Concurrent and future risk of endometrial cancer in women with endometrial hyperplasia: A systematic review and meta-analysis.

BACKGROUND: To inform treatment decisions in women diagnosed with endometrial hyperplasia, quantification of the potential for concurrent endometrial cancer and the future risk of progression to cancer is required.
METHODS: We identified studies up to September 2018 that reported on the prevalence of concurrent cancer (within three months of endometrial hyperplasia diagnosis), or the incidence of cancer, identified at least three months after hyperplasia diagnosis. Random-effects meta-analyses produced pooled estimates and 95% confidence intervals (CIs).
RESULTS: A total of 36 articles were identified; 15 investigating concurrent and 21 progression to cancer. In pooled analysis of 11 studies of atypical hyperplasia, the pooled prevalence of concurrent endometrial cancer was 32.6% (95% CI: 24.1%, 42.4%) while no studies evaluated concurrent cancer in non-atypical hyperplasia. The risk of progression to cancer was high in atypical hyperplasia (n = 5 studies, annual incidence rate = 8.2%, 95% CI 3.9%, 17.3%) and only one study reported on non-atypical hyperplasia (annual incidence rate = 2.6%, 95% CI: 0.6%, 10.6%).
CONCLUSIONS: Overall, a third of women with atypical hyperplasia had concurrent endometrial cancer, although the number of studies, especially population-based, is small. Progression to cancer in atypical hyperplasia was high, but few studies were identified. Population-based estimates are required, in both atypical and non-atypical hyperplasia patients to better inform treatment strategies.

Introduction

Endometrial cancer is the 6th most commonly diagnosed cancer in women worldwide, with the highest rates observed in developed countries, including the United States and Europe [1]. The incidence of endometrial cancer has increased in many countries over the past few decades [2], a trend which is hypothesized to be due to the rising prevalence of obesity, as well as shifts in female reproductive patterns [3]. Although there are currently no well-established screening programs for endometrial cancer, endometrial hyperplasia is a recognized precursor lesion of the most common type of endometrial cancer (endometrioid) and its detection offers opportunities for prevention [4].

Endometrial hyperplasia is diagnosed histologically in the presence of a proliferation of the endometrial glands resulting in an increase in gland-to-stroma ratio [5]. While endometrial hyperplasia can progress to endometrial cancer, the rate of progression depends on factors such as the degree of architectural abnormality and the presence or absence of nuclear atypia [6]. It is well-established that progression to endometrial cancer is higher in women with atypical compared with non-atypical hyperplasia but the magnitude of this risk is uncertain [7, 8], as most published studies have been conducted in single-center and tertiary referral centers which could overestimate risk in comparison to population-based studies. Endometrial hyperplasias (and even low-grade endometrioid cancers) can be conservatively managed by hormone therapies (e.g. oral and/ or intrauterine progestogens), especially among women who wish to maintain fertility. Currently if fertility preservation is not an issue, hysterectomy is generally recommended for women with atypical hyperplasia, due to the presumed significant risk of concurrent future endometrial cancer, and for women with persistent non-atypical hyperplasia [9, 10]. Accurately quantifying endometrial cancer risk in women diagnosed with endometrial hyperplasia is therefore crucial to inform shared decision making regarding the most appropriate clinical management strategies.

Recent clinical guidelines recommend that in women with endometrial hyperplasia who undergo conservative medical (non-surgical) management, endometrial biopsy should be undertaken at least every three months, until two consecutive negative biopsies are obtained, especially in patients with atypical hyperplasia[10]. A diagnosis of endometrial cancer within the first three months of an incident hyperplasia diagnosis is likely to reflect a concurrent finding that was missed at the initial investigation due to undersampling or was underdiagnosed by the reporting pathologist. Previous studies evaluating the prevalence of concurrent endometrial cancer in women with endometrial hyperplasia have reported wide-ranging estimates of between 30–50% [11-13]. However, prior systematic reviews have been restricted to women with atypical hyperplasia [11] and the results cannot be extrapolated to women diagnosed with the more common non-atypical endometrial hyperplasia (i.e. simple or complex hyperplasia using the 2003 World Health Organization (WHO) Classification [14]). The potential for concurrent endometrial cancer in women diagnosed with endometrial hyperplasia raises questions around the need for specialist pathology review, further endometrial sampling and/or hysterectomy in these patients, in addition to the identification of biomarkers that could assist in identifying those cases of endometrial hyperplasia which have the highest risk of concurrent cancer.

The aim of this study was to systematically review all studies which assessed the concurrent and future risk of endometrial cancer in women diagnosed with endometrial hyperplasia.

Materials and methods

This systematic review was undertaken and reported in adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the Meta‐analysis of Observational Studies in Epidemiology (MOOSE) guidelines [15]. Three electronic databases including MEDLINE, EMBASE, and Web of Science were searched from 1994 up to September 2018 for relevant studies using a search‐construct adapted for each database, see S1 Appendix. The databases were searched from 1994 as the WHO Classification of endometrial hyperplasia was established in that year based on criteria suggested by Kurman et al. [6].

Review articles, animal studies and articles written in languages other than English were excluded.

Inclusion criteria

Titles and abstracts of identified articles were independently screened by at least two of four researchers (OBS, MTD, HGC, ÚMcM). At least two of the four reviewers then independently screened full texts to identify studies that met the pre-set inclusion criteria:

Participants: Women aged 18 and above who have received a diagnosis of endometrial hyperplasia

Interventions: Report on risk of concurrent or future diagnosis of endometrial cancer, including the timeframes for follow-up. Endometrial cancer diagnosed within three months of a diagnosis of endometrial hyperplasia was categorized as concurrent disease while cancer diagnosed more than three months following endometrial hyperplasia diagnosis was regarded as disease progression. The three month cut-off timeline was chosen to account for diagnostic work-up [10].

Comparators: Women aged 18 and above without a concurrent diagnosis of cancer or who did not progress to endometrial cancer

Outcome: Risk of endometrial cancer

For a study to be eligible for inclusion, it had to include a minimum of 10 cases of endometrial hyperplasia to help ensure the inclusion of meaningful estimates of concurrent cancer risk or progression to cancer. Bibliographies of included studies were also reviewed. Any discrepancies throughout were discussed and resolved by agreement.

Data extraction

Relevant information about study design, number of cases, controls, age and menopausal status of the study population, initial investigation method, cancer diagnosis method, WHO endometrial hyperplasia classification, intervention/ treatments received, time between diagnosis and treatment, and follow-up time were extracted in duplicate from full text articles. The Newcastle Ottawa Scale [16] was used to derive a quality score for each of the studies included in the review.

Statistical analysis

Statistical analyses were conducted using STATA version 14. The proportion of prevalent endometrial cancer diagnosed in patients with endometrial hyperplasia was converted to a log odds along with corresponding 95% confidence intervals (CIs), the random effects model was applied and the pooled log odds and 95% CIs back-transformed [17]. Incidence rates of endometrial cancer were calculated for studies that examined endometrial hyperplasia progression to endometrial cancer based upon the number of cases and the person years within each study, from multiplying the number of endometrial hyperplasia cases by the mean (two studies) or median (eight studies) follow-up time. Similarly, incidence rates were converted to the log incidence rates and corresponding 95% CIs and random effects meta-analysis was applied. Heterogeneity of studies included in meta-analyses were assessed using the I2 statistic [18]; I2 values of 25%, 50% and 75% are typically interpreted as low, moderate and high heterogeneity, respectively. Sub-group analyses were planned by type of hyperplasia and where possible, by menopausal status and method of hormone therapy administration. Separate sensitivity analyses were performed restricting to studies with a quality score of less than five and more than or equal to five and by systematically removing each study in turn in order to determine its effect on the overall pooled estimates. We conducted additional sensitivity analyses investigating the impact of duration of follow-up in studies of endometrial hyperplasia progression to endometrial cancer (less than 24 months average follow-up, more than or equal to 24 months average follow-up). It was impossible to calculate rates per 1,000 person-years in 11 studies of future risk of endometrial cancer due to unavailability of information regarding follow-up and the results from these studies were narratively summarized. Publication bias was evaluated using a funnel plot, showing the standard error of log incidence against each study’s prevalence or incidence rate.

Results

After application of our search strategy, and removal of duplicates, a total of 1,587 titles and abstracts were reviewed to determine potentially relevant studies for inclusion. After title and abstract review, 148 full text and abstracts were reviewed, of which 70 were excluded (see Fig 1). A further 44 articles that assessed endometrial cancer risk were excluded as it was unclear whether cancer was identified within three months of endometrial hyperplasia diagnosis. Results from these 44 studies are outlined in S1 Table and S2 Table; S1 Table details 21 studies in which it was unclear if endometrial cancer was diagnosed within three months of hyperplasia diagnosis while S2 Table lists 23 studies that investigated concurrent endometrial cancer according to the author’s own definitions, but did not report the time between endometrial biopsy and hysterectomy. Four further articles were identified for inclusion from review of reference lists. Two articles from the supplementary material did not meet the inclusion criteria for concurrent endometrial cancer; however, they were included in the review as they met the inclusion criteria for incident endometrial cancer. This left a total of 36 articles included, see Fig 1.

Fig 1

Flow diagram of study selection for the systematic review of prevalence of concurrent and risk of future endometrial cancer among patients with endometrial hyperplasia.

*Two articles outlined in the supplementary material did not meet the criteria for inclusion in the concurrent endometrial cancer investigation but were included in the review as they met the inclusion criteria for the incident endometrial cancer investigation. EC = endometrial cancer, EH = endometrial hyperplasia.

Characteristics of the included studies are outlined in Tables 1–3. Fifteen of the included articles assessed concurrent endometrial cancer (Table 1) and 21 assessed the risk of future endometrial cancer in women with endometrial hyperplasia (Tables 2 and 3). Fifteen studies were conducted in Europe, 12 in Asia, eight in North America (one study included patients from the US and Europe) and one in Australia. The majority of studies were single or two center studies, and only one study was population-based. Endometrial biopsy or dilatation and curettage was the most common method of endometrial hyperplasia diagnosis; however, some studies used other methods such as hysteroscopic resection [19]. Most studies were classified as being of low-to-moderate quality, with quality scores ranging from four to six out of a total of nine.

Table 1

Characteristics of studies which assessed the prevalence of concurrent endometrial cancer in women with endometrial hyperplasia (n = 15).

Author, Year Location	Study population	Study design	Recruitment period	No. EH cases	No EC cases	% concurrent EC	Age (mean) (SD)	Method of initial investigation	Time from biopsy to hysterectomy	EH investigated	Quality score
Agostini, 2003 France [19]	Hôspital la Conception	Single-center retrospective cohort	1994–2001	17	1	5.9	54.4	Hysteroscopic resection	3 weeks	AH	4
Bilgin, 2004 Turkey [20]	Uludag University Hospital	Single-center retrospective cohort	Not reported	46	11 (1 SH, 10 CAH)	23.9	48.9 (8.3)	D&C, pipelle biopsy	Within 6 weeks	AH	4
Dolanbay, 2015 Turkey [21]	Erciyes University	Single-center retrospective cohort	2009–2013	82 (40 CAH, 13 SAH, 20 SH, 9 CH)	39 (28 CAH, 7 SAH, 4 CH)	47.5	54 (8.7)	Pipelle biopsy, D&C	< 6 weeks	All	4
Gungorduk, 2014 Turkey [22]	Tepecik Hospital, Bulent Ecevit University, Sisli Etfal Hospital, Istanbul Education & Research Hospital	Multicenter retrospective cohort	1996–2003	128	68	53.1	54.2 (30–82)	Pipelle biopsy, D&C	2 weeks (median, range 1–4)	CAH	4
Hahn, 2010 Korea [23]	Cheil General Hospital and Women’s Healthcare Center	Two-center retrospective cohort	1999–2008	126 (24 SAH, 102 CAH)	13	10.3	45.4 (6.6)	D&C, biopsy, hysteroscopic polypectomy	< 12 weeks	AH	4
Karamursel, 2005 Turkey [24]	Ankara Maternity & Women’s Health Teaching Hospital, Hacettepe University Hospital	Two-center retrospective cohort	1990–2003	204 (56 AH, 148 NAH)	43 (35 AH, 8 NAH)	21.1	57.4 (range 28–87)	D&C	Within 1 month	All	5
Kimura, 2003 Japan [25]	Osaka Medical Center for Cancer and Cardiovasucular Diseases.	Single-center retrospective cohort	1992–2002	33	9	27.3	51.7 (EC cases) 50.0 (EC non- cases)	Biopsy	8 weeks	AH	4
Lai, 2014 Taiwan [26]	National Defense Medical Center, Taipei	Single-center retrospective cohort	Not reported	61	14	23	Not reported	Biopsy	Within 3 months	AH	4
Merisio, 2005 Italy [27]	University of Parma, Policlinico san Matteo Hospital	Two–center retrospective cohort	1992–2003	70	30	42.9	55.5 (11.9) (range 38–80)	Pipelle biopsy, D&C	2–8 weeks	AH	4
Morotti, 2012 Italy [28]	San Martino Hospital	Single-center retrospective cohort	2000–2011	66	35	53	58.5 (median, range 34–76)	Biopsy, D&C, pelvic lymph node dissection	< 6 weeks	AH	4
Mutter, 2008 USA [29]	Gynecologic Oncology Group trial 167A	Multicenter retrospective cohort	1998–2003	289	124	42.9	Not reported	Pipelle biopsy, D&C	Within 3 months	AH	5
Pavlakis, 2010 Greece [30]	IASO Women’s Hospital	Single-center retrospective cohort	Not reported	83 (4 SH, 19 CH, 27 CAH)	33 (31 CAH, 2 CH)	39.7	35–67 (range)	D&C	Within 12 weeks	SH, CH, CAH	4
Rakha, 2012 UK [31]	Nottingham University Hospital	Single-center retrospective cohort	1987–2011	219	59	27	Not reported	Biopsy	Within 3 months	AH	4
Salman, 2010 Turkey [32]	Hacettepe University Hospital	Single-center retrospective cohort	2007–2009	49 (3 SAH, 12 CH, 34 CAH)	9 (CAH)	18.4	51.5 (range 36–79)	Biopsy	Within 2 weeks	All	4
Valenzuela, 2003 Spain [33]	University Hospital Principe de Asturias	Single-center retrospective cohort	1988–2001	23	12	52.2	52 (range 30–83)	Biopsy, fractional curettage	10.5 weeks	AH	4

EH- endometrial hyperplasia, EC- endometrial cancer, AH- atypical hyperplasia, SH-simple hyperplasia, CAH- complex atypical hyperplasia, D&C- dilation and curettage, SAH- simple atypical hyperplasia, CH-complex hyperplasia, NAH- non-atypical hyperplasia

Table 3

Characteristics of studies which assessed the risk of future endometrial cancer in women with endometrial hyperplasia which did not report mean or median follow-up and for which rates per person-years calculations were not possible (n = 11).

Author, Year Location	Study population	Study design	Recruitment period	No. EH cases	No EC cases	% progression	Age (mean)	Method of initial investigation	Method of follow-up investigation	Follow-up time	EH investigated	Quality score
Anastasiadis, 2000 Greece [44]	General Hospital of Alexandroupolis	Single-center retrospective cohort	1986–1998	294 (258 NAH, 36 AH)	4 (1 SH, 2 CH, 1 AH)	1.4	Not reported	D&C, hysteroscopy	D&C	At least 6 months	All	4
Chen, 2016 China [45]	Peking Union Medical College Hospital	Single-center retrospective cohort	2000–2011	16	2	12.5	20–42 (range)	Biopsy, D&C, hysteroscopy	Hysterectomy	At least 3 months	CH	5
Hecht, 2005 Israel [46]	Beth Israel Hospital	Single-center retrospective cohort	1998–2000	84 (21 CAH, 15 CH, 48 SH)	8 (5 CAH, 2 CH, 1 SH)	9.5	Not reported	Biopsy, D&C	Hysterectomy, endometrial sampling or clinical follow-up	Not reported	All	4
Inversen, 2018 Denmark [47]	Regional Hospital Holstebro, Aarhus University Hospital	Two-center retrospective cohort	2000–2005	114	17	14.9	59.1	Biopsy, D&C, Trans cervical hysteroscopic endometrial resection	Hysterectomy	9–14 years	CH	5
Lacey, 2008 USA [48]	Kaiser Permanente Northwest	Population-based nested case-control	1970–2003	368 (127 cases and 241 controls)	127	Not applicable	52	Biopsy, D&C	Hysterectomy	6.7 years (median, range 1–24.5)	All	7
Minig, 2011 Italy [49]	European Institute of Oncology, Milan	Single-center prospective cohort	1996–2009	20	1	5	Not reported	Pipelle biopsy, D&C, hysteroscopy	Hysterectomy	At least 6 months	AH	5
Orbo, 2000 Norway [50]	Northen Norway	Multicenter retrospective cohort	Not reported	68 (9 SH, 10 CH, 13 SAH, 36 CAH)	18 (1 CH, 1 SAH, 16 CAH)	26	28–77 (range)	D&C	Hysterectomy	10–20 yearsa	All	5
Simpson, 2014 Canada [51]	Princess Margaret Hospital and Odette Cancer Center	Two-center retrospective cohort	2000–2011	19	6	31.6	All <45	Biopsy, D&C	Hysterectomy	39 months (median, range 5–128)b	CAH	5
Tabata, 2001 Japan [52]	Yamada Red Cross Hospital	Single-center prospective cohort	1989–1996	77 (48 SH, 17 CH, 1 SAH, 11 CAH)	1 (CAH)	1.3	47.2 (SH), 46.6 (CH), 52.0 (SAH), 47.9 (CAH)	D&C	D&C	At least 1 year	All	4
Ushijima, 2007 Japan [53]	Japan Gynecologic Cancer Study Group	Multicenter prospective trial	Not reported	17	2	11.8	20–39 (range)	D&C	Hysterectomy	At least 8 weeks	AH	5
Wheeler, 2007 USA [54]	Johns Hopkins Hospital	Single-center retrospective cohort	Not reported	18	2	11.1	34 (median, range 24–47)c 61 (median, range 50–77)d	Biopsy, D&C	Biopsy, hysterectomy	3–25 months	CAH	4

EH- endometrial hyperplasia, EC- endometrial cancer, AH- atypical hyperplasia, SH-simple hyperplasia, CAH- complex atypical hyperplasia, D&C- dilation and curettage, SAH- simple atypical hyperplasia, CH-complex hyperplasia, TVUS- transvaginal ultrasound scan, NAH- non-atypical hyperplasia

a Follow-up is among EH patients who developed endometrial cancer

b Follow-up time also includes grade 1 EC patients (n = 25)

c Premenopausal women

d Postmenopausal women

Table 2

Characteristics of studies which assessed the risk of future endometrial cancer in women with endometrial hyperplasia and for which rates per person-years were calculated (n = 10).

Author, Year Location	Study population	Study design	Recruitment period	No. EH cases	No EC cases	% progression	Rates per 1000 person-years	Age (mean) (SD)	Method of initial investigation	Method of follow-up investigation	Follow-up time	EH investigated	Quality score
Baak 2005 Europe/USA [34]	6 European centers, 2 US centers	Multicenter prospective cohort	Not reported	477 (289 SH, 65 CH, 67 SAH, 56 CAH)	264 (2 SH, 6 CH, 5 SAH, 11 CAH)	5	12.6	Not reported	Biopsy, D&C	Biopsy	48 months (median) (range 13–120)	All	6
Brownfoot, 2014 Australia [35]	Royal Women’s Hospital, Melbourne	Single-center retrospective cohort	1999–2012	42a	2a	4.8a	23.8a	Premenopausal: 37 years (7.6)	Biopsy, hysteroscopy	Hysteroscopy, biopsy, hysterectomy	24 months (median)a,36 months (median)b	CAH	5
				19b	6b	31.6b	105.3b	Postmenopausal: 61 years (11.4)
Edris, 2007 Canada [36]	University of Western Ontario	Single-center prospective cohort	1990–2005	16	1	6.3	12.5	24–78 (range)	Hysteroscopy	Hysteroscopy, hysterectomy	5 years (median, range 1.5–12)	AH	5
Gallos, 2013 UK [37]	Birmingham Women’s Hospital	Single-center comparative study	1998–2007	250c	6c	2.4c	4.3c	52.7 (10.6)c	Biopsy	Hysterectomy	66.9 months (median, range 12–148.2)c, 87.2 months (median, range 13.2–162)d	CH, CAH	5
				94d	4d	4.3d	5.9d	48.5 (11.6)d
Garuti, 2005 Italy [38]	Lodi Hospital	Single-center prospective cohort	1997–2003	24 (20 SH, 4 CH)e	2 (1 SH, 1 CH)	8.3	26.3	62.3 (8.7)f	Hysteroscopy, biopsy	Hysterectomy	38 months (median, range 12–60)	SH, CH	5
Gonthier, 2015 France [39]	French gynecological units	Multicenter retrospective cohort	2001–2013	32	9	13.2	70.3	34 (33.6)	Biopsy D&C	Biopsy D&C	48 months (mean, range 7–121)	AH	4
								(range 23–42)
Horn, 2004 Germany [40]	University of Leipzig	Single-center retrospective cohort	Not reported	215 (208 CH, 7 AH)	5 (2 CH, 3 AH)	2.3	58.1	Not reported	Fractional curettage	Fractional curettage	4.8 months (median, range 3–22 months)	CH, AH	5
Mentrikoski, 2012 USA [41]	University of Virginia, and Emory University	Two-center retrospective cohort	Not reported	18	3	16.7	133.3	38 (range,	Biopsy, D&C	Hysterectomy	15 months (mean)	CAH	5
								25–39)a 57 (range, 50–74)b
Steinbakk, 2011 Norway [42]	Stavanger University Hospital	Single-center retrospective cohort	1980–2004	152 (114 SH, 4 SAH, 26 CH, 8 CAH)	11 (4 SH, 1 SAH, 2 CH, 4 CAH)	7.2	15.2	53 years (range 21–88)	D&C	Not reported	57 months (median, range 12–283)	All	4
Tierney, 2014 USA [43]	Los Angeles County + USC Medical Center	Single-center retrospective cohort	2003–2011	61	6	9.8	287.9	72% were <40 years old.	Biopsy	Biopsy	4.1 months (median, range 1.1, 29.2)	CAH	4

EH- endometrial hyperplasia, EC- endometrial cancer, AH- atypical hyperplasia, SH-simple hyperplasia, CAH- complex atypical hyperplasia, D&C- dilation and curettage, SAH- simple atypical hyperplasia, CH-complex hyperplasia, NAH- non-atypical hyperplasia

a Premenopausal women

b Postmenopausal women

cLNG-IUS (levonorgestrel intrauterine system) treated group

d Oral progesterone-treated group

e Cohort comprises patients with a prior diagnosis of breast cancer

f Includes two patients who underwent hysterectomy after EH diagnosis

g Patients received first post-treatment biopsy after at least 3 months of progestin therapy.

Proportion of concurrent endometrial cancer diagnosed in women with endometrial hyperplasia

The prevalence of endometrial cancer diagnosed in endometrial hyperplasia patients was assessed in 15 studies [19-33] including 1,496 women (range 17–289), Table 1. The majority of studies investigated atypical hyperplasia only (n = 11) [19, 20, 22, 23, 25–29, 31, 33] and four studies investigated any type of hyperplasia [21, 24, 30, 32]. Hysterectomy was the method of follow-up investigation in all studies. None of the identified studies evaluated concurrent endometrial cancer in women with non-atypical hyperplasia only. The prevalence of concurrent endometrial cancer diagnosed within three months of an endometrial hyperplasia diagnosis ranged from 5.9% to 53.1%.

The overall pooled proportion of concurrent endometrial cancer in all 15 studies was 32.1% (95% CI: 26.1%, 40.0%) and high heterogeneity (I2 = 87.6%) was observed (Fig 2). In a pooled analysis of 11 studies, the pooled proportion of concurrent endometrial cancer in women with atypical hyperplasia was 32.6% (95% CI 24.1%, 42.4%) and high heterogeneity was observed (I2 = 87.9%), as shown in Fig 2. A slightly lower proportion concurrent endometrial cancer was observed after pooling the four studies that included a mixture of atypical and non-atypical hyperplasia (30.8%, 95% CI: 18.6%, 46.4%) but heterogeneity was high (I2 = 88.3%). The funnel plot for studies evaluating concurrent endometrial cancer did not appear to show any strong evidence of a lack of symmetry and therefore was not indicative of publication bias (S1 Fig).

Fig 2

Forest plot of proportion of concurrent endometrial cancer diagnosed within three months of endometrial hyperplasia diagnosis.

Sensitivity and subgroup analysis

Results remained similar, and heterogeneity remained high, in sub-group analysis by study quality and in sensitivity analyses excluding individual studies, see S3 Table. All studies included both pre and postmenopausal women (three studies did not specify [22, 26, 29]) but there were too few stratified results by menopausal status to allow the conduct of sub-group analysis.

Risk of future endometrial cancer diagnosis in women with endometrial hyperplasia

A total of 21 studies including 2,495 women assessed the risk of future endometrial cancer in women with endometrial hyperplasia [34-54], see Tables 2 and 3. Nine of the studies [35–38, 45, 46, 50, 51, 54] investigated atypical hyperplasia only, three investigated non-atypical hyperplasia [39, 43, 44], while nine studies investigated any type of hyperplasia [34, 40–42, 47, 49, 48, 52, 53].

Incidence rates per 1000 person-years were calculated for 10 studies that assessed the risk of future endometrial cancer and reported mean or median follow-up time (Table 2). Two studies reported mean follow-up [38, 45], eight reported median follow-up [34, 39, 41, 46, 47, 50–52]. The rate of future endometrial cancer in women with endometrial hyperplasia ranged from 4.3 to 287.9 per 1000 person-years with follow-up time ranging from three months to 23 years.

Pooled analysis of five individual studies (including six estimates) including 169 women with atypical hyperplasia showed that the incidence rate of endometrial cancer was 82.3 per 1,000 person-years (95% CI 39.3, 172.6), equivalent to 8.2% per year, with high heterogeneity observed (I2 = 70%), Fig 3. Only one study included only non-atypical hyperplasia patients [39] and reported a much lower rate of progression to cancer of 26.3 per 1,000 person-years (95% CI: 6.6, 105.6), or 2.6% per year. Among 4 studies (including 5 estimates), that included both atypical and non-atypical hyperplasia patients, the pooled rate of progression to cancer was 12.4 per 1,000 person-years (95% CI: 6.2, 24.9), or 1.2% per year (again incorporating high heterogeneity, I2 = 81%), Fig 3. After pooling results from all 10 studies (including 12 estimates), with 1,400 women with any type of endometrial hyperplasia, the incidence rate for progression to endometrial cancer was 31 per 1,000 person-years (95% CI: 14.7, 65.6), equivalent to 3.1% per year. There was high heterogeneity (I2 = 90%), Fig 3.

Fig 3

Forest plot of incidence rates of endometrial cancer diagnosed after three months of endometrial hyperplasia diagnosis.

aPremenopausal women, bPostmenopausal women, cLNG-IUS (levonorgestrel intrauterine system) treated group, dOral progesterone-treated group.

Although it was impossible to calculate rates per 1,000 person-years due to unavailability of information regarding follow-up time in 11 studies including 1,095 women [35–37, 40, 42, 43, 44, 48, 49, 53, 54], the total percentage of patients who progressed from hyperplasia to cancer was calculated and ranged from 1.3% to 31.6%, see Table 3. Follow-up time in these studies ranged from three months to 20 years. We identified only one population-based study that assessed future endometrial cancer risk at least three months after hyperplasia diagnosis; Lacey et al. [53] reported that the relative risk was three times higher in endometrial hyperplasia patients compared to patients with disordered proliferative endometrium after one year, and that the risk was more marked for atypical hyperplasia [53]. However, due to the nested case-control study design used, we were unable to include this study in our meta-analysis, as we could not calculate an incident rate ratio. There was no strong evidence of a lack of symmetry based on the funnel plot of studies investigating progression to endometrial cancer, which therefore was not indicative of publication bias (S2 Fig).

In analysis by study quality, the risk of progressing to cancer was higher when restricting to studies deemed to be of lower quality (6.6% per year, 95% CI 1.23%, 33.86%) but heterogeneity remained high, see S3 Table. Results were largely similar (and heterogeneity remained high) in sensitivity analyses excluding individual studies (S3 Table). Most studies included both pre and post-menopausal women but one study included only postmenopausal women [39]; in another, we could only include results for premenopausal women [39]. Brownfoot et al. [50] presented results for atypical hyperplasia patients stratified by menopausal status and showed that postmenopausal women were more likely to progress to cancer compared to premenopausal women (10.5% versus 2.4% progression per year, respectively) but too few other studies stratified results by menopausal status and therefore a sub-group analysis was precluded. Six studies reported information on exposure to progestogen therapy [38, 45, 47, 50, 51, 52], with women treated either orally or via an intrauterine device. Gallos et al. [47] provided results by progestogen therapy type and found that women with complex non-atypical or atypical hyperplasia who were treated with oral progestogens were more likely to progress to cancer compared to women treated with the levonorgestrel-releasing intrauterine system (5.9% versus 4.3% progression per year, respectively).

Results from sensitivity analyses stratifying on average duration of follow-up are presented in S3 Fig and S4 Fig. Pooled analysis of three studies with an average follow-up of less than 24 months, including 121 women with atypical hyperplasia, showed that the incidence rate of endometrial cancer was 107 per 1,000 person-years (95% CI 27.6, 414.9), equivalent to 10.7% per year, with high heterogeneity observed (I2 = 78.3%), S3 Fig. Among three studies with an average follow-up of more than or equal to 24 months, pooled analysis including 67 women with atypical hyperplasia showed a lower incidence rate of endometrial cancer (66.1 per 1,000 person-years, 95% CI 30.4, 144), equivalent to 6.6% per year, with moderate heterogeneity observed (I2 = 49.5%), S4 Fig. Only one study evaluated progression to endometrial cancer specifically in women with non-atypical endometrial hyperplasia [39], which precluded meta-analysis. Four studies that included both atypical and non-atypical hyperplasia patients, had an average follow-up of more than or equal to 24 months (n = 973 women) and pooled analysis showed that the incidence rate of endometrial cancer was 9.2 per 1,000 person-years (95% CI 5.4, 15.9), equivalent to 0.9% per year, with high heterogeneity observed (I2 = 87.7%), S4 Fig. We identified no studies that investigated both atypical and non-atypical hyperplasia patients with an average follow-up of less than 24 months.

Discussion

Our meta-analysis of 15 studies showed that approximately 32% of women with endometrial hyperplasia received a concurrent diagnosis of endometrial cancer, with the majority of studies only including women diagnosed with atypical hyperplasia (n = 11). The overall future risk of progression to endometrial cancer was 3% per year, and this was markedly higher for patients with atypical hyperplasia (8%). However, high heterogeneity was observed in pooled analyses and the majority of the studies were of relatively low quality and few specifically included premenopausal women.

Our findings regarding concurrent endometrial cancer risk are similar to those reported in an earlier systematic review which investigated the risk of concurrent endometrial cancer in hysterectomy specimens comparing three methods of endometrial sampling (curettage, hysteroscopically guided biopsy and hysteroscopic resection) [12]. In that review, the rates of concurrent endometrial cancer were 32.7%, 45.3% and 5.8% following an endometrial hyperplasia diagnosis by curettage, hysteroscopically guided biopsy and hysteroscopic resection, respectively. However, the review was restricted to studies published up to 2013, included only atypical hyperplasia patients, and the authors did not specify a cut-off time for endometrial cancer identification. In another previous systematic review which included a sub-set of endometrial hyperplasia patients (atypical hyperplasia occurring within a polyp), a much lower proportion were found to have concurrent endometrial cancer (5.6%) [55]. However, unlike the current study, estimates from that review are likely not generalizable to women with endometrial hyperplasia not confined to polyps. More recently, a meta-analysis by Travaglino et al. [56] of studies conducted after 2008, found that women with atypical hyperplasia were over 11 times more likely to have coexistent cancer, which the authors defined as cancer occurring within a year of hyperplasia diagnosis, compared to women with non-atypical hyperplasia and the results were similar when evaluating studies using the alternative endometrial intraepithelial neoplasia (EIN) system for classification of the precursor lesions of endometrioid cancer. A further systematic review investigated occult cancer risk in complex non‑atypical endometrial hyperplasia and found that cancer was present in 2% of surgical specimens in women diagnosed with simple endometrial hyperplasia and 12.4% in women diagnosed with complex endometrial hyperplasia, suggesting that complexity of glandular architecture is an important marker of occult cancer [57]. However, unlike our systematic review, there was no time cut-off used to define occult cancer and the time to hysterectomy ranged from 4 days to 7 years within the individual studies, meaning that the outcomes may have represented progression to cancer rather than coexistent cancer. Underdiagnosis of endometrial cancer can result in inadequate staging and potentially suboptimal treatment; therefore, high-quality, population-based studies are required to more accurately determine the proportion of concurrent cancer in women diagnosed with both atypical and non-atypical endometrial hyperplasia.

In pooled analysis of studies evaluating progression to endometrial cancer, we identified a high rate of progression in women diagnosed with atypical hyperplasia (8.2% per year), while the risk among women with non-atypical hyperplasia was much lower at 2.6% per year but only one study was identified [39]. The risk of progressing from atypical hyperplasia to endometrial cancer was higher in studies with less than 2 years average follow-up (10.7% per year), suggesting that closer surveillance may be necessary during this period, however risk of progression was still high among studies with follow-up of more than 2 years on average (6.6% per year). A previous systematic review of women diagnosed with atypical hyperplasia or endometrial cancer reported that 15% of those who used oral progestogens had endometrial cancer with at least myometrial invasion on the hysterectomy specimen after a mean follow-up of 49 months, however estimates for atypical hyperplasia were not reported [7]. In another review including 12 studies and restricted to atypical hyperplasia, 2.7% of patients who used oral progestogen for more than six months progressed to endometrial cancer [8]. These earlier systematic reviews reported rates of progression to endometrial cancer in terms of crude percentages rather than the more clinically meaningful percentage progression per year that we report. Moreover, most prior studies were conducted in single-center and tertiary referral centers, which could overestimate risk in comparison to population-based studies. One of the few prior population-based studies, conducted by Reed et al. [58], demonstrated a much lower risk of endometrial cancer (0.9% per year) among 1,443 complex or atypical endometrial hyperplasia patients identified from a health insurance Group Health plan, in Washington State, USA. This study was included in the supplemental material of our review as the minimum time between diagnosis of hyperplasia and cancer was less than three months. Future population-based studies of endometrial cancer progression in women with endometrial hyperplasia are therefore required to provide robust risk estimates. Furthermore, considering the rising incidence of endometrial cancer in younger women [2], future studies should aim to specifically include premenopausal hyperplasia patients.

The reasons underlying the high proportion of concurrent endometrial cancers in women diagnosed with endometrial hyperplasia, especially atypical hyperplasia, are complicated but are likely to include undersampling and suboptimal histopathological diagnosis. Many endometrial biopsies, especially outpatient pipelle biopsies and curettages, are scanty with little tissue represented and the absence of invasion or stroma on slides makes the diagnosis more challenging and risks potentially missing the most significant lesion. Therefore, pathologists may be less likely to make a firm cancer diagnosis.

In addition, it is well known amongst pathologists that there is significant interobserver variability in the reporting of endometrial hyperplasias, including the distinction between benign lesions and non-atypical hyperplasias at the lower end of the spectrum, the distinction between non-atypical and atypical hyperplasia and at the upper end of the spectrum the distinction between atypical hyperplasia and low-grade endometrioid carcinoma [59-61]. The recently published International Society of Gynecological Pathologists endometrial cancer recommendations discuss that in some cases the distinction between atypical hyperplasia and low-grade endometrioid carcinoma is problematic and states “If the morphologic features are suspicious but do not fully meet the criteria for endometrioid carcinoma, this concern should be communicated descriptively in the pathology report rather than being classified as atypical hyperplasia without further comment. There are no diagnostically useful biomarkers to distinguish between atypical hyperplasia and low-grade endometrioid carcinoma” [62]. An additional confounding factor is that in many institutions, most endometrial biopsies are reported by non-specialist pathologists where there is likely to be more interobserver variability than amongst specialist gynecological pathologists.

To our knowledge, this is the first systematic review examining both the prevalence of concurrent and risk of future endometrial cancer in women with endometrial hyperplasia. The use of three large databases and robust screening of articles by at least two independent reviewers minimized the potential for selection bias. Other strengths include its large size and comprehensive inclusion of all endometrial hyperplasia types. We conducted novel meta-analyses for assessment of future endometrial cancer risk and reported the more clinically meaningful percentage progression per year in endometrial hyperplasia patients rather than total percentage of progression. We applied a strict cut-off of three months to distinguish between concurrent and future endometrial cancer on the basis of clinical recommendations for hyperplasia (in particular atypical hyperplasia) follow-up investigations [10].

This review was limited by the high degree of heterogeneity across the included studies, which is likely due to differences in study populations, methods used to diagnose endometrial hyperplasia, as well as the wide variation in the time between biopsy and hysterectomy, which ranged from three months to 12 years in studies of endometrial cancer progression. Few studies included results specifically for non-atypical endometrial hyperplasia, which limited sub-group analyses by hyperplasia type. We were unable to conduct sub-group analyses by menopausal status because the majority of included studies did not stratify by menopausal status. Moreover, few studies included sufficiently detailed information on patient management, including progestogen use, which limited conclusions around the impact of fertility-sparing therapies on cancer risk and the lack of information on these treatments may have affected prevalence and incidence estimates. Considering the rising incidence of endometrial cancer in both pre and postmenopausal women [63], temporal population-based estimates of progression to cancer in endometrial hyperplasia are warranted and such studies should account for treatments and other important clinical factors.

Conclusion

In conclusion, a third of women with atypical endometrial hyperplasia were found to receive a concurrent diagnosis of endometrial cancer; however most studies were small in size and no study reported estimates specifically for non-atypical hyperplasia patients. The risk of progression from atypical hyperplasia to endometrial cancer was 8% per year, but few studies were identified. Population-based studies, which include both atypical and non-atypical hyperplasia patients, are required to identify women at risk of concurrent and future endometrial cancer, in whom preventative interventions can be targeted. Additional robust evidence is necessary to reliably inform treatment decisions for endometrial hyperplasia patients, something which is particularly pertinent for women who do not wish to undergo hysterectomy because of fertility issues or in whom hysterectomy is contraindicated because of comorbidities.

PRISMA 2009 checklist.

(DOC)

Click here for additional data file.

Characteristics of studies which assessed endometrial cancer in women with endometrial hyperplasia but unclear if cancer assessed within or after 3 months of hyperplasia diagnosis (n = 21).

EH- endometrial hyperplasia, EC- endometrial cancer, AH- atypical hyperplasia, SH-simple hyperplasia, CAH- complex atypical hyperplasia, D&C- dilation and curettage, SAH- simple atypical hyperplasia, CH-complex hyperplasia, TVUS- transvaginal ultrasound scan, NAH- non-atypical hyperplasia. aMean age includes 8 patients diagnosed with endometrial cancer. bLikely includes n = 17 AH patients included in Agostini (2003) study. c Endometrial cancer rate per 1000 person-years was 9.3. d Follow-up time is for 249 hyperplasia patients who did not undergo hysterectomy initially.

(DOCX)

Click here for additional data file.

Characteristics of studies which assessed the prevalence of concurrent endometrial cancer in women with endometrial hyperplasia which did not report time between biopsy and hysterectomy (n = 23).

(DOCX)

Click here for additional data file.

Summary of sub-group and sensitivity analyses for concurrent and future risk endometrial cancer in women with endometrial hyperplasia.

(DOCX)

Click here for additional data file.

Search strategy used to identify relevant studies.

(DOCX)

Click here for additional data file.

Funnel plot of studies investigating concurrent endometrial cancer diagnosed within three months of endometrial hyperplasia diagnosis.

(TIF)

Click here for additional data file.

Funnel plot of studies investigating future endometrial cancer diagnosed after three months of endometrial hyperplasia diagnosis.

(TIF)

Click here for additional data file.

Forest plot of incidence rates of endometrial cancer diagnosed after three months of endometrial hyperplasia diagnosis in studies with less than 24 months average follow-up.

(TIF)

Click here for additional data file.

Forest plot of incidence rates of endometrial cancer diagnosed after three months of endometrial hyperplasia diagnosis in studies with more than or equal to 24 months average follow-up.

bPostmenopausal women. cLNG-IUS (levonorgestrel intrauterine system) treated group. dOral progesterone-treated group.

(TIF)

Click here for additional data file.

28 Jan 2020

PONE-D-19-35122

Concurrent and Future risk of Endometrial Cancer in women with Endometrial Hyperplasia: A systematic review and meta-analysis

PLOS ONE

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While it is an imporatnt topic but I am not convinced if this study, by addition of a meta analysis that was not very helpfuldue due to the high heterogeneity of the studies, is superior to another review recently completed in 2019 covering very similar material. I would like to see more clarification of this hetergenity plus having results of sensitivity analysis proposed by reviewers.

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Reviewer #1: I have read with interest the manuscript of Dr. Doherty and colleagues. They are to be commended on a thorough and painstaking review of a relevant clinical question. The manuscript merits publication in my estimation, but there are few issues which I think should be addressed prior to acceptance. I have listed these below as either major (thematic) or minor (semantic).

Major

1. The stated goal of the manuscript is to more accurately assess the risk of concurrent or subsequent cancer among patients with hyperplastic conditions. While this is addressed in many ways one confounding variable I think should be addressed is the effect of treatment on observed concurrence of progression. In multiple of the studies patients we treated with IUD or oral progestin – and then went on to a more definitive procedure – however the indications for the procedure may impact the incidence/prevalence of a cancer diagnosis (ie a medically treated patient who ultimately required a hysterectomy may represent an “at risk” population) This should be discussed further.

2. Be careful about repeating (or listing) results in the discussion section. Reserve the discussion for the interpretation of the results. Much of page 20 can be moved to results, though discussion of how your data compares to the current literature should be in the discussion.

Minor

1. Table 1 – I would omit columns for which all of the data is the same (eg method of follow-up examination) – this will declutter the table and can be mentioned in the body of the tex.

2. Table 1 and 2 - There are abbreviations described that I did not see used in the table (eg TVUS); likewise there are abbreviations which are not standard and not described (Perma, and btw?)

3. Table 2 – keep the footnote references in the same column if possible e is in column 1 and the rest are in later columns (5-7)

4. Table 3 – I am not sure why the wheeler reference has two age groups – but only one results data point (we know that postmenopausal groups are older than premenopausal groups – I assume the progression rates are a summary stat – the ages should be summary in that case.

5. Discussion (page 21) I think a better descriptions of why a pathologist is prone to under-calling the pathology (as opposed to reluctant- as this implies he/she could but isn’t). Specifically the absence of invasion or stroma on slide makes the diagnosis more challenging and the guidelines generally recommend under- rather than over- calling on a biopsy

Reviewer #2: This manuscript describes a systematic review and meta-analysis evaluating the prevalence of endometrial cancer concurrent with an endometrial hyperplasia diagnosis and the future risk of endometrial cancer in women with such a diagnosis. Overall, the systematic review appears to have been done in accordance with standard guidelines and the data are generally clearly presented. I have only a few minor comments:

1. Page 4, line 80: The clinical guidelines are not stated exactly correctly. The cited guidelines state that endometrial biopsies should be done every 3 months until 2 consecutive negative biopsies are obtained.

2. Page 4, line 84: It should be previous studies evaluating the prevalence (not incidence) of concurrent endometrial cancer.

3. Page 7, line 152: The sensitivity analyses by quality score are not described accurately (less than or more than five would exclude studies with a score of 5).

4. Page 8, line 179: It would be helpful to add in a sentence summarizing the quality scores of the studies.

5. Page 8, line 192: The data reported are from Figure 2, not Figure 1.

6. When examining the results for the incidence of endometrial cancer (Figure 3), it appears that the highest estimates tend to be higher in studies that have a shorter duration of follow-up. A sensitivity analysis stratifying by duration of follow-up (perhaps <=24 months vs >24 months) may provide useful information about the timeframe after diagnosis of endometrial hyperplasia when the risk of progression is higher, which in turn may inform screening recommendations.

Reviewer #3: Concurrent and Future risk of Endometrial Cancer in women with Endometrial Hyperplasia: A systematic review and meta-analysis is an important area of research. However, there were numerous limitations. The empirical analysis was troublesome given the heterogeneity of findings, lack of population based studies, very low number of patients in some included studies, and lack of other characteristics that may influence the findings, such as pathology review, health care system, etc. To some extent, this feels more relevant as a systematic review (both another may have done this---Travaglino, 2019).

Intro was very well written

Line 177: “seven in North America, one in USA” Does in NA mean Canada? If so, please state.

By Line 182, I begin to wonder about the eligibility criteria and/or aim of each study included. In Table 1, it is hard to believe that only 42 cases of endometrial hyperplasia was found in the presumably chart review over a 10 year period (Osaka Medical Center) or 18 cases of endometrial hyperplasia over a 7 year period in Hospital la conception. There were several studies in which the number of cases was very small over many years which seems odd. That left me wondering about the aim of the study and if these included had a significant bias.

It seems that it would be reasonable in this electronic era to email authors of studies to determine the recruitment period as well as any other missing information populating the tables for their paper since a few studies had missing info.

Lines 214-218: this was unsatisfying results given the range was very wide (4.3to 287.9 per 1000 person-years with follow-up time ranging from three months to 23 years). Is there another way to analyze these data to have a more meaningful result? It seems that the meta-analyses was done by using data extracted from the studies versus obtaining the data from each site? Although it would take a lot of work, a much more meaningful analysis would use the raw data.

Line 220: I don’t know what “”Pooled analysis of five studies (including six estimates)” means. What does the six estimates mean. In this case it seems you are using raw data? But what is the estimates. Did I miss something?

Line 223: Do you think the results are sufficient to advance our understanding given the very high heterogeneity of the studies?

No line numbers in discussion but the stated limitation of prior studies ’ Moreover, most prior studies were conducted in single-center and tertiary referral centers which could overestimate risk in comparison to population-based studies.” Is also an issue here since I believe only one study was population based.

“An additional confounding factor is that in many institutions, most endometrial biopsies are reported by non-specialist pathologists” Having this information for this paper would be helpful although it would likely take work to find that out.

Overall, it seems that raw data were not used for the meta-analysis and this is a significant limitation.

**********

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Reviewer #2: No

Reviewer #3: No

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13 Mar 2020

Dear Prof Beiki,

We thank the PLOS One reviewers and the editorial staff for taking the time to consider our revised manuscript and for their comments. We have responded to each comment below. We have conducted additional analyses as suggested (e.g. sensitivity analysis of duration of follow-up) and we have made numerous changes to the manuscript.

Please note that during the conduct of the suggested revisions, we noted a small error in the method used to pool the studies of concurrent endometrial cancer. We have now re-ran these analyses and although the results were largely unchanged, we have amended the tables and figures accordingly, as well as including a reference for the specific method used.

We think the revised manuscript is an improvement and hope that it is now suitable for publication in the PLOS One, but we are happy to consider further changes if necessary.

Best wishes,

Dr Úna McMenamin (on behalf of the authors)

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*The manuscript has now been modified according to the style requirements of PLOS One.

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*We have carried out an in-depth online literature review (e.g. Pubmed, Google Scholar) since the cut-off for our original search and did not find any articles that would have met our inclusion criteria. Therefore, we are confident that there are no subsequently published studies that would be relevant for inclusion in our review. Unfortunately, the time required to update the search strategy in all bibliographic databases and to independently review titles, abstracts and full-texts would exceed the time required to return the revised manuscript.

4. In the Methods, please specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies). Please ensure that the specific method of assessment (funnel plot, Egger's test, Begg's test, etc) is mentioned.

*Funnel plots evaluating potential publication bias have now been added as supplementary figures (S1 and S2 Figs). There was no strong evidence of publication bias in either studies investigating concurrent endometrial cancer or progression to endometrial cancer and the methods and results text have been amended accordingly.

5. PLOS requires an ORCID iD for the corresponding author in Editorial Manager on papers submitted after December 6th, 2016. Please ensure that you have an ORCID iD and that it is validated in Editorial Manager. To do this, go to ‘Update my Information’ (in the upper left-hand corner of the main menu), and click on the Fetch/Validate link next to the ORCID field. This will take you to the ORCID site and allow you to create a new iD or authenticate a pre-existing iD in Editorial Manager. Please see the following video for instructions on linking an ORCID iD to your Editorial Manager account: https://www.youtube.com/watch?v=_xcclfuvtxQ

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Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I have read with interest the manuscript of Dr. Doherty and colleagues. They are to be commended on a thorough and painstaking review of a relevant clinical question. The manuscript merits publication in my estimation, but there are few issues which I think should be addressed prior to acceptance. I have listed these below as either major (thematic) or minor (semantic).

*We thank the reviewer for their detailed review of our manuscript and we provide responses below to each of their queries.

Major

1. The stated goal of the manuscript is to more accurately assess the risk of concurrent or subsequent cancer among patients with hyperplastic conditions. While this is addressed in many ways one confounding variable I think should be addressed is the effect of treatment on observed concurrence of progression. In multiple of the studies patients we treated with IUD or oral progestin – and then went on to a more definitive procedure – however the indications for the procedure may impact the incidence/prevalence of a cancer diagnosis (ie a medically treated patient who ultimately required a hysterectomy may represent an “at risk” population) This should be discussed further.

*We agree with the reviewer and have now extended the limitations section of our discussion in an effort to acknowledge this and highlight the need for additional studies that include detailed information on progestin-based treatments, see below.

“…Moreover, few studies stratified results on progestogen use, which limited conclusions around the impact of progestin-based therapies on cancer risk and the lack of information on these treatments may have affected prevalence and incidence estimates. Considering the rising incidence of endometrial cancer in both pre and postmenopausal women61, temporal population-based estimates of progression to cancer in endometrial hyperplasia are warranted and such studies should account for treatments and other important clinical factors.”

61. Crosbie E, Morrison J. The emerging epidemic of endometrial cancer: Time to take action. Cochrane database Syst Rev. 2014;12:ED000095.

2. Be careful about repeating (or listing) results in the discussion section. Reserve the discussion for the interpretation of the results. Much of page 20 can be moved to results, though discussion of how your data compares to the current literature should be in the discussion.

*We have now reduced and removed some of the description of results from the discussion and have placed this in the results section.

Minor

1. Table 1 – I would omit columns for which all of the data is the same (eg method of follow-up examination) – this will declutter the table and can be mentioned in the body of the tex.

*We have removed the column “Method of follow-up investigation” in Table 1 as suggested and described this in the body of the text.

2. Table 1 and 2 - There are abbreviations described that I did not see used in the table (eg TVUS); likewise there are abbreviations which are not standard and not described (Perma, and btw?)

*Only abbreviations used within the tables are now included in the table footnotes.

3. Table 2 – keep the footnote references in the same column if possible e is in column 1 and the rest are in later columns (5-7)

*Footnote ‘e’ has been moved to column 5 to align with the other footnotes. We are keen to keep other footnotes in the current format, as we believe they better identify the stratified groups (columns 5-8; e.g. pre-, postmenopausal women) however we will modify this at the discretion of the Editor.

4. Table 3 – I am not sure why the wheeler reference has two age groups – but only one results data point (we know that postmenopausal groups are older than premenopausal groups – I assume the progression rates are a summary stat – the ages should be summary in that case.

*In Table 3, in an effort to avoid presenting missing information, we presented the average age of participants according to menopausal status for the study conducted by Wheeler et al. as unfortunately the authors did not present the mean age for the whole study population.

5. Discussion (page 21) I think a better descriptions of why a pathologist is prone to under-calling the pathology (as opposed to reluctant- as this implies he/she could but isn’t). Specifically the absence of invasion or stroma on slide makes the diagnosis more challenging and the guidelines generally recommend under- rather than over- calling on a biopsy

*We have changed the wording of this sentence, as suggested by the reviewer to better reflect the problem of under-diagnosis of endometrial cancer in women with endometrial hyperplasia, please see below.

“Many endometrial biopsies, especially out-patient pipelle biopsies and curettages, are scanty with little tissue represented and the absence of invasion or stroma on slides makes the diagnosis more challenging and risks potentially missing the most significant lesion. Therefore, pathologists may be less likely to make a firm cancer diagnosis.”

Reviewer #2: This manuscript describes a systematic review and meta-analysis evaluating the prevalence of endometrial cancer concurrent with an endometrial hyperplasia diagnosis and the future risk of endometrial cancer in women with such a diagnosis. Overall, the systematic review appears to have been done in accordance with standard guidelines and the data are generally clearly presented. I have only a few minor comments:

*We thank the reviewer for their positive comments on our manuscript and provide responses to their specific questions below.

1. Page 4, line 80: The clinical guidelines are not stated exactly correctly. The cited guidelines state that endometrial biopsies should be done every 3 months until 2 consecutive negative biopsies are obtained.

*We have modified the sentence as requested, to better clarify with the current clinical guidelines.

2. Page 4, line 84: It should be previous studies evaluating the prevalence (not incidence) of concurrent endometrial cancer.

*We have corrected the sentence accordingly.

3. Page 7, line 152: The sensitivity analyses by quality score are not described accurately (less than or more than five would exclude studies with a score of 5).

*We have now changed this line to “…restricting to studies with a quality score of less than five and more than or equal to five.”

4. Page 8, line 179: It would be helpful to add in a sentence summarizing the quality scores of the studies.

*In the description of study characteristics, we now state that “most studies were classified as being of low-to-moderate quality, with quality scores ranging from four to six out of a total of nine.”

5. Page 8, line 192: The data reported are from Figure 2, not Figure 1.

*Thank you, we have now rectified this error.

6. When examining the results for the incidence of endometrial cancer (Figure 3), it appears that the highest estimates tend to be higher in studies that have a shorter duration of follow-up. A sensitivity analysis stratifying by duration of follow-up (perhaps <=24 months vs >24 months) may provide useful information about the timeframe after diagnosis of endometrial hyperplasia when the risk of progression is higher, which in turn may inform screening recommendations.

*We agree that a sensitivity analysis based on average duration of follow-up would be useful and have included this as supplemental material (Supplemental Figures 1 and 2). The risk of progressing to endometrial cancer was indeed higher in studies with shorter follow-up; pooled analysis of three studies with an average follow-up of less than 24 months (including 121 women with atypical hyperplasia), showed that the incidence rate of endometrial cancer was 107 per 1,000 person-years (95% CI 27.6, 414.9), equivalent to 10.7% per year, with high heterogeneity observed (I2=78.3%). Among three studies with an average follow-up of less than or equal to 24 months, pooled analysis of 67 women with atypical hyperplasia showed a lower incidence rate of endometrial cancer (66.1 per 1,000 person-years, 95% CI 30.4, 144), equivalent to 6.6% per year, with moderate heterogeneity observed (I2=49.5%). Only one study evaluated progression to endometrial cancer specifically in women with non-atypical endometrial hyperplasia, which therefore precluded meta-analysis.

Four studies that included both atypical and non-atypical hyperplasia patients, had an average follow-up of more than or equal to 24 months (n=973 women) and pooled analysis showed that the incidence rate of endometrial cancer was 9.2 per 1,000 person-years (95% CI 5.4, 15.9), equivalent to 0.9% per year, with high heterogeneity observed (I2=87.7%). We identified no studies that investigated both atypical and non-atypical hyperplasia patients with an average follow-up of less than 24 months.

We have amended the methods, results and discussion section accordingly to describe and interpret these additional sensitivity analyses.

Reviewer #3: Concurrent and Future risk of Endometrial Cancer in women with Endometrial Hyperplasia: A systematic review and meta-analysis is an important area of research. However, there were numerous limitations. The empirical analysis was troublesome given the heterogeneity of findings, lack of population based studies, very low number of patients in some included studies, and lack of other characteristics that may influence the findings, such as pathology review, health care system, etc. To some extent, this feels more relevant as a systematic review (both another may have done this---Travaglino, 2019).

*We thank the reviewer for conducting a thorough review of our manuscript. As described earlier, we have highlighted these specific limitations within the discussion of our manuscript but we have now added additional recommendations for the conduct of future studies that are population-based, include both pre and postmenopausal women and incorporate important clinical data such as progestogen therapies. In an effort to avoid the inclusion of very small studies from the outset, our pre-specified article selection criteria excluded studies with fewer than 10 cases of endometrial hyperplasia. Moreover, we conducted sensitivity analysis restricting to higher quality studies, classified using a validated quality assessment tool.

We also now include a description of another recently conducted systematic review by Travaglino et al1, which investigated risk of occult endometrial cancer in complex non‑atypical endometrial hyperplasia. However, unlike our systematic review, there was no time cut-off used to define concurrent endometrial cancer; the time from endometrial hyperplasia diagnosis to hysterectomy ranged from 4 days to 7 years within individual studies meaning that outcomes may have represented progression to cancer rather than coexistent cancer. Moreover, the review by Travaglino et al. restricted to women diagnosed with complex non‑atypical endometrial hyperplasia whereas our review includes all types of hyperplasia, thereby adding considerable value to the current evidence base.

1Travaglino A, Raffone A, Saccone G, et al. Significant risk of occult cancer in complex non-atypical endometrial hyperplasia. Arch Gynecol Obstet 2019; 300: 1147-1154.

Intro was very well written

*We thank the reviewer for their positive feedback.

Line 177: “seven in North America, one in USA” Does in NA mean Canada? If so, please state.

*We have now revised this sentence which we hope clarifies the description of study location; “Fifteen studies were conducted in Europe, 12 in Asia, eight in North America (one study included patients from the US and Europe) and one in Australia”

By Line 182, I begin to wonder about the eligibility criteria and/or aim of each study included. In Table 1, it is hard to believe that only 42 cases of endometrial hyperplasia was found in the presumably chart review over a 10 year period (Osaka Medical Center) or 18 cases of endometrial hyperplasia over a 7 year period in Hospital la conception. There were several studies in which the number of cases was very small over many years which seems odd. That left me wondering about the aim of the study and if these included had a significant bias.

* We were restricted to the information that authors provided in the original manuscripts but we have no reason to believe that this information is incorrect. Both studies that the reviewer highlights were conducted in single-centre institutions and only included women diagnosed with atypical hyperplasia, the less common type of endometrial hyperplasia. The aim of the study by Agostini et al (2003), conducted within the Hospital la Conception, was to determine the rate of concurrent endometrial cancer in women diagnosed with atypical hyperplasia using hysteroscopic resection, so therefore atypical hyperplasia cases diagnosed using other methods may not have been included. We have modified the information in Table 1 and in the results section to better clarify the method of hyperplasia diagnosis within included studies.

Within our discussion, we acknowledge that small case numbers within individual studies is a limitation of our review and we have called for larger (population-based) studies to be carried out. As described, in an effort to minimise the impact from these studies, we conducted sensitivity analysis restricting to higher quality studies and our pre-specified article selection criteria excluded studies with fewer than 10 cases of endometrial hyperplasia. This therefore helped ensure the inclusion of meaningful estimates of concurrent cancer risk or progression to cancer.

It seems that it would be reasonable in this electronic era to email authors of studies to determine the recruitment period as well as any other missing information populating the tables for their paper since a few studies had missing info.

*During the conduct of the search strategy, efforts were made to email some authors for additional information; however, as there was limited response, we were restricted to including the information presented in the study articles.

Lines 214-218: this was unsatisfying results given the range was very wide (4.3to 287.9 per 1000 person-years with follow-up time ranging from three months to 23 years). Is there another way to analyze these data to have a more meaningful result? It seems that the meta-analyses was done by using data extracted from the studies versus obtaining the data from each site? Although it would take a lot of work, a much more meaningful analysis would use the raw data.

*As the reviewer highlights, obtaining the raw data from individual studies included in this systematic review would take a considerable amount of time and unfortunately would not be feasible within the time requested to return the manuscript (six weeks).

Line 220: I don’t know what “”Pooled analysis of five studies (including six estimates)” means. What does the six estimates mean. In this case it seems you are using raw data? But what is the estimates. Did I miss something?

*In this particular analysis, one study only presented estimates according to menopausal status (Brownfoot et al. 2014) and so we included both of these estimates (pre- and postmenopausal status), as outline in Figure 3. We have modified this line to clarify that two estimates were extracted from one individual study.

Line 223: Do you think the results are sufficient to advance our understanding given the very high heterogeneity of the studies?

*We agree that the high heterogeneity observed in our meta-analysis is a limitation and we have acknowledged this in our discussion. We also suggest that the observed heterogeneity could be due to differences in study populations, methods used to diagnose endometrial hyperplasia, as well as the wide variation in the time between biopsy and hysterectomy, which ranged from three months to 12 years in studies of endometrial cancer progression. Despite this, the findings from our comprehensive systematic review, which used clinically relevant time cut-off points for the identification of cancer, provide a broad overview of the current evidence to date on the risk of concurrent and future risk of endometrial cancer in women diagnosed with endometrial hyperplasia and will therefore be of value to clinicians, researchers and patients. As described earlier, we now include a sensitivity analysis stratifying on average duration of follow-up, which resulted in reduced heterogeneity (e.g. 49.5% heterogeneity in pooled analysis of progression to endometrial cancer in women with atypical hyperplasia among studies with less than 24 months average follow-up).

Overall, we believe that our systematic review will stimulate the conduct of higher quality, population-representative studies, which will allow for the calculation of more accurate risk estimates to better-inform decision making between endometrial hyperplasia patients and their clinicians, particularly with respect to surveillance and treatments options.

No line numbers in discussion but the stated limitation of prior studies ’ Moreover, most prior studies were conducted in single-center and tertiary referral centers which could overestimate risk in comparison to population-based studies.” Is also an issue here since I believe only one study was population based.

*Within our discussion, we already call for the conduct of future population-based studies in order to provide more accurate estimates of risk of progression to endometrial cancer in women diagnosed with endometrial hyperplasia. As outlined earlier however, we have now extended this to request that population-based studies also ensure the inclusion of important clinical data to allow stratification by factors that may affect risk of endometrial cancer.

We have also now included line numbers in the discussion.

“An additional confounding factor is that in many institutions, most endometrial biopsies are reported by non-specialist pathologists” Having this information for this paper would be helpful although it would likely take work to find that out.

*Unfortunately, information on the type of pathologist conducting histopathological review of biopsies was not uniformly reported within the individual studies. Moreover, details of the reporting pathologists was not part of our pre-specified data extraction plan for this systematic review.

Overall, it seems that raw data were not used for the meta-analysis and this is a significant limitation.

*Please see earlier response with respect to the lack of availability of raw data for this systematic review.

10 Apr 2020

Concurrent and future risk of endometrial cancer in women with endometrial hyperplasia: a systematic review and meta-analysis

PONE-D-19-35122R1

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16 Apr 2020

PONE-D-19-35122R1

Concurrent and future risk of endometrial cancer in women with endometrial hyperplasia: a systematic review and meta-analysis

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