Risk of cervical intraepithelial neoplasia grade 2 or worse in women aged ≥ 69 referred to colposcopy due to an HPV-positive screening test.

BACKGROUND: Cervical cancer incidence and mortality rates are high in older women in many developed countries, including Denmark. Therefore, Danish women aged 69 and older were invited for one additional human papilloma virus (HPV) based screening test in 2017. Here, we describe the clinical management and detection rate of cervical intraepithelial neoplasia grade 2 or worse (CIN2 +) in screen-positive women referred for colposcopy. METHODS: We conducted an observational study in public gynecology departments in Central Denmark Region, Denmark. Women were eligible for enrolment if they were aged 69 + in 2017, HPV positive on a screening test taken between April 20th, 2017, and December 31st, 2017, and had been referred for direct colposcopy. Data on participants' characteristics, colposcopic findings, and histological outcomes were collected from medical records and the Danish Pathology Databank. We estimated the proportion of women with CIN2 + at the first colposcopy visit and at end of follow up including 95% confidence intervals (CIs). RESULTS: A total of 191 women were included with a median age of 74 years (IQR: 71-78). Most women (74.9%) did not have a fully visible transformation zone at colposcopy. At the first visit 170 women (89.0%) had a histological sample collected, 34 of whom (20.0%, 95% CI 14.3-26.8%) had CIN2 + diagnosed, 19 had CIN3 + , and two had cervical cancer). During follow-up additional CIN2 + were detected resulting in a total of 42 women (24.4%, 95% CI: 18.2-31.5%) being diagnosed with CIN2 + , 25 with CIN3 + , and three with cervical cancer. When restricting to women with paired histologic results (i.e., biopsies and a loop electrosurgical excision procedure (LEEP) specimen), we found that CIN2 + was missed in 17.9% (95% CI 8.9-30.4%) of biopsies compared to the LEEP. CONCLUSION: Our findings suggest a potential risk of underdiagnosis in older postmenopausal women referred to colposcopy. Future studies should explore potential risk-markers for discrimination of women at increased risk of CIN2 + from those at low risk, as this would reduce risk of underdiagnosis and overtreatment.

[HPV vaccination for women].

HPV vaccination is associated with a reduced risk of cervical cancer and its precursors, with greatest protection when the vaccine is administered before sexual debut. This review aims to discuss whether immunization with the nonavalent HPV vaccine should be recommended to women who have previously been vaccinated with the bi- or quadrivalent HPV vaccine and to women who have previously undergone treatment for condylomas or dysplasia of the vulva, vagina, or cervix.

Fresh and cryopreserved ovarian tissue transplantation for preserving reproductive and endocrine function: a systematic review and individual patient data meta-analysis.

BACKGROUND: Ovarian tissue cryopreservation involves freezing and storing of surgically retrieved ovarian tissue in liquid or vapour nitrogen below -190°C. The tissue can be thawed and transplanted back with the aim of restoring fertility or ovarian endocrine function. The techniques for human ovarian tissue freezing and transplantation have evolved over the last 20 years, particularly in the context of fertility preservation in pre-pubertal cancer patients. Fresh ovarian tissue transplantation, using an autograft or donor tissue, is a more recent development; it has the potential to preserve fertility and hormonal function in women who have their ovaries removed for benign gynaecological conditions. The techniques of ovarian tissue cryopreservation and transplantation have progressed rapidly since inception; however, the evidence on the success of this intervention is largely based on case reports and case series. OBJECTIVE AND RATIONALE: The aim of this study was to systematically review the current evidence by incorporating study-level and individual patient-level meta-analyses of women who received ovarian transplants, including frozen-thawed transplant, fresh or donor graft. SEARCH METHODS: The review protocol was registered with PROSPERO (CRD42018115233). A comprehensive literature search was performed using MEDLINE, EMBASE, CINAHL and Cochrane Central Register of Controlled Trials from database inception to October 2020. Authors were also contacted for individual patient data if relevant outcomes were not reported in the published manuscripts. Meta-analysis was performed using inverse-variance weighting to calculate summary estimates using a fixed-effects model. OUTCOMES: The review included 87 studies (735 women). Twenty studies reported on ≥5 cases of ovarian transplants and were included in the meta-analysis (568 women). Fertility outcomes included pregnancy, live birth and miscarriage rates, and endocrine outcomes included oestrogen, FSH and LH levels. The pooled rates were 37% (95% CI: 32-43%) for pregnancy, 28% (95% CI: 24-34%) for live birth and 37% (95% CI: 30-46%) for miscarriage following frozen ovarian tissue transplantation. Pooled mean for pre-transplant oestrogen was 101.6 pmol/l (95% CI: 47.9-155.3), which increased post-transplant to 522.4 pmol/l (95% CI: 315.4-729; mean difference: 228.24; 95% CI: 180.5-276). Pooled mean of pre-transplant FSH was 66.4 IU/l (95% CI: 52.8-84), which decreased post-transplant to 14.1 IU/l (95% CI: 10.9-17.3; mean difference 61.8; 95% CI: 57-66.6). The median time to return of FSH to a value <25 IU/l was 19 weeks (interquartile range: 15-26 weeks; range: 0.4-208 weeks). The median duration of graft function was 2.5 years (interquartile range: 1.4-3.4 years; range: 0.7-5 years). The analysis demonstrated that ovarian tissue cryopreservation and transplantation could restore reproductive and hormonal functions in women. Further studies with larger samples of well-characterized populations are required to define the optimal retrieval, cryopreservation and transplantation processes. WIDER IMPLICATIONS: Ovarian tissue cryopreservation and transplantation may not only be effective in restoring fertility but also the return of reproductive endocrine function. Although this technology was developed as a fertility preservation option, it may have the scope to be considered for endocrine function preservation.

Preoperative prediction of high-risk endometrial cancer by expert and non-expert transvaginal ultrasonography, magnetic resonance imaging, and endometrial histology.

OBJECTIVE: To identify women with high-risk endometrial cancers using expert and non-expert transvaginal ultrasonography (TVS) and MRI. STUDY DESIGN: Myometrial involvement was prospectively evaluated in patients with atypical hyperplasia or endometrial cancer on ultrasound by non-experts at first visit (non-expert-TVS: n = 266) and experts (expert-TVS: n = 188) at second visit. MRI (n = 175) was performed when high-risk cancer was suspected on non-expert-TVS. Preoperatively, high-risk cancer was defined as myometrial involvement ≥50 %, or preoperative unfavorable tumor histology (grade 3 endometrioid, non-endometrioid tumors, or tumor in cervical biopsies) obtained by endometrial sampling or hysteroscopic biopsies. Preoperative evaluations were compared with final histopathology obtained at surgery, high-risk cancer being defined as unfavorable tumor histology or patients with FIGO stage ≥1b. RESULTS: Preoperative unfavorable tumor histology was seen in 64 women and correctly identified 63 of 128 high-risk cancers. Preoperative diagnosis of unfavorable tumor histology or myometrial involvement ≥50 %, i.e. judged high-risk, had an area under the curve (AUC), sensitivity, and specificity of 79.5 %, 93.8 %, 65.2 % on non-expert-TVS; 85.5 %, 84.4 %, 86.5 % on expert-TVS, and 85.4 %, 89.6 %, 81.2 % on MRI. AUC values were not significantly different between MRI and expert-TVS, but lower on non-expert-TVS (p < 0.02). However, sensitivity was highest on non-expert-TVS, where a low cutpoint for myometrial involvement was used (included potentially deep and difficult evaluations) in contrast to an exact cutpoint of myometrial involvement ≥50 % used on expert-TVS and MRI. The highest AUC, 88.6 %, was seen when MRI was performed in patients with myometrial involvement ≥50 %, determined on non-expert TVS. Sensitivity was reduced to 85.9 %, while specificity increased to 91.3 %. Thus, MRI was needed for risk classification in only 104 (39 %) patients. CONCLUSION: Diagnostically, expert-TVS and MRI were comparable and superior to non-expert-TVS. However, non-expert-TVS classified all patients with unclear myometrial involvement ≥50 %, and thereby only misdiagnosed 6.2 % of high-risk cases. Non-expert-TVS combined with MRI when myometrial involvement was ≥50 % on non-expert-TVS was a simple and effective method comparable with expert imaging to identify low- and high-risk cancer and select patients for SLND. Addition of MRI to the diagnostic regimen was needed in only 39 % of our patients.

Reproductive outcomes after in vitro fertilization treatment in a cohort of Danish women transplanted with cryopreserved ovarian tissue.

OBJECTIVE: To evaluate ovarian stimulation regimens and reproductive outcomes in a cohort of women undergoing ovarian tissue cryopreservation (OTC) and ovarian tissue transplantation (OTT). DESIGN: Retrospective cohort study. SETTING: University hospital and fertility clinics. PATIENTS: Twenty-eight women undergoing OTT and in vitro fertilization (IVF) from 2012 to 2017. INTERVENTION: OTC, OTT, and IVF. MAIN OUTCOME MEASURES: Ovarian stimulation and IVF outcomes. RESULTS: In total, 99 cycles were performed in 28 patients. In 19 patients responding to stimulation, a median of 3.0 cycles per patient (range: 1-14 cycles) was performed, and 2.0 mature oocytes were retrieved per cycle. The empty follicle rate was 35.9%. Eleven women achieved 15 pregnancies, of which 60% were lost during the first or second trimester, resulting in 5 of 28 women having ≥1 live births, and seven healthy children being born. In breast cancer patients (mean age at OTC: 33.0 years), the pregnancy rates (PR) and live birth rates (LBR) were 35.0% and 5.0% per embryo transfer, respectively. Patients aged ≥34.5 years at OTC all had breast cancer and did not achieve any pregnancies. For all other diagnoses (mean age at OTC: 26.6 years), PR and LBR were 50.0% and 37.5% per embryo transfer, respectively. Collectively, 39% of patients conceived at least once, and 17.9% delivered. Frozen-thawed embryo transfer (FET) resulted in more pregnancies than did fresh embryo transfer. CONCLUSION: Our results suggest that women of advanced maternal age undergoing OTC and IVF have a poor ovarian reserve, resulting in a poor reproductive outcome. Interestingly, FET appeared to be superior to fresh transfer.

Ultrasound Scoring of Endometrial Pattern for Fast-track Identification or Exclusion of Endometrial Cancer in Women with Postmenopausal Bleeding.

STUDY OBJECTIVE: To evaluate the risk of endometrial cancer (REC) scoring system for the prediction of high and low probability of endometrial cancer (EC) in women with postmenopausal bleeding (PMB). DESIGN: A prospective study (Canadian Task Force classification II-1). SETTING: An academic hospital. PATIENTS: Nine hundred fifty consecutive patients with PMB underwent transvaginal ultrasonography (TVS) and REC scoring between November 2013 and December 2015. INTERVENTIONS: Obstetrics and gynecology residents supervised by trained physicians scored endometrial patterns according to the previously established REC scoring system. The reference standard was endometrial samples, endometrial thickness (ET, 4-4.9 mm), operative hysteroscopy or hysterectomy (ET ≥5 mm), and 1-year follow-up in all patients presenting with ET <4 mm. Diagnostic performance for the prediction of probability of malignancy was assessed using the REC scoring system. MEASUREMENTS AND MAIN RESULTS: The area under the receiver operating characteristic curve of the TVS REC scoring system was 97% (95% confidence interval [CI], 95%-98%) for the prediction of malignancy. In 656 patients with ET ≥4 mm, REC scoring effectively predicted a high probability of malignancy with sensitivity (95% confidence interval) of 92% (95% CI, 87%-95%) and specificity of 94% (95% CI, 91%-96%). An REC score of 0 was present in 206 (32%) patients with ET ≥4 mm and was associated with a low negative likelihood ratio of 0.026 for EC. There were only 7 patients with EC/atypical hyperplasia among these 206 patients. CONCLUSION: The REC scoring system identified or ruled out most ECs, clearly showing that more specific image analysis at first-line TVS can accelerate the diagnosis of EC in patients with PMB and may allow for improved selection of second-line strategies in patients with ET ≥4 mm.

Structured imaging technique in the gynecologic office for the diagnosis of abnormal uterine bleeding.

The aim in the diagnosis of abnormal uterine bleeding (AUB) is to identify the bleeding cause, which can be classified by the PALM-COEIN (Polyp, Adenomyosis, Leiomyoma, Malignancy (and hyperplasia), Coagulopathy, Ovulatory disorders, Endometrial, Iatrogenic and Not otherwise classified) classification system. In a gynecologic setting, the first step is most often to identify structural abnormalities (PALM causes). Common diagnostic options for the identification of the PALM include ultrasonography, endometrial sampling, and hysteroscopy. These options alone or in combination are sufficient for the diagnosis of most women with AUB. Contrast sonography with saline or gel infusion, three-dimensional ultrasonography, and magnetic resonance imaging may be included. AIM: The aim of this article is to describe how a simple structured transvaginal ultrasound can be performed and implemented in the common gynecologic practice to simplify the diagnosis of AUB and determine when additional invasive investigations are required. Structured transvaginal ultrasound for the identification of the most common endometrial and myometrial abnormalities and the most common ultrasound features are described. Moreover, situations where magnetic resonance imaging may be included are described. This article proposes a diagnostic setup in premenopausal women for the classification of AUB according to the PALM-COEIN system. Moreover, a future diagnostic setup for fast-track identification of endometrial cancer in postmenopausal women based on a structured evaluation of the endometrium is described.

Structured Hysteroscopic Evaluation of Endometrium in Women With Postmenopausal Bleeding.

STUDY OBJECTIVE: To evaluate visual pattern parameters obtained with hysteroscopy for the prediction of endometrial cancer, to evaluate observer variation of these parameters, and to present a scoring system of the parameters for the prediction of malignancy compared with subjective evaluation. DESIGN: A prospective controlled study (Canadian Task Force classification II-1). SETTING: A university clinic. PATIENTS: One hundred forty-nine consecutive women with postmenopausal bleeding and an endometrium thickness ≥ 5 mm. Sixty-one (41%) had endometrial cancer. Forty-six of 149 women were referred based on suspected malignancy. INTERVENTIONS: Endometrial pattern characteristics for endometrial cancer were evaluated in hysteroscopic video clips. The reference standard was pathologic evaluation of resectoscopic samples or hysterectomy. Using multivariate logistic regression, image parameters were correlated with the presence of endometrial cancer. A scoring system of visual parameters for the prediction of malignancy was compared with subjective evaluation of malignancy. MEASUREMENTS AND MAIN RESULTS: A score for lesion surface, necrosis, and vessels had an area under the curve (AUC) of 0.89, 0.89, and 0.87, respectively. A hysteroscopic cancer (HYCA) scoring system based on unsmooth lesion surface, papillary projections, surface necrosis, "candy floss" necrosis, white hyperintense spots, irregular branching vessels, and irregular distribution of irregular vessels was able to predict cancer (AUC = 0.964) with higher accuracy than subjective evaluation (AUC = 0.859, p < .01). At a score value ≥ 3, sensitivity was 89% and specificity was 92% with moderate agreement between observers (kappa = 0.56 [0.42-0.71]). CONCLUSION: A systematic pattern evaluation of optimal parameters by a HYCA scoring system based on systematically defined terms may increase accuracy in the diagnosis of endometrial cancer and should be further elaborated and external validity tested in unselected women with postmenopausal bleeding.

Reproducibility of Endometrial Pathologic Findings Obtained on Hysteroscopy, Transvaginal Sonography, and Gel Infusion Sonography in Women With Postmenopausal Bleeding.

STUDY OBJECTIVE: To evaluate and compare interobserver variation in endometrial pattern recognition with hysteroscopy (HY) and transvaginal sonography (TVS) and gel infusion sonography (GIS) with regard to the diagnosis of endometrial pathology. DESIGN: Prospective study (Canadian Task Force II-1). SETTING: University clinic. PATIENTS: One hundred twenty-two consecutive women with postmenopausal bleeding and an endometrium thickness ≥ 5 mm. INTERVENTION: Two observers using HY and 2 others using TVS and GIS evaluated the endometrial pattern in recorded video clips. Interobserver agreement regarding findings obtained with TVS, GIS, and HY for a diagnosis of cancer, hyperplasia, polyps, and no endometrial pathology was expressed by κ coefficients and compared. MEASUREMENT AND MAIN RESULTS: Interobserver agreement (κ) was as follows: identification of normal endometrium: HY (.74), TVS (.68), and GIS (.48); diagnosis of cancer: HY (.56), TVS (.59), and GIS (.34); classification in all categories of endometrial pathology: HY (.70), TVS (.47), and GIS (.41) (p < .05 HY vs GIS). The presence of additional endometrial polyps decreased agreement on HY in patients with hyperplasia or cancer. Observer agreement was poor regarding the diagnosis of hyperplasia by all techniques. CONCLUSION: Observer agreement regarding both HY and TVS was reliable for the diagnosis of a normal endometrium but poor with HY, TVS, and especially GIS for a diagnosis of cancer. In patients with hyperplasia or cancer, agreement between observers was especially low in the presence of additional polyps when HY was used. These findings call attention to the need for systematic methods to improve reliability in endometrial pattern recognition.