cancer patients treated with third generation aromatase inhibitors. Gynecol Oncol 2006;103:599–603. [25] Medical Association World. Declaration of Helsinki: recommendations guiding physicians in biomedical research involving human subjects. JAMA 1997;277:925–6. [26] World Health Organization Classification of Tumours. In: Tavassoli FA, Devilee P, editors. Pathology and genetics of tumours of the breast and female genital organs. Lyon: ARC Press; 2003. p. 218–30. [27] Sherman ME, Mazur MT, Kurman RJ. Benign diseases of the endometrium. In: Kurman RJ, editor. Blaustein's pathology of the female genital tract. New York: Springer-Verlag; 2002. p. 421–66. [28] Dreisler E, Stampe Sorensen S, Ibsen PH, Lose G. Prevalence of endometrial polyps and abnormal uterine bleeding in a Danish population aged 20–74 years. Ultrasound Obstet Gynecol 2009;33:102–8. [29] Nagele F. O'Connor H, Davies A, Badawy A, Mohamed H, Magos A. 2500 outpatient diagnostic hysteroscopies. Obstet Gynecol 1996;88:87–92.

62

D.Mª. Lubián López et al. / Gynecologic Oncology 133 (2014) 56–62

[30] Kremer C, Barik S, Duffy S. Flexible outpatient hysteroscopy without anaesthesia: a safe, successful and well tolerated procedure. Br J Obstet Gynaecol 1998;105:672–6. [31] Bakkum-Gamez JN, Laughlin SK, Jensen JR, Akogyeram CO, Pruthi S. Challenges in the gynecologic care of premenopausal women with breast cancer. Mayo Clin Proc 2011;86:229–40. [32] de Kroon CD, de Bock GH, Dieben SW, Jansen FW. Saline contrast hysterosonography in abnormal uterine bleeding: a systematic review and meta-analysis. BJOG 2003;110:938–47. [33] Gumus II, Keskin EA, Kiliç E, Aker A, Kafali H, Turhan NO. Diagnostic value of hysteroscopy and hysterosonography in endometrial abnormalities in asymptomatic postmenopausal women. Arch Gynecol Obstet 2008;278:241–4. [34] Antunes Jr A, Costa-Paiva L, Arthuso M, Costa JV, Pinto-Neto AM. Endometrial polyps in pre- and postmenopausal women: factors associated with malignancy. Maturitas 2007;20(57):415–21. [35] Costa-Paiva L, Godoy C, Antunes A, Caseiro J, Arthuso M, Pinto-Neto A. Risk of malignancy in endometrial polyps in premenopausal and postmenopausal women according to clinicopathologic characteristics. Menopause 2011;18:1278–82. [36] Hileeto D, Fadare O, Martel M, Zheng W. Age dependent association of endometrial polyps with increased risk of cancer involvement. World J Surg Oncol 2005;3:8. [37] Savelli L, De Iacco P, Santini D, et al. Histopathologic features and risk factors for benignity, hyperplasia, and cancer in endometrial polyps. Am J Obstet Gynecol 2003;188:927–31. [38] Fernandez-Parra J, Rodriguez Oliver A, Lopez Criado S, Parrilla Fernandez F, MontoyaVentoso F. Hysteroscopic evaluation of endometrial polyps. Int J Gynaecol Obstet 2006;95:144–8.

[39] Ben-Arie A, Goldchmit C, Laviv Y, et al. The malignant potential of endometrial polyps. Eur J Obstet Gynecol Reprod Biol 2004;115:206–10. [40] Duffy S, Jackson TL, Lansdown M, et al. The ATAC (Arimidex, Tamoxifen, Alone or in Combination) adjuvant breast cancer trial: first results of the endometrial subprotocol following 2 years of treatment. Hum Reprod 2005;110:1099–2006. [41] Bergman L, Beelen ML. GalleeMP, Hollema H, Benraadt J, van Leeuwen FE. Risk and prognosis of endometrial cancer after tamoxifen for breast cancer. Comprehensive Cancer Centres ALERT Group. Assessment of liver and endometrial cancer risk following tamoxifen. Lancet 2000;356:881–7. [42] Cohen I. Endometrial polyps in pre-and postmenopausal women: factors associated with malignancy. Maturitas 2008;20(59):99–100. [43] Coombes RC, Kilburn LS, Snowdon CF, et al. Survival and safety of exemestane versus tamoxifen after 2–3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomized controlled trial. Lancet 2007;369:559–70. [44] Mouridsen H, Giobbie-Hurder A, Goldhirsch A, et al. Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer. N Engl J Med 2009;361:766–76. [45] van de Velde CJ, Rea D, Seynaeve C, et al. Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trial. Lancet 2011;377:321–31. [46] Lubián López DM, González Fernández Y, Rodríguez Rodríguez B, Orihuela López FM, Comino Delgado R. Value of the progesterone test in screening for endometrial pathology in asymptomatic postmenopausal women receiving treatment with tamoxifen. Menopause 2010;17:487–93.