The natural history of endometrial polyps

Abstract

STUDY QUESTION

What is the natural history of endometrial polyps in women who are managed expectantly?

SUMMARY ANSWER

The growth rates of expectantly managed polyps vary considerably and cannot be accurately predicted.

WHAT IS KNOWN ALREADY

The majority of polyps detected on ultrasound are treated surgically, and therefore little is known about their natural history. Some polyps have been reported to regress spontaneously without the need for treatment; however, the factors predictive of regression are unknown.

STUDY DESIGN, SIZE, DURATION

This was a retrospective cohort study conducted at the Department of Gynaecology, University College London Hospitals. We searched our ultrasound clinic database between July 1997 and September 2015, to identify women aged 18 years or older with endometrial polyps that were managed expectantly for ≥6 months. All women attended for a minimum of two ultrasound scans.

PARTICIPANTS/MATERIALS, SETTING, METHODS

A single expert operator performed all ultrasound scans. Those with <6-month follow-up and those who were taking hormonal contraception, HRT or tamoxifen were excluded from the study. The mean diameter of each polyp was calculated from the measurements in three perpendicular planes. The polyp growth rate was expressed as annual percentage change in the mean diameter. Non-parametric tests and the Fisher's exact test were used to compare differences in polyp mean diameters and growth rates between women of different demographic characteristics. To correct for multiple significance testing, we used the Bonferroni method, giving the level of probability at which findings were considered significant as P < 0.0029 (as 17 tests were undertaken).

MAIN RESULTS AND THE ROLE OF CHANCE

We included 112 women with endometrial polyps, which were expectantly managed over a median period of 22.5 months (range, 6–136). The annual endometrial polyp growth rate varied with a median of 1.0% (interquartile range, −6.5 to 14.3). There was no association between women's demographic characteristics or polyps’ morphology and their growth rates. Eleven out of 75 (15% (95% CI, 6.9%−23.1%)) women who initially did not have abnormal uterine bleeding subsequently developed abnormal bleeding during the follow-up period. Polyp growth rate was not associated with the subsequent development of abnormal uterine bleeding (P = 0.397). Seven out of 112 (6.3% (95% CI, 1.8%−10.8%)) women had complete regression of their polyps without treatment during a median follow-up period of 28 months (range, 9–56). Spontaneous regression appeared to occur more frequently in premenopausal women (P = 0.016) and in those who presented with abnormal uterine bleeding at diagnosis (P = 0.004); however, the differences did not reach statistical significance after correction for multiple comparisons.

LIMITATIONS, REASONS FOR CAUTION

This study was retrospective and therefore may be prone to selection and information biases. The lack of histological confirmation on all ultrasound diagnoses may also be considered as a limitation.

WIDER IMPLICATIONS OF THE FINDINGS

Women should be advised that the growth pattern of an individual polyp cannot be accurately predicted; however, a small proportion of polyps do regress spontaneously. There was no correlation between polyps’ growth rate and the subsequent development of abnormal uterine bleeding. In view of that, routine monitoring of asymptomatic polyps by ultrasound is not helpful and encouraging women to report clinical symptoms is more useful in deciding whether treatment is required. In contrast to previous studies, we found that polyps may regress more frequently in premenopausal women and in those who presented with abnormal uterine bleeding; a larger sample size would give us greater power to detect a difference in these subgroups of women.

STUDY FUNDING/COMPETING INTERESTS

No study funding was received and no competing interests are present.

TRIAL REGISTRATION NUMBER

N/A

endometrial polyp, natural history, expectant management, polyp regression, ultrasound

Introduction

Endometrial polyp is defined as localized hyperplastic overgrowth of endometrial glands and stroma around a vascular core that project from the surface of the endometrium (Mutter et al., 2009). Prevalence of endometrial polyp varies depending on the population studied and the method used to detect polyps. In a randomly selected group of Danish women who were screened for endometrial polyps using saline hydrosonography (SHG), the prevalence of polyps was 7.8%. Polyps were rarely found in women younger than 30 years, and the peak prevalence was in postmenopausal women (Dreisler et al., 2009). Other authors confirmed that increasing age and the use of tamoxifen were the two most significant risk factors for the development of endometrial polyps (Nappi et al., 2009; Cohen, 2004). Obesity, hypertension and diabetes mellitus were reported to increase the risk of polyps, but Nappi et al. (2009) found that none of them is significant when women's age is taken into consideration.

Incidental finding of endometrial polyps is common; Hassa et al. (2006) reported that 44.4% of polyps in women of reproductive age and 36.1% in postmenopausal women are asymptomatic. Hyperplastic polyps and those with focal malignant changes are found in 1.7% in premenopausal and 5.42% postmenopausal women (Lee et al., 2010). These changes are less common in asymptomatic women in whom expectant management could be a safe management option (Gambadauro et al., 2015). However, in routine clinical practice, most polyps detected on imaging are surgically removed; hence, little is known of their natural history.

The main objective of this retrospective longitudinal study was to assess the variations in size of endometrial polyps that are managed expectantly over a long period of time. We tried to identify factors that are predictive of polyp's growth rate. We also looked at the spontaneous regression rates and tried to identify factors associated with polyps becoming symptomatic during follow-up.

Materials and Methods

This study was conducted at the Department of Gynaecology, University College London Hospitals. We retrospectively searched our ultrasound clinic database (PIA Fetal Database, version 2.23; Viewpoint Bildverarbeitung GmbH, Munich, Germany) between July 1997 and September 2015 to identify women aged 18 years or older with endometrial polyps that were managed expectantly for ≥6 months. All women were examined at least twice by a single expert ultrasound operator with a minimum interval of 6 months between the examinations. We excluded women who were using hormonal contraception, HRT or medications that affected the endometrium such as tamoxifen. In addition, we also excluded women who fell pregnant during follow-up.

In our practice, we routinely record the indications for examination, demographic data, gynaecological, obstetric and medical history in all women who presented to our clinic. All scans are performed in a standardized way. First, the cervix and uterine corpus are identified in the transverse plane. The uterine corpus is then assessed in a systematic way by examining a series of parallel scanning planes starting from the internal cervical os to the top of the uterine fundus. This facilitates the diagnosis of congenital and acquired uterine anomalies such as adenomyosis and fibroids. Endometrial polyps appear on ultrasound as focal hyperechoic lesions within the endometrial cavity. The ultrasound features of benign polyps are smooth and well-defined hyperechoic borders, single feeder vessel on Doppler examination and morphologically normal endometrium adjacent to the polyp (Valentin, 2014). The presence of a positive vascular pedicle sign improves the specificity of ultrasound diagnosis (Timmerman et al., 2003). Polyps with irregular surface, multiple feeding vessels, abnormal adjacent endometrium or signs of myometrial invasion are classified as potentially malignant, and they are not managed expectantly (Alcazar et al., 2003).

Polyp's size, position and vascular pattern on Doppler ultrasound are routinely recorded in our database. We defined the position of endometrial polyps only when a single pedicle vessel could be seen arising from the uterine wall. Each polyp was measured in three perpendicular planes in the longitudinal and transverse views of the uterus, and its maximum and mean diameters were recorded. In cases where multiple polyps were present, only the largest polyp for each woman was included in our analysis in order to ensure consistency of measurement during follow-ups. Follow-up examinations were conducted in the same way. We used SHG selectively to confirm the diagnosis of polyp in women with suspicious but not conclusive findings. Abnormal uterine bleeding was defined as women's subjective reporting of excessive menstrual blood loss, intermenstrual bleeding, irregular periods or postmenopausal bleeding. Women were considered symptomatic if they complained of abnormal uterine bleeding. Complete spontaneous regression was reported when a previously diagnosed endometrial polyp was no longer detectable on follow-up ultrasound examination in women who did not undergo any medical or surgical treatments that could result in removal of the polyp.

Statistical analysis

We used the measurements as recorded in our database at the time of examination to calculate the mean diameter (d_m) of endometrial polyps, d_m = (d₁ + d₂ + d₃)/3. Percentage change in polyp size (r) was calculated as r = ((d_m2 - d_m1)/d_m1) x 100% (where d_m1 and d_m2 are the mean diameters measured at times of t₁ and t₂, respectively), and annual percentage change in size (r_y) was calculated as r_y = (r/interval in months) x 12.

A database was created to facilitate data entry and retrieval (Excel 2011; Microsoft, Redmond, WA, USA). Data analysis was performed using SPSS 20.0 (SPSS Inc., Chicago, IL, USA). The distribution for polyp mean diameter and annual percentage growth in polyp size were examined using the Kolmogorov–Smirnov test for normality. The null hypothesis of the sample distributions being normal was rejected (P < 0.01); therefore, non-parametric tests were used. The Mann–Whitney rank-sum test was used to detect differences in polyp growth rate between two independent ordinal clinical variables, whereas the Kruskal–Wallis test was used when there were more than two variables. Age as an independent variable was normally distributed; the Student's t test was used. Categorical data displayed in the contingency tables were analysed using the Fisher's exact test. To correct for multiple significance testing, we used the Bonferroni method, giving the level of probability at which findings were considered significant as P < 0.0029 (as 17 tests were undertaken).

Results

A total of 3008 women were diagnosed with endometrial polyp at our institution between July 1997 and September 2015. Among them, 163 women were examined at least twice by a single, expert operator. Of note, 51 of 163 women were excluded for the following reasons: interval between the initial and follow-up scans was < 6 months (n= 16); the use of HRT (n = 15); polypectomy < 6 months from the initial scan (n = 12); the use of hormonal contraception (n = 4) and the use of tamoxifen (n = 4). Table I presents the indications for examination in the 112 women who were included in our study. One hundred eight of 112 women were analysed for polyps’ growth as 4 of 112 women were found to have no evidence of polyp at their first follow-up scan.

Table I

Primary indications for examination in the study population (n = 112).

Indication	n (%)
Ovarian cancer screening	22 (19.6)
Irregular menstrual bleeding	21 (18.8)
Pelvic pain	18 (16.1)
Suspected ovarian cyst	17 (15.2)
Postmenopausal bleeding	12 (10.7)
Suspected fibroid/other pelvic masses	9 (8.0)
Menorrhagia	4 (3.6)
Abdominal bloating	3 (2.7)
Subfertility	2 (1.7)
Others	4 (3.6)
Total	112 (100.0)

The mean age of women at the initial scan was 54.1 years (range, 25–93). Sixty-seven of 112 (60%) women were postmenopausal. The median examination interval between the initial and final scans was 22.5 months (range, 6–136); the majority of women (104/112, 93%) had a single polyp diagnosed at presentation. Twenty-one of 112 (19%) women were diagnosed with a recurrence of polyp following previous polypectomy.

There was no significant difference in the median diameter of polyps between 37/112 (33%) women who presented with abnormal uterine bleeding (median, 7.3 mm (interquartile range (IQR), 5.4–9.9)) and 75/112 (67%) women who did not have abnormal bleeding (median, 6.7 mm (IQR, 5.1–9.3)) (P = 0.453).

During the study period, the mean diameter of the polyps did not change significantly between the initial scan (median, 7.0 mm (IQR, 5.3–9.6)) and the final scan (median, 7.3 mm (IQR, 5.3–9.6)) (P = 0.589). The corresponding median yearly percentage change in the polyp diameter was 1.0% (IQR, −6.5 to 14.3). There was no significant difference in the polyp growth rates between women who presented with abnormal uterine bleeding and women who did not have abnormal bleeding (P = 0.503).

The effects of patients’ demographics and polyps’ morphological characteristics on polyps’ growth rates are summarized in Table II. There was no association between women's age, menopausal status, parity, presence of the pedicle sign on scan, polyp's position or size with polyps’ growth rates.

Table II

The effects of patients’ demographics and polyps’ morphological characteristics on polyps’ growth rates.

Patient/polyp characteristics	n (%)	Polyp's mean diameter (mm), median (interquartile range)		Growth rate (%/yr), median (interquartile range)	P
		At presentation	Final
Age (years)
≤45	28 (26)	8.0 (5.5 to 11.5)	8.9 (5.7 to 11.2)	0.2 (−11.2 to 18.4)	0.589
>45	80 (74)	6.3 (5.0 to 8.7)	7.0 (5.0 to 9.3)	1.0 (−5.4 to 12.2)
Menopausal status
Premenopausal	41 (38)	7.3 (5.5 to 10.4)	9.0 (5.9 to 11.2)	2.2 (−5.9 to 19.7)	0.373
Postmenopausal	67 (62)	6.3 (5.0 to 8.7)	7.0 (5.0 to 9.0)	0 (−6.6 to 11.3)
Parity
0	50 (46)	6.7 (5.0 to 9.0)	7.7 (5.3 to 10.3)	3.4 (−4.9 to 19.8)	0.150
≥1	58 (54)	7.15 (5.3 to 10.0)	7.0 (5.3 to 9.3)	−0.7 (−7.0 to 10.0)
Previous history of polyp
Yes	21 (19)	7.3 (6.0 to 9.0)	7.3 (5.85 to 9.2)	−2.8 (−7.1 to 14.9)	0.401
No	87 (81)	7.0 (5.0 to 9.7)	7.7 (5.0 to 11.0)	1.6 (−5.7 to 14.7)
Pedicle sign on ultrasound
Present	81 (75)	7.3 (5.7 to 9.9)	8.0 (5.7 to 11.0)	1.0 (−6.6 to 16.5)	0.944
Absent	27 (25)	6.0 (4.7 to 7.3)	5.3 (4.3 to 8.0)	0 (−6.6 to 12.5)
Polyp position
Fundal	26 (32)	7.0 (5.7 to 9.7)	8.0 (5.7 to 11.0)	0.5 (−5.7 to 19.8)	0.603
Anterior	22 (27)	8.2 (6.3 to 12.3)	9.2 (6.0 to 11.7)	−1.2 (−8.8 to 10.9)
Posterior	15 (19)	7.0 (4.7 to 11.7)	9.3 (5.7 to 11.3)	5.9 (−2.7 to 18.5)
Others	18 (22)	6.7 (5.3 to 9.0)	6.7 (5.3 to 9.0)	1.3 (−7 to 12.6)
Polyp size at diagnosis
≤10 mm	84 (78)	6.0 (5 to 7.3)	6.5 (5 to 8.7)	1.0 (−6.4 to 15.9)	0.542
>10 mm	24 (22)	12.3 (11.3 to 15)	12.9 (9.5 to 14.9)	0 (−7.2 to 13.8)

Seventy five out of 108 (69%) women did not complain of abnormal uterine bleeding at the time of polyps’ diagnosis. However, during the follow-up period, 11 of 75 (15%) women later developed abnormal bleeding. Patients’ demographics and polyps’ morphological characteristics according to the development of abnormal bleeding are summarized in Table III. Comparing women who became symptomatic and those who remained asymptomatic there was no significant difference in their age, menopausal status, presence of the pedicle sign on scan, polyps’ size or growth rate.

Table III

Comparison of patients’ demographic and polyps’ morphological characteristics between women who remained asymptomatic and those who became symptomatic of abnormal uterine bleeding during the follow-up period.

Patient/polyp characteristics	Remained Asymptomatic (n = 64)	Became Symptomatic (n = 11)	P
Age	56.6 (53.3 to 59.9)+	50.5 (43.8 to 57.3)+	0.167
Menopausal status
Premenopausal (%)	19 (30)	6 (55)	0.164
Postmenopausal (%)	45 (70)	5 (45)
Pedicle sign on ultrasound
Present (%)	45 (70)	10 (91)	0.269
Absent (%)	19 (30)	1 (9)
Polyp mean diameter at presentation (mm)	6.3 (5.0 to 9.5)*	7.7 (6.3 to 9.3)*	0.252
Polyp growth rate (%/yr)	1.9 (−5.8 to 19.8)*	−4.0 (−6.2 to 12.6)*	0.397

⁺mean (95% confidence interval)

^*median (interquartile range)

Seven women in total had spontaneous regression of their polyps; this included four women who received two scans and three women who received multiple scans. The observed regression rate was 7/112 (6.3% (95% CI 1.8–10.7)). Table IV summarizes the comparison of patients’ and polyps’ characteristics between regressed and persisted polyps. On bivariate analysis, spontaneous regression of polyps appeared to occur more frequently in premenopausal women (P = 0.016) and in those who presented with abnormal uterine bleeding (P = 0.004); however, the differences did not reach statistical significance after Bonferroni correction.

Table IV

Comparison of patients’ demographic and polyps’ morphological characteristics between polyps that persisted during the follow-up period and those who underwent complete spontaneous regression.

Patient/polyp characteristics	Polyp persisted (n = 105)	Polyp regressed (n = 7)	Pa
Age	54.8 (52.2–57.3)+	43.7 (39.0–48.4)+	0.017
Menopausal status
Premenopausal (%)	39 (37)	6 (86)	0.016
Postmenopausal (%)	66 (63)	1 (14)
Parity
0 (%)	48 (46)	4 (57)	0.703
≥1 (%)	57 (54)	3 (43)
Symptomatic of abnormal uterine bleeding at presentation
Symptomatic (%)	30 (29)	6 (86)	0.004
Asymptomatic (%)	75 (71)	1 (14)
Mean diameter of polyp at presentation (mm)
≤10 mm (%)	82 (78)	6 (86)	1.000
>10 mm (%)	23 (22)	1 (14)

^aAfter Bonferroni correction for 17 comparisons, the threshold for statistical significance is P < 0.0029.

⁺mean (95% confidence interval).

All statistical analysis based on polyps’ mean diameter was also repeated using polyps’ volume; this assumed all polyps to be ellipsoid in shape, polyp volume = 4/3 x π x d₁ x d₂ x d₃. The results obtained were not significantly different whether polyps’ volume or mean diameter was used. We decided to present our results in polyps’ mean diameter, because not all polyps were ellipsoid in shape. Clinically, it is also more convenient to measure polyp's mean diameter rather than calculating its volume.

Nine out of 105 (9%) women with persisted polyps underwent hysteroscopic polypectomy at the end of the study period. The diagnosis of benign endometrial polyp was confirmed in all women on histological examination.

Discussion

Summary of the main results

Our results showed that endometrial polyp growth rate varied considerably among women who were managed expectantly; while some polyps may grow in size, others spontaneously regress over time. Women's age, menopausal status, sizes of the polyp or its location within the endometrial cavity were not predictive of individual polyp's growth.

Quality of the study

This was a retrospective study and therefore may be prone to selection and information biases. The lack of histological confirmation on ultrasound diagnoses could also be considered as a limitation. However, the majority (84/112, 75%) of our polyps demonstrated the positive pedicle sign that has a high positive predictive value for the presence of endometrial polyp (Timmerman et al., 2003). Alcazar et al. (2004) prospectively compared the performance of transvaginal ultrasound with colour Doppler (TVCD) versus SHG and showed that TVCD had an equal positive predictive value compared to SHG when the typical appearance of polyp and the pedicle artery sign are present. It is also reassuring that the diagnosis of benign endometrial polyp was confirmed in all women who underwent surgical excision of polyps. The strength of our study lies in the large cohort size of women and the long follow-up period. All ultrasound examinations were performed by a single expert operator, which reduces the risk of error due to inter-observer variability.

Agreement and disagreement with previous research

Prolonged and unopposed oestrogen exposure has traditionally been considered as a contributor to the development of endometrial polyps. This is supported by an immunohistochemistry study that showed an increased expression of oestrogen receptors in endometrial polyps (Maia et al., 1998). However, our study did not find women's age or menopausal status significantly affected the growth rate of polyps, suggesting not all polyps are hormone dependent. Some studies have shown that the development of polyps could be due to a dysregulation of apoptosis (Taylor et al., 2003; McGurgan et al., 2006). These possibly non-oestrogen–dependent polyps may differ in their behaviour and malignant potential compared to oestrogen-related polyps. In view of a likely multifactorial pathogenesis of endometrial polyps, the growth pattern of an individual polyp can be difficult to predict (Indraccolo et al. 2013).

Current management of endometrial polyp is largely dependent on whether women are symptomatic of abnormal uterine bleeding (Salim et al., 2011). Hassa et al. (2006) reviewed 155 women retrospectively and found that there was no association between symptoms and polyp's size (P = 0.334), site (P = 0.699) or number (P = 0.677) in both premenopausal and postmenopausal women. In our study, we analysed 75 women who were initially asymptomatic of abnormal uterine bleeding. Subsequently, 11 of 75 (15%) women became symptomatic over a median period of 21 months (range, 10–59). We found no association between the development of abnormal uterine bleeding and polyps’ growth rate. In other words, routine ultrasound scans to monitor polyps’ growth could not be used to predict the onset of symptoms. This finding supports the clinical rationale to encourage women with asymptomatic polyps to report symptoms rather than having routine ultrasound scans to monitor polyp's growth. In young and asymptomatic women, the risk of malignant endometrial polyp is low (Gambadauro et al., 2015); but it remains to be determined whether ultrasound monitoring of asymptomatic polyps in postmenopausal women can predict malignancy potential.

Spontaneous complete regression of endometrial polyps has previously been reported. DeWaay et al. (2002) prospectively assessed seven women with asymptomatic polyps. SHG was performed both at the time of diagnosis and after a follow-up period of 2.4–2.7 years. A significant number of polyps, 4 of 7 (57.1%) women had completely regressed and were undetectable on subsequent scans. Lieng et al. (2009) also prospectively assessed 31 women aged between 45 and 50 years with symptomatic and asymptomatic polyps; SHG were performed 12 months apart, and they reported a complete regression rate of 27%. In addition, smaller polyps (mean diameter, 10.7 mm) were found to regress more frequently compared to larger polyps (mean diameter 15.1 mm).

Polyp regression was not merely observed in ultrasound. Haimov-Kochman et al. (2009) described the ‘vanishing’ of three polyps measuring 5–8 mm in sizes in women attending for repeat hysteroscopies. However, this observation may be partly related to the trauma caused during hysteroscopies.

In our study, the polyp regression rate was 6.3% during a median follow-up period of 28 months (range, 9–56). Although statistical significance was not reached, polyps appeared to regress more frequently in premenopausal women (P = 0.016) and in those who presented with abnormal uterine bleeding (P = 0.004). When symptomatic polyps were examined microscopically, ischaemic tissue necrosis was more frequently observed at the apical portion compared to the same area in asymptomatic polyps. This is thought to be due to thrombosis in subsurface terminal vessels or in the feeding vessel (Ferenczy, 2003). This histological observation may explain why some symptomatic polyps may be more likely to regress compared to asymptomatic polyps.

In contrast to Lieng et al. (2009), we did not find that the size of endometrial polyps was predictive of spontaneous regression. Overall, our rate of complete regression was lower compared to DeWaay et al. (2002) and Lieng et al. (2009). This may be explained by our older study population that included a higher number of postmenopausal women.

Implications for practice

Women should be advised that the growth pattern of an individual polyp cannot be accurately predicted; however, a small proportion of polyps do regress spontaneously. The use of ultrasound to monitor asymptomatic polyp's size routinely is not recommended as it does not inform whether women would become symptomatic of abnormal uterine bleeding.

Implications for research

Future prospective studies are needed to evaluate our findings. A larger sample size of spontaneously regressed polyps should be included to assess the predictive factors for polyp regression. Furthermore, the role of expectant management should also be examined in premenopausal women who are symptomatic of abnormal uterine bleeding.

Conclusion

We conclude that the growth rates of expectantly managed endometrial polyps varied considerably and were not determined by women's age or menopausal status. We found no association between polyps’ growth rate and the development of abnormal uterine bleeding. A small proportion of polyps can undergo spontaneous regression; this may be occurring more frequently in premenopausal women and in those who presented with abnormal uterine bleeding.

Authors’ roles

D.J. and M.W. conceived and designed the study. M.W., B.C., V.L. and K.R. collected the data. M.W. and D.J. analysed the data and wrote the article. All authors approved the final manuscript.

Funding

No external funding was either sought or obtained for this study.

Conflict of interest

None declared.