Abstract

Background: To test the efficacy of levonorgestrel-release intrauterine device (LNG-IUD) plus gonadotropin-releasing hormone (GnRH) for treating women aged <40 years with atypical endometrial hyperplasia (AEH) or presumed International Federation of Gynecology and Obstetrics stage IA limited to the endometrium, well differentiated (G1), endometrioid endometrial cancer (EC), who wish to preserve their fertility.

Patients and methods: A prospective observational study was conducted. Treatment consisted on the insertion of an LNG-IUD for 1 year plus GnRH analogue for 6 months.

Results: From January 1996 to June 2009, 20 and 14 patients with AEH and EC, respectively, were studied. Complete response rate was 95% in patients with AEH and 57.1% in women with EC-G1. A progression of the disease was observed in one (5%) and in four patients (28%) with AEH and EC, respectively. Four of 20 patients with AEH and 2 of 14 with EC-G1 experienced recurrences. The average relapse time was 36 months (range: 16–62 months). All of them were alive without evidence of disease at the last follow-up, mean: 29 months (range: 4–102 months). Nine women achieved 11 spontaneous pregnancies.

Conclusions: The combined treatment showed effectiveness in a substantial proportion of patients with AEH and EC. Close follow-up during and after treatment is crucial.

introduction

Between 3% and 5% of affected women with endometrial cancer (EC) are <40 years [1, 2] and >70% of them are nulliparous at the time of diagnosis [2]. Histologically, 90% of all cases are well-differentiated (G1) carcinomas and are frequently accompanied by endometrial hyperplasia [1, 2]. Patients with EC are cured by hysterectomy in exchange for losing their fertility.

Given the demonstrated overexpression of estrogens, progesterone, and gonadotropin-releasing hormone (GnRH) receptors in endometrial cancer cells [3], there have been published successful fertility-preserving hormones therapies (usually oral progestins) for atypical endometrial hyperplasia (AEH) and EC, arising in young women [4]. However, disparities in dosage and duration of treatment, selection criteria, and follow-up surveillance have been noted in the studies. Therefore, neither the dose nor the schedule for progestational agents has been standardized. The progesterone-releasing intrauterine device (IUD) is a newly available delivery system for treatment of estrogen-dependent endometrial cancer [5]. The rationale for treating endometrial malignancy with this device, instead of oral progesterone, is that it provides very high doses of the hormone at the specific site of the pathology. This avoids the adverse effects produced by systemic administration, which include serious medical complications and suboptimal compliance [6].

We here test the combination of a levonorgestrel-release intrauterine device (LNG-IUD; Mirena®; Bayer Health Care Pharmaceutical Inc., Wayne, NY) and a GnRH analogue as a potential conservative management option for women aged <40 years with AEH or presumed International Federation of Gynecology and Obstetrics (FIGO) stage IA, G1, endometrioid adenocarcinoma, who wish to preserve their fertility.

patients and methods

study subjects

A prospective observational study was done. From January 1996 to June 2009, 43 patients were referred to the European Institute of Oncology, Milan, Italy, to evaluate conservative treatment of AEH and EC. The patients were offered uterus-sparing hormonal treatment with progesterone-impregnated IUD if inclusion criteria were met: (i) age between 20 and 40 years; (ii) strong desire to preserve fertility; (iii) pathological confirmation by central review of the material as AEH or well-differentiated (G1) EC, presumed FIGO stage IA limited to the endometrium. Patients were excluded if any of the following conditions were present: (i) suspicion of myometrial invasion on pelvic ultrasound or magnetic resonance imaging (MRI) in patients with EC, (ii) laparoscopic confirmation of endometrial cancer outside myometrium or ovarian cancer ≥FIGO stage IB, (iii) endometrial biopsy confirming differentiation of EC ≥moderately differentiated (G2) (Figure 1). Data regarding age, gravidity, parity, infertility, obesity [defined as body mass index (BMI) ≥27.3], diabetes, and polycystic ovary syndrome were obtained.

Figure 1.

Graphic design. AEH, atypical endometrial hyperplasia; EC, endometrial carcinoma; TVS, vaginal ultrasonography; MRI, magnetic resonance imaging; LNG-IUD, levonorgestrel intrauterine device; GnRH, gonadotropin-releasing hormone; CR, complete response; PD, progressive disease; SD, stable disease; G1, well differentiated; ^One patient was excluded after hysteroscopy + biopsy evaluation because EC; G2, moderately differentiated.

Figure 1.

Graphic design. AEH, atypical endometrial hyperplasia; EC, endometrial carcinoma; TVS, vaginal ultrasonography; MRI, magnetic resonance imaging; LNG-IUD, levonorgestrel intrauterine device; GnRH, gonadotropin-releasing hormone; CR, complete response; PD, progressive disease; SD, stable disease; G1, well differentiated; ^One patient was excluded after hysteroscopy + biopsy evaluation because EC; G2, moderately differentiated.

pretreatment assessment

The initial histological diagnosis was made by using dilatation and curettage most of the time during a hysteroscopic procedure. All the samples were reviewed by at least two independent gynecological pathologists. In cases of discordance with the initial diagnosis made at the referring institution, the slides were reviewed by another expert pathologist at our institution. The criteria of Kurman and Norris were used to classify endometrial hyperplasia [7]. Endometrial carcinoma was diagnosed if any of the following microscopic features were noted: (i) an irregular infiltration of glands associated with a desmoplastic stromal response; (ii) confluence of glands with no intervening stroma, often with a resulting cribriform pattern; (iii) an extensive papillary pattern; or (iv) replacement of stroma by masses of squamous epithelium associated with a desmoplastic stromal response or a confluent glandular pattern. Tumors were assigned a grade based on new classification of FIGO criteria [8]. The histological type was also noted. The study was approved by the hospital’s institutional review board.

All patients underwent MRI and pelvic ultrasound. In addition, a diagnostic laparoscopy was carried out in all patients to rule out the presence of extrauterine disease. Forty-one eligible patients were accepted to participate in the clinical protocol. A written informed consent was provided in all cases after extensive counseling.

treatment

At the time of therapy initiation, all patients were inserted an LNG-IUD system (Mirena®; Bayer Health Care Pharmaceutical Inc., Wayne, NY) in utero for 1 year (Figure 1). The IUD consists of a T-shaped polyethylene device [9] that release 20 μg of LNG daily for up to 5 years [10]. In addition, all patients received monthly depot injection of 3.75 mg of GnRH analogue for 6 months.

evaluation of response and follow-up

After starting the combination treatment, the response was evaluated by pelvic ultrasound by hysteroscopy and endometrial biopsy with cold noncrushing devices (pipelle or dilatation and curettage) at 6 months and 1 year with the IUD in place (Figure 1). The histological diagnosis of all obtained samples was carried out by the study pathologist. Treatment response was defined based on a comparison of the index sample with the last available specimen during and after the completion of therapy. The following criteria were adopted: complete response (CR) was indicated if the last biopsy showed normal endometrial histological characteristics, stable disease (SD) was indicated if the last biopsy had the same histopathological appearance as the index sample, and progressed disease (PD) was defined as the appearance of EC in those patients with initial AEH. Recurrence was defined as the presence of a new AEH or EC lesion in patients who underwent conservative treatment following a negative biopsy. Surgical staging was carried out in the following situations: PD in the first endometrial biopsy, SD and PD in the second endometrial biopsy, and recurrent disease at follow-up in patients with initial CR. Patients underwent follow-up with pelvic ultrasound, hysteroscopy, and endometrial biopsy every 6 months until 40 years of age or until the first pregnancy, at which time where surgical staging was advised. The follow-up started at the moment of IUD insertion.

end points

The primary outcome of the present report was CR rate after 1 year of treatment. Adverse effects, overall survival, failure of treatment rates, pregnancy rates, recurrence rates, and final diagnosis in the hysterectomy specimen were the secondary end points.

statistical analysis

CR rate was evaluated by using two-sided 90% confidence intervals for the AEH and EC subgroups. The lower bounds of the two-sided 90% confidence intervals serve as one-sided 95% lower confidence bounds on the observed CR rates as well. The confidence intervals were calculated by exact binomial distribution methods.

results

patients characteristic

The patients characteristics are shown in Table 1. Forty-two patients were eligible for uterus-sparing treatment. Three patients refused the proposed treatment: two electing hysterectomies and one self-referred to another institution. Five patients are still under treatment and thus excluded for this analysis. One patient was excluded at the moment of initial hysteroscopy evaluation because an endometrial cancer G2 was diagnosed. Disease outside uterus–ovaries was found in any cases at laparoscopy evaluation. This left a total of 20 eligible women with AEH and 14 with EC that had complete data for inclusion in the final analysis (Figure 1). The median (range) follow-up was 29 (4–102) months. The mean age of patients was 34 years (range 22–40 years). The distribution of comorbidities is detailed in Table 1. The initial diagnosis was carried out by using cold noncrushing devices (pipelle or dilatation and curettage) in all cases. In addition, hysteroscopy evaluation at our institution was carried out in all but eight patients, 4 of the 20 patients with AEH (20%) and 4 (29%) of the 14 patients with EC.

Table 1.

Patients characteristics

Characteristics Patients 
Histology, n (%)  
    Endometrial carcinoma, G1 14 (41.1) 
    Atypical endometrial hyperplasia 20 (58.8) 
Age in years, mean (range) 34 (22–40) 
Follow-up in months, median (range) 29 (4–102) 
BMI, mean (range) 21 (17–41) 
Nulliparity, n (%) 29 (85.2) 
Comorbidity, n (%)  
    Obesity 4 (11.7) 
    Diabetic mellitus 1 (2.9) 
    Hypertension 2 (5.8) 
    Polycystic ovarian syndrome 4 (11.7) 
Characteristics Patients 
Histology, n (%)  
    Endometrial carcinoma, G1 14 (41.1) 
    Atypical endometrial hyperplasia 20 (58.8) 
Age in years, mean (range) 34 (22–40) 
Follow-up in months, median (range) 29 (4–102) 
BMI, mean (range) 21 (17–41) 
Nulliparity, n (%) 29 (85.2) 
Comorbidity, n (%)  
    Obesity 4 (11.7) 
    Diabetic mellitus 1 (2.9) 
    Hypertension 2 (5.8) 
    Polycystic ovarian syndrome 4 (11.7) 

G1, well differentiated; BMI, body mass index.

histopathology central review

Table 2 shows the correlation of the diagnosis between the referral centers and study pathologist. One patient with an initial diagnosis of AEH was upgraded to EC-G1. Of the 14 patients referred with an initial diagnosis of EC-G1, 3 were downgraded to AEH. It is interesting to note that one patient originally diagnosed as EC-G2 and was downgraded to EC-G1 and another with an outside diagnosis of carcinosarcoma downgraded to EC-G1. Another patient with atypical polypoid adenoma had a final diagnosis of AEH. All of them were included in this analysis.

Table 2.

Histopathological diagnosis correlation between referrals center and IEO

Study pathologist EC-G1 AEH Total 
Initial    
AEH 16 17 
EC-G1 11 14 
EC-G2 
Carcinosarcoma 
Atypical polypoid adenomyoma 
Total 14 20 34 
Study pathologist EC-G1 AEH Total 
Initial    
AEH 16 17 
EC-G1 11 14 
EC-G2 
Carcinosarcoma 
Atypical polypoid adenomyoma 
Total 14 20 34 

IEO, European Institute of Oncology; AEH, atypical hyperplasia; EC, endometrial carcinoma; G1, well differentiated; G2, moderate differentiated.

initial response rate

The treatment response is detailed in Figure 1. The CR rate was 95% (n = 19/20) (90% confidence interval: 0.784–0.997) in patients with AEH and 57.1% (n = 8/14) (90% confidence interval: 0.325–0.794) in women with EC-G1. One important point is that all these women experienced CR at their first follow-up, which was 6 months after the initiation of treatment (Table 3) A progression of the disease was observed in one (5%) and in four patients (28%) with AEH and EC, respectively. This included one EC FIGO stage IIIA, G2 in the patient with initial AEH. Patients with initial EC-G1 progressed as FIGO stage IA limited to the endometrium, G2; FIGO stage IB, G1; FIGO stage IIB, G2; and FIGO stage IIIA, G2. Two patients (14.3%) with EC had SD (Table 4). All of them were treated according to standard care and were alive without evidence of disease at the last follow-up.

Table 3.

Time to CR since starting treatment

Histology Total (NMonth 6, n (%) Month 12, n (%) 
AEH, CR 20 18 (90.0) 19 (95.0) 
EC, CR 14 8 (57.1) 8 (57.1) 
Histology Total (NMonth 6, n (%) Month 12, n (%) 
AEH, CR 20 18 (90.0) 19 (95.0) 
EC, CR 14 8 (57.1) 8 (57.1) 

AEH, atypical endometrial hyperplasia; CR, complete response; EC, endometrial carcinoma.

Table 4.

Histopathological finding and current status of disease in patients with initial AEH and EC underwent surgical staging

Case Age (years) Initial diagnosis Response Relapse (months) Final histology FIGO stage Current status Follow-up (months) 
Women without initial response 
    1 24 AEH PD — EC-G2 IIIAa NED 98 
    2 34 EC PD — EC-G2 IIBb NED 46 
    3 35 EC PD — EC-G2 IA NED 47 
    5 37 EC PD — EC-G2 IIIAc NED 40 
    6 36 EC PD — EC-G1 IB NED 35 
    4 34 EC SD — EC-G1 IB NED 47 
    7 32 EC SD — EC-G1 IA NED 27 
Women with relapse 
    8 23 AEH CR 25 EC-G1 IB NED 115 
    9 39 AEH CR 62 EC-G1 IB NED 83 
    10 37 AEH CR 39 AEH — NED 62 
    11 35 AEH CR 44 EC-G1 IA NED 40 
    12 35 EC CR 16 EC-G1 IIIAc NA NA 
    13 36 EC CR 30 EC-G1 IA NED 70 
Mean 33.6 — — 36 — — — 59 
Case Age (years) Initial diagnosis Response Relapse (months) Final histology FIGO stage Current status Follow-up (months) 
Women without initial response 
    1 24 AEH PD — EC-G2 IIIAa NED 98 
    2 34 EC PD — EC-G2 IIBb NED 46 
    3 35 EC PD — EC-G2 IA NED 47 
    5 37 EC PD — EC-G2 IIIAc NED 40 
    6 36 EC PD — EC-G1 IB NED 35 
    4 34 EC SD — EC-G1 IB NED 47 
    7 32 EC SD — EC-G1 IA NED 27 
Women with relapse 
    8 23 AEH CR 25 EC-G1 IB NED 115 
    9 39 AEH CR 62 EC-G1 IB NED 83 
    10 37 AEH CR 39 AEH — NED 62 
    11 35 AEH CR 44 EC-G1 IA NED 40 
    12 35 EC CR 16 EC-G1 IIIAc NA NA 
    13 36 EC CR 30 EC-G1 IA NED 70 
Mean 33.6 — — 36 — — — 59 
a

Adriamycin–Carboplatin.

b

Radiotherapy.

c

Paclitaxel–Epirubicin–Carboplatin.

AEH, atypical endometrial hyperplasia; EC, endometrial carcinoma; FIGO, International Federation of Gynecology and Obstetrics; PD, progressive disease; SD: stable disease; CR, complete response; G1, well differentiated; G2, moderate differentiated; NED, no evidence of disease; NA, not available (lost in follow-up).

recurrence rate

In the present study, 4 of 20 patients with AEH and 2 of 14 with EC-G1 experienced recurrences (Figure 1). The average relapse time was 36 months (range 16–62 months). All women with recurrences underwent surgical staging (Figure 1). The final diagnosis in patients with initial AEH revealed two cases of EC-G1 FIGO stage IB, one IA, and the last relapsed as AEH. Patients with initial EC-G1 relapsed as EC-G1 FIGO stage IA and IIIA (Table 4). It is important to note that one patient with AEH relapsed 24 months after the first treatment, was retreated conservatively, and had CR after the second treatment. All patients who experienced relapse were alive and without evidence of disease at the last follow-up, except one who was lost to follow-up (Table 4). All of them underwent surgical staging and received adjuvant radiotherapy and/or chemotherapy according to standard guidelines.

adverse effects

No major complications or adverse effect, which required suspension of treatment, were recorded in this trial.

pregnancy outcomes

A total of 27 patients had a CR after conservative treatment, 9 of whom have achieved 11 spontaneous pregnancies (Table 5). Seven full-term pregnancies were obtained without major complications, and two others terminated in miscarriage at the 9th and 10th weeks. All these women have no associated polycystic ovarian syndrome or obesity.

Table 5.

Pregnancy outcomes

Case Age Histology Numbera of pregnancies Complication 
39 EC No 
40 AEH No 
3b 28 AEH 3c No 
33 AEH No 
41 AEH No 
6b 42 AEH No 
34 AEH Miscarriage (9th week) 
36 AEH NA 
29 AEH 1a Miscarriage (10th week) 
Case Age Histology Numbera of pregnancies Complication 
39 EC No 
40 AEH No 
3b 28 AEH 3c No 
33 AEH No 
41 AEH No 
6b 42 AEH No 
34 AEH Miscarriage (9th week) 
36 AEH NA 
29 AEH 1a Miscarriage (10th week) 

No patients presented obesity or polycystic ovarian syndrome.

a

Pregnancy obtained by ovulation induction.

b

Conservative treatment with associated early-stage ovarian cancer.

c

Third ongoing.

AEH, atypical endometrial hyperplasia; EC, endometrial carcinoma; NA, not available.

concomitant early stage of ovarian cancer

Concomitant early-stage ovarian cancer was confirmed in five women (14%) at laparoscopic evaluation before starting conservative treatment for EC or AEH. The histology revealed three cases of endometrioid adenocarcinoma, one case of serous adenocarcinoma, and one of endometrioid adenocarcinoma in a mostly borderline tumor. All these patients did not receive adjuvant chemotherapy, they underwent conservative treatment of the endometrial disease, and they are still under follow-up. It is interesting to note that two of these women had a full-term pregnancy.

discussion

This study shows that women <43 years with AEH or well-differentiated EC limited to the endometrium can be successfully managed by uterus-sparing hormonal treatment with intrauterine LNG and intramuscular GnRH analogue. A CR rate of 95% and 57.1% was seen with these staring diagnoses, respectively. To the best of our knowledge, this is the first prospective clinical trial using this treatment in this setting of women.

The efficacy of this combined treatment is comparable with previous studies using other hormonal treatments, even if the results obtained in patients with EC are in the lower range of the reported literature data. It is interesting to note that given the small sample size, just few patients are enough to significantly change the response rate. In addition, the population of the present investigation is slightly different from other series; in a 2005 series of a similar patient population from the MD Anderson Cancer Center, 58% of patients had a BMI >30 and in a recent paper from Italy [11], median BMI was 27.7; in the present series, we observed a median BMI value as low as 21; this observation may also explain the response rate in the slightly lower ranges of the reported literature data. The reported response rate to oral progestin in young women with well-differentiated EC is 60%–75% [12–15], with an average response time of 12 weeks [12]. One study in 12 postmenopausal older patients with EC presumed FIGO stage IA limited to the endometrium treated with LNG-IUD showed 50% CR [16]. In contrast, in patients with AEH, literature data on oral progestin treatment show a CR comparable with the present results, in the range of 80%–100%, and even when LNG-IUD was used for the treatment of simple endometrial hyperplasia [17–19], no difference in response rate with oral progestin was reported. We think that the LNG-IUD treatment is ideally suited for the young patient who is not immediately searching pregnancy and deserves a prolonged treatment.

Patient evaluation before treatment is a crucial point in conservative approach. Difficulties in the diagnosis of AEH and well-differentiated EC limited to the endometrium have been previously described. A recent Gynecologic Oncology Group (GOG) study [20] showed poor reproducibility of the diagnosis of AEH between referring institution and a panel of gynecological pathologists. The authors found low correlation coefficient (κ = 0.28) between pathologists for the diagnosis of AEH, underestimation or overestimation of the severity of the lesion, and they found that >20% of patients initially diagnosed as AEH actually had less disease [20]. In our study, most of the cases were referred to our institution; all the diagnoses made by external pathologists were reviewed by an internal pathologist; in case of discrepancies (internal versus external), slides were reviewed by another internal blinded pathologist. In addition, all the diagnoses originally made at our institution were reviewed in double. Theoretically, overdiagnosis might have occurred, leading to overtreatment and, finally, overstating the response rate of our treatment. Thus, to improve the accuracy of the diagnosis, we propose that in these selected groups of patients, a second independent pathology review should be done in all cases, as in the present investigation.

On the other hand, although most young women with EC-G1 will have stage I malignancy at diagnosis, some of them will also have extension of the disease beyond the uterine corpus. The GOG reported the risk of pelvic or aortic lymph node metastasis in EC-G1 to be 3%–5% [21]. Radiological assessment of lymph node metastases is more difficult, reporting a sensitivity of 57%, 50% [22], and 67% [23] for computed tomography scan, MRI, and 2-[fluorine-18]fluoro-2-deoxy-D-glucose–positron emission tomography scan, respectively. Apart from the possibility of having myometrial invasion and nodal metastases, ovarian involvement in young patients with early-stage EC has been reported to be 5% [24]. In addition, in 11%–29% of young women with endometrial cancer, a synchronous ovarian cancer has been also found [2]. Thus, laparoscopic evaluation before initiation of conservative therapy has been suggested by several authors [25, 26]. As a result, the possibility of having disease beyond the endometrium or outside the uterus, even after using the current diagnostic tools, should be discussed with patients as a potential risk before initiating any type of nonsurgical treatment for AEH and EC. Improved staging procedures, perhaps using molecular biomarkers or molecular imaging studies, may help physicians identify those patients best suited to uterus-sparing treatment.

Estrogen and progesterone receptors are present in the great majority of AEH and EC-G1 tissues [3], but hormonal treatment success cannot be predicted by pretreatment receptor status alone [27]. Three studies have reported patients with positive progesteroge receptor (PR) only, who underwent conservative hormonal treatment for EC, showing a mean CR rate of 73.3% (range 45%–100%) [14, 15, 28]. Moreover, Dhar et al. [29] studied the utility of LNG-IUD for the treatment of four young EC-G1 patients with positive PR and found a CR rate of 25%. Two isoforms of both estrogen receptor (ER) (ERα and ERβ) and PR (PRα and PRβ) have been described [30]. Progesterone treatment is capable of inhibiting invasion of endometrial cells by downregulating a number of genes, e.g. integrins and K-cadherin. PRα is nuclear, whereas PRβ shuttles between the nucleus and the cytoplasm. Thus, beyond the receptor status of endometrial cancer cells, additional underlying molecular mechanism might be involved, explaining these results. Additional molecular research should address this topic.

Our study suggests that the duration of hormonal therapy required to maximize therapeutic response is at least 6 months. At that time, all patients with AEH and EC had some kind of response. The added clinical benefit of LNG-IUD during the second 6 months of treatment requires further evaluation. The ideal treatment interval could further be affected by the changes in the dose, administration modality (systemic versus local), and administration schedule of the progestin used. There is some evidence that interrupted, rather than continuous, progestin therapy may have added benefit [11]. Progestin acts directly on endometrial cancer by inducing endometrial epithelial apoptosis and indirectly on withdrawal by physical shedding of tumor tissue. The direct progestin induction of apoptosis is extinguished after just a few days of continuous exposure in part through feedback-mediated downregulation of the progesterone receptor itself by its ligand. Withdrawal of progestin after a priming interval induces the highest apoptotic death rates, an order of magnitude greater than achieved with any continuous dose [31]. Thus, cyclic withdrawal of progestin, rather than continuous therapy, has been proposed as an alternative strategy for patient treatment [31]. The receptors themselves are not the sole participants in this process, however, as the response to treatment with progestin may be further modified by tumor-specific perturbations of the downstream cellular apoptotic signaling pathways [31].

conclusions

Uterus-sparing hormonal treatment of AEH and well-differentiated carcinoma with a combination of injected GnRH analogue and progestin-impregnated IUD can be effective in some patients. Patient qualification to exclude preexisting myoinvasive or distant disease is a crucial, although imperfect, prerequisite. Given the risks of disease progression or relapse, only those patients with significant expected benefit from uterine retention should be considered and then only following an adequate pretreatment evaluation. Close follow-up during and after treatment to monitor failures is crucial for timely triage into alternative, usually surgical, therapies. Further optimization and standardization of hormonal administration regimens may increase treatment efficacy. Development of new molecular or imaging tools for identification of those patients most likely to respond would enable us to better counsel patients in advance.

disclosure

The authors declare no conflict of interest.

The authors thank George L. Mutter, MD (Department of Pathology, Division of Women's and Perinatal Pathology, Brigham and Women's Hospital, Boston, USA) for his constructive suggestions and Larry V. Rubinstein, PhD (Biometric Research Branch, National Cancer Institute, National Institutes of Health) for his contribution in the statistical analysis. In addition, we thank Mary Ryan, MLS (National Institutes of Health Library, Bethesda, MD, USA) and Nadia Caroppo, MD (Preventive Gynecology Unit, European Institute of Oncology, Milan, Italy) for editing the manuscript.

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