Obstetrics & Gynecology

Invasive Cervical Cancer After a Positive Pap Test Result and Negative Human Papillomavirus Test Result

The majority of cervical cancers after Pap-test–positive, human papillomavirus test–negative co-tests are symptomatic or clinically apparent.

Complications and Recurrence After Pelvic Exenteration for Gynecologic Malignancies

OBJECTIVE: To collect data from patients undergoing pelvic exenteration in recent clinical practice. The primary aim was 5-year disease-free survival. Secondary aims were 5-year overall survival, patterns of recurrence, identification of subgroups at higher risk of recurrence and death, survival associated with lymph node metastasis, and development of a prognostic score. METHODS: This was a retrospective, multicenter, international study conducted in tertiary national gynecologic oncology referral centers. Inclusion criteria included cervical, vaginal, vulvar, or endometrial cancer; anterior or total pelvic exenteration performed between January 2005 and March 2023; curative or palliative intent; and with or without laterally extended endopelvic or pelvic resection. Patients were excluded if they underwent posterior pelvic exenteration only or if preoperative computed tomography (CT), positron emission tomography (PET)–CT, or PET was not performed. A prognostic score was developed that was based on multivariable analysis. RESULTS: Eight hundred sixty-two patients were included. Surgical margins were tumor free in 676 (78.4%). In patients treated with curative intent, total pelvic exenteration, positive surgical margins, and presence of lymphovascular space invasion were independently associated with worse disease-free survival. Performance of lymphadenectomy was associated with better disease-free survival. Total pelvic exenteration, positive surgical margins, and presence of lymphovascular space invasion were factors independently associated with decreased overall survival. Performing pelvic exenteration at time of persistent (instead of recurrent) disease negatively affected overall survival. Prognostic score identified four risk groups with a 5-year disease-free survival of 43.7%, 24.9%, 22.2%, and 8.0% (P<.001). The 5-year overall survival in the four risk groups was 54.3%, 40.4%, 24.0%, and 4.3% (P<.001). The most frequent sites of recurrence were distant in 166 patients (32.1%). The 5-year disease-free survival and cancer-specific survival in patients with para-aortic lymph node metastasis were significantly worse compared with those in patients with pelvic-only metastatic nodes or with negative nodes (P=.002 and P<.001, respectively). CONCLUSION: Independent factors associated with worse disease-free survival and overall survival and subgroups of patients at higher risk of recurrence and death were identified. A multivariable prognostic score was developed that can be used for patient counseling and surveillance strategies and for future prospective studies.

Health Disparities in Ovarian Cancer

Health disparity, defined by the Centers for Disease Control and Prevention (CDC) as “preventable differences in the burden of disease, injury, violence, or opportunities to achieve optimal health that are experienced by socially disadvantaged populations,” is seen across multiple diseases. We conducted an evidence review of health disparities and inequities and their mitigation strategies related to ovarian cancer as part of a CDC-sponsored project to develop educational materials for clinicians on the prevention and early diagnosis of gynecologic cancers. Our review found profound disparities in outcomes such as survival, treatment, and stage at diagnosis by factors such as race and ethnicity, insurance, socioeconomic status, and geographic location. We found little direct evidence on mitigation strategies. Studies support equivalent response to equivalent treatment between groups, suggesting that adherence to National Comprehensive Cancer Network guidelines can at least partially mitigate some of the differences.

Low-Grade Endometrial Stromal Sarcoma Diagnosed 8 Years After Hysterectomy With Morcellation

BACKGROUND: Morcellation at the time of minimally invasive hysterectomy or myomectomy for presumed benign indications carries a risk of disseminating undiagnosed uterine malignancies. CASE: A 57-year-old woman with a remote history of laparoscopic hysterectomy with morcellation of a cellular leiomyoma presented with a newly diagnosed complex pelvic mass. Owing to adherence of the mass to the rectum and numerous peritoneal tumor implants, a surgical cytoreductive procedure was performed. The pelvic mass, implants, and original hysterectomy specimen were histologically identical and consistent with low-grade endometrial stromal sarcoma. Owing to lack of tumor–myometrial interface on the original morcellated specimen, this malignant diagnosis was not made at the time of hysterectomy. CONCLUSION: Morcellation of the uterus can hinder an accurate pathologic diagnosis of uterine stromal neoplasms.

Occult Tubal Carcinoma After Risk-Reducing Salpingo-oophorectomy

OBJECTIVE: To perform a systematic review of the literature to estimate the prevalence and outcomes of occult tubal carcinoma in BRCA mutation carriers and high-risk patients undergoing risk-reducing salpingo-oophorectomy. DATA SOURCE: A search was done using OVID MEDLINE, EMBASE, and ClinicalTrials.gov between 1946 and March 2019 with keywords and MeSH terms selected by an expert medical librarian and coauthors. METHODS OF STUDY SELECTION: Two independent reviewers performed study selection with an initial screen on abstracts and a second on full articles. Articles were rejected if they were irrelevant to the study question, pertained to a different population or did not report occult tubal neoplasia. Quality was assessed using methodologic index for nonrandomized studies criteria. TABULATION, INTEGRATION, AND RESULTS: Data were extracted and recorded in an Excel database. Forest plots for the prevalence of occult carcinoma were done using STATA. Among 2,402 studies assessed, 27 met the inclusion criteria for qualitative and quantitative analysis. A total of 6,283 patients underwent risk-reducing salpingo-oophorectomy between 2002 and 2019: 2,894 cases were BRCA1, 1,579 BRCA2, and 1,810 high-risk based on family history. Among these, 75 patients were diagnosed with occult tubal carcinoma at the time of surgery. The pooled prevalence was 1.2% (I2=7.1%, P=.363) occurring at a median age of 53.2 years (range 42.4–67). In a subanalysis of 18 studies reporting follow-up data, 10 recurrences (18.7%, 95% CI 7.5–53%) and 24 cases of post–risk-reducing salpingo-oophorectomy peritoneal cancer (0.54%, 95% CI 0.4–1.9%) were reported after a median follow-up of 52.5 months. BRCA1, older age, and previous breast cancer were more often associated with occult malignancy. CONCLUSION: Occult tubal carcinomas found at risk-reducing salpingo-oophorectomy in high-risk patients and BRCA mutation carriers have significant potential for recurrence despite the frequent administration of postoperative chemotherapy.

Tracking the Cesarean Delivery–Postmolar Gestational Trophoblastic Neoplasia Link

OBJECTIVE: To evaluate whether the history of cesarean delivery influences the risk or clinical aggressiveness of postmolar gestational trophoblastic neoplasia. METHODS: This retrospective cohort study involved two gestational trophoblastic disease reference centers in Brazil and the United States. Medical records from patients with histopathologically confirmed hydatidiform mole between January 2002 and December 2022 were reviewed. Patients were grouped according to the presence or absence of prior cesarean delivery. The primary outcome was the development of postmolar gestational trophoblastic neoplasia; the secondary outcome was resistance to single-agent chemotherapy. Multivariable logistic regression models adjusted for relevant confounders were used to identify independent predictors. RESULTS: Among 2,904 patients with hydatidiform mole, prior cesarean delivery was associated in a multivariable logistic regression with an increased risk of postmolar gestational trophoblastic neoplasia (adjusted odds ratio [aOR] 1.45, 95% CI, 1.13–1.85) that was independent of age, complete hydatidiform mole histology, city of uterine evacuation, pre-evacuation human chorionic gonadotropin level, and year of hydatidiform mole diagnosis. Furthermore, neither the number of previous cesarean deliveries (aOR 1.43, 95% CI, 0.91–2.24) nor an elective indication (aOR 1.12, 95% CI, 0.60–2.08) appeared to modify this risk. Cesarean delivery history (aOR 1.27, 95% CI, 0.59–2.73) and number of (aOR 0.22, 95% CI, 0.02–1.89) or indication for (aOR 0.36, 95% CI, 0.06–2.03) prior cesarean delivery were not significantly associated with chemoresistance among 621 patients with low-risk gestational trophoblastic neoplasia. CONCLUSION: A history of cesarean delivery is associated with a 45.0% increased risk of postmolar gestational trophoblastic neoplasia without evidence of greater chemoresistance. These findings support current management protocols while indicating that patients with prior cesarean delivery may benefit from heightened clinical vigilance during standard postmolar surveillance.

Fragmented Care and Guideline-Concordant Treatment in Locally Advanced Cervical Cancer

OBJECTIVE: To characterize and estimate rates of fragmented care, to investigate its association with the receipt of guideline-concordant treatment, and to evaluate treatment components at risk with fragmented care. METHODS: This is a single-institution retrospective study of patients with locally advanced cervical cancer (stage IB3–IVA) from January 2003 to September 2023. We stratified patients into fragmented and nonfragmented care groups based on receipt of all care at our institution or if they received any component of care outside of our institution. The primary outcome, receipt of guideline-concordant treatment, was defined as a composite of 1) completion of treatment within 56 days, 2) completion of brachytherapy, and 3) receipt of concurrent chemotherapy. Demographic and treatment data were collected, including the Social Vulnerability Index (SVI), a census tract–based measure of disadvantage. Univariate and multivariate analyses were performed. RESULTS: Two hundred eighty-six patients were identified; 75.5% received fragmented care. Those receiving nonfragmented care were significantly more likely to receive guideline-concordant treatment than those receiving fragmented care (71.4% vs 50.9%, P=.003). This was driven primarily by rates of timely completion (81.4% vs 60.6%, P=.001). Univariate analysis indicated that fragmented care (odds ratio [OR] 0.42, 95% CI, 0.23–0.74) and Medicaid insurance (OR 0.40, 95% CI, 0.20–0.78) were significantly associated with lower odds of guideline-concordant treatment. Multivariate analyses controlling for a priori confounders of insurance type and SVI showed that fragmented care (OR 0.45, 95% CI, 0.23–0.90) and Medicaid insurance (OR 0.42, 95% CI, 0.19–0.89) were independently associated with lower odds of guideline-concordant treatment. Multivariate analysis controlling for demographic covariates found even lower odds of receiving guideline-concordant treatment in those who received fragmented care (OR 0.39, 95% CI, 0.18–0.84) and who had Medicaid insurance (OR 0.35, 95% CI, 0.16–0.78). CONCLUSION: More than 75% of patients received fragmented care, which had a significant clinical effect and was associated with significantly lower rates of guideline-concordant treatment.

Effectiveness of Artificial Intelligence–Assisted Colposcopy in a Resource-Limited Population

OBJECTIVE: This study evaluates the performance of artificial intelligence (AI) colposcopy in detecting cervical cancer and precancerous lesions in real-world scenarios within resource-limited areas. METHODS: This is a cross-sectional study. Participants with positive human papilloma virus results or who were cytologic positive were referred for colposcopy, during which AI colposcopy was implemented. Biopsies were performed for positive findings suggested by either the colposcopist or the AI system. For the analysis, we calculated the sensitivity, specificity, positive predictive value, negative predictive value, and area under the curve for detecting cervical intraepithelial neoplasia (CIN) 2+ and CIN 3+. Histopathology was the gold standard for disease diagnosis. RESULTS: A total of 825 women underwent colposcopy, with 99 (12.0%) diagnosed with CIN 2+ and 53 (6.4%) with CIN 3+. Positive findings were reported in 392 women (47.5%) under conventional colposcopy and 640 (77.6%) with AI colposcopy. The sensitivity for detecting CIN 2+ was significantly higher for AI colposcopy (96.0%) and AI-assisted colposcopy (100%) than for conventional colposcopy (85.9%, P=.026, P<.001, respectively). In postmenopausal women, the sensitivities of AI colposcopy (94.3%) and AI-assisted colposcopy (100%) surpassed that of conventional colposcopy (77.4%, P=.026, P<.001, respectively). Artificial intelligence–assisted colposcopy also significantly enhanced the sensitivity of junior colposcopists with less than 10 years of clinical experience, achieving 100% compared with 84.6% by conventional colposcopy (P=.001), and improved detection in women with a squamocolumnar junction that was not visible (100% vs 70.4%, P=.004). For CIN 3+, the sensitivity of AI-assisted colposcopy was superior to that of conventional colposcopy (100% vs 86.8%, P=.013). In postmenopausal women, the sensitivities of both AI colposcopy and AI-assisted colposcopy were 100%; however, the sensitivity of conventional colposcopy was 77.8% (P=.023). CONCLUSION: Artificial intelligence–assisted colposcopy enhances sensitivity in detecting CIN 2+ and CIN 3+, particularly among postmenopausal women. Moreover, it improves the diagnostic performance of junior colposcopists and improves detection in women with a squamocolumnar junction that is not visible.

Implementation of Human Papillomavirus Self-Collection and Barriers to Follow-Up Among Unhoused Individuals in Texas

OBJECTIVE: Although cervical cancer rates are low in the United States, certain populations experience disproportionate incidence and mortality attributable to inadequate access to screening, diagnosis, or treatment. High-risk human papillomavirus (HPV) self-collection is an effective strategy to increase uptake of cervical cancer screening; however, its effectiveness among unhoused individuals is unknown. The objective of this study was to assess the feasibility of HPV self-collection among unhoused individuals and to identify barriers to follow-up diagnosis and treatment. METHODS: This is a single-arm feasibility trial. Unhoused individuals aged 25 years or older were prospectively enrolled in Austin, Texas, at community resource centers. They were offered brief education about cervical cancer and the opportunity to screen with high-risk HPV self-collection. Samples were sent to a commercial laboratory for testing. Result notification occurred in person or by telephone. Participants with high-risk HPV–positive results were navigated to follow-up with colposcopy. All participants answered an exit survey. RESULTS: From May to October 2024, 89 participants were enrolled, of whom 87 collected samples. There were six invalid samples (6.9%), two of which were recollected. Of the 83 valid samples, 21 (25.3%) were positive for high-risk HPV and 62 (74.7%) were negative for high-risk HPV. Only 46 of 87 participants who collected samples (52.9%) received their results despite multiple attempts to contact them. Of the 21 participants with high-risk HPV–positive results, four (19.0%) have undergone colposcopy. There were numerous barriers to follow-up care. CONCLUSION: Our results suggest that it is feasible to implement high-risk HPV self-collection among unhoused individuals; however, there are significant barriers to follow-up for those who test positive. Although high-risk HPV self-collection may improve cervical cancer screening rates among underscreened populations, follow-up diagnosis and treatment of precancerous lesions are necessary to prevent cervical cancer. Future research is needed to identify strategies to decrease loss to follow-up rates. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT06109870.

Preferences Among U.S. Women for Cervical Cancer Screening with Self-Collected Specimens for Human Papillomavirus Testing

OBJECTIVE: To examine preferences for human papillomavirus (HPV) specimen self-collection, and collection location, in a nationally representative sample of reproductive-aged women in the United States. METHODS: This cross-sectional analysis used household population-based data from the National Survey of Family Growth (January 2022–December 2023) and was limited to women aged 21–49 years without a history of hysterectomy or cervical cancer (sample n=4,465). Survey weights and design variables were applied to generate nationally representative population frequencies and percentages of preference for HPV self-collection compared with clinician collection, and preference for collection location (ie, at home or in office). RESULTS: Among eligible U.S. women, 42.9% preferred HPV self-collection, 28.5% preferred clinician collection, and 28.6% expressed no preference. An estimated 41.7 million (71.5%) U.S. women aged 21–49 years were open to HPV self-collection (either preferring it or having no preference), including 9.7 million women who were underscreened or never screened. Among women who were open to HPV self-collection, more than half (52.1%) preferred self-collection at home, 14.7% preferred to do self-collection in a doctor's office, and 33.2% had no preference for location. More underscreened or never-screened women preferred HPV self-collection (54.0%) and at-home collection (59.3%) compared with those who were up to date with screening (40.3% and 50.2%, respectively, P <.001). Preference for self-collection also varied by race and Hispanic origin, education, income, parity, sexual orientation, and prior experience of nonvoluntary vaginal intercourse. CONCLUSION: In this nationally representative study, more than 7 in 10 U.S. women aged 21–49 years were open to HPV self-collection for cervical cancer screening, with more than half favoring at-home collection. Preference was higher among women who were not up to date with screening. These findings provide timely evidence to inform future policy decisions and implementation strategies to improve access to cervical cancer screening.

Association Between Comorbidity and Clinical Trial Enrollment for Patients With Uterine Cancer

OBJECTIVE: To characterize the presenting comorbidity profile of patients with uterine cancer by race and ethnicity and use real-world data to quantify expected effects of common comorbidity eligibility criteria on uterine cancer trial accrual. METHODS: This observational, cross-sectional study used the Vizient Clinical Data Base to identify individuals aged 18 years or older with a uterine cancer diagnosis from 2002 to 2021. Demographic variables and comorbidity diagnoses were identified by International Classification of Diseases, Ninth and Tenth Revision codes and used to construct Charlson, Elixhauser, and National Cancer Institute comorbidity indices. Summary theoretical ineligibility rates were calculated by race based on a modified set of comorbidity-eligibility criteria. Ineligibility rates were compared between groups and differences assessed with logistic regression. RESULTS: We identified 384,093 patients with uterine cancer; 70.0% of the patients were non-Hispanic White, 13.4% were non-Hispanic Black, 7.1% were of unknown race, and 2.8% were non-Hispanic Asian. Across all comorbidity indices, non-Hispanic Black individuals persistently had the highest scores among all racial groups. Comorbidity prevalence varied significantly by race. Non-Hispanic Black individuals had the highest rates of renal failure (11.6%), diabetes (23.4%), and hypertension (49.8%) compared with non-Hispanic White and non-Hispanic Asian individuals. In modeling analyses, non-Hispanic Black individuals had twofold higher odds of trial exclusion based on comorbidities than non-Hispanic White individuals (adjusted odds ratio [aOR] 2.06; 95% CI, 2.02–2.10). Those of unknown race had slightly higher odds (aOR 1.02; 95% CI, 0.99–1.05) and non-Hispanic Asians slightly lower odds (aOR 0.98; 95% CI, 0.94–1.02) of being ineligible relative to non-Hispanic White individuals. CONCLUSION: For patients with uterine cancer, comorbidity prevalence and comorbidity index scores varied by race. This results in differences in trial eligibility at baseline before any patient engagement. Quantifying the distribution of comorbidities is critical because it allows us to statistically anticipate how individual comorbidity eligibility criteria may hamper the accrual of patients from minoritized groups. This, in turn, can support equity efforts to plan trial eligibility criteria and targeted recruitment.

Etiology, Natural History, and Management of Recent Advances in Molar Pregnancy

Molar pregnancy is a rare reproductive anomaly that globally affects 1:1,000–1,500 pregnancies. It is caused by aberrant fertilization and can be associated with medical complications or progress to postmolar gestational trophoblastic neoplasia. Molar pregnancy presents with two distinct entities, complete and partial hydatidiform mole, which differ in their clinical, genetic, and prognostic aspects. Maternal age and history of molar pregnancy are the main risk factors for the occurrence of molar pregnancy. Early diagnosis of molar pregnancy by ultrasonography is associated with a decrease in medical complications but not decreased postmolar gestational trophoblastic neoplasia. After the diagnosis of a presumed molar pregnancy, patients should be referred to an expert with experience taking care of molar pregnancy or to a reference center for uterine evacuation and postmolar follow-up, which facilitates early diagnosis of gestational trophoblastic neoplasia. Weekly human chorionic gonadotropin measurement is essential to confirm remission and to identify cases of gestational trophoblastic neoplasia that will require further treatment. To maintain the reliability of this tumor marker, hormonal contraception is indicated during postmolar follow-up. The postmolar follow-up should extend for 1 month and from 3 to 6 months after remission in cases of partial and complete hydatidiform mole, respectively. The reproductive outcomes after molar pregnancy are comparable with those of the general population, except for the higher occurrence of recurrent molar pregnancy, affecting 1.0–2.0% of subsequent pregnancies. The considerable psychosocial repercussions of molar pregnancy require a multidisciplinary approach to minimize the repercussions of this disease on mental health.

Prediction of Treatment Failure After Excisional Treatment of Cervical Precancer

OBJECTIVE: To evaluate the diagnostic accuracy and clinical utility of posttreatment tests to predict treatment failure after excisional treatment of cervical intraepithelial neoplasia grade 2 or worse (CIN 2+). DATA SOURCES: Electronic databases (EMBASE, PubMed MEDLINE) were searched for studies published from January 1975 to August 2024 assessing the occurrence of treatment failure in women who underwent excisional treatment for histologically confirmed CIN 2+ lesion. METHODS OF STUDY SELECTION: Previously published meta-analyses were extended and updated. A total of 1,802 studies were reviewed. Studies that assessed the diagnostic accuracy of the margin status, cytologic testing, combination of cytology and high-risk human papillomavirus (HPV), or combination of margin status and high-risk HPV compared with high-risk HPV testing were included. The primary outcome was treatment failure (residual or recurrent CIN 2+) and the absolute and relative diagnostic accuracy to predict this outcome. Studies with at least 18 months of follow-up were included. TABULATION, INTEGRATION, AND RESULTS: Forty-six studies and 20,385 women were included in the analysis. Treatment failure occurred in 6.6% of patients. The pooled sensitivity and specificity of high-risk HPV testing were 86.8% and 80.5%, respectively. Cytology had a sensitivity of 70.8% and a specificity of 85.7%, pooled from 34 studies. Compared with high-risk HPV testing in the same studies, cytology was 6.5% more specific (95% CI, 1.024–1.108) but 21.3% less sensitive (95% CI, 0.702–0.882). Assessment of the margin status was 39.9% less sensitive (95% CI, 0.532–0.678) but similarly specific (95% CI, 0.970–1.069) to high-risk HPV testing in 29 studies, with a pooled sensitivity and specificity of 48.9% and 82.5%, respectively. Co-testing with cytology and high-risk HPV was similarly sensitive (95% CI, 0.992–1.061) but 10.5% less specific (95% CI, 0.850–0.944) compared with high-risk HPV testing in 16 studies, with a pooled sensitivity and specificity of 94.7% and 69.9%, respectively. The pooled sensitivity and specificity of co-testing with margin status and high-risk HPV were 96.9% and 55.7%, respectively, 6.6% more sensitive (95% CI, 1.021–1.114) but 26.7% less specific (95% CI, 0.637–0.844) than high-risk HPV testing in eight studies. Involved resection margins, abnormal cytology, and a positive high-risk HPV test result were associated with a failure risk of 16.1%, 29.0%, and 26.1%, respectively. Women with negative margins, normal cytology, and a negative high-risk HPV test result had a failure risk of 3.6%, 2.3%, and 0.9%, respectively. The risk of treatment failure was highest for women with involved margins and a positive high-risk HPV test result (45.3%) and lowest for women with negative margins and a negative high-risk HPV test result (0.3%). Abnormal cytology and a positive high-risk HPV test result increased the risk of treatment failure to 42%, whereas normal cytology and a negative high-risk HPV test result decreased the risk to 0.6%. CONCLUSION: High-risk HPV testing is highly sensitive and specific to predict residual or recurrent CIN 2+ after excisional treatment. Cytologic testing and assessment of the margin status are slightly more and similarly specific, respectively, but both are significantly less sensitive. High-risk HPV testing can sufficiently inform the posttreatment management based on the posttest risk of treatment failure, unlike both cytology and assessment of the margin status. High-risk HPV testing alone performs similarly to co-testing with cytology or margin status. Posttreatment high-risk HPV testing is therefore an accurate predictor of treatment failure in women treated for CIN 2+.

Self-Collection for Human Papillomavirus Testing in Clinical Settings

Cervical cancer remains a preventable yet significant public health concern, particularly among rural, racial and ethnic minority, and LGBTQ+ (lesbian, gay, bisexual, transgender, queer+) populations who are more likely to be unscreened or underscreened. The recent draft guidance by the U.S. Preventive Services Task Force of human papillomavirus (HPV) self-collection for cervical cancer screening offers a transformative opportunity to overcome barriers to traditional cervical cancer prevention methods. Clinician collection and self-collection show strong agreement with HPV test results; however, clinician collection is still more sensitive than self-collection for CIN 2 or worse detection. Human papillomavirus self-collection at health care facilities, as recommended, addresses patient-centric challenges such as embarrassment, discomfort, and logistical constraints, thereby enhancing accessibility and engagement. Despite its potential, self-collection is currently approved by the U.S. Food and Drug Administration only for health care settings, limiting its reach and utility in underserved areas. To maximize the effect of self-collection, targeted educational campaigns for both clinicians and patients are essential to ensure proper utilization. At the patient level, strategies such as mobile clinics and mailed HPV testing kits could improve access, particularly among populations that, despite all other efforts, have not been reached. Clear guidelines at both the system and clinician levels regarding ordering responsibility, result notification for patients, follow-up protocols, specimen processing, and health insurance coverage at each step will be essential for successful implementation.

Trends in Uterine Cancer Cases After the Coronavirus Disease 2019 (COVID-19) Pandemic

We assessed the temporal trends in diagnosis of uterine cancer before and during the coronavirus disease 2019 (COVID-19) pandemic using data from the United States Cancer Statistics database spanning from 2001 to 2020. A comparison between projected and observed new cases in 2020 revealed a 4,232-case discrepancy, indicating 9.3% fewer diagnosed cases than predicted based on trends. Hispanic and Asian and Pacific Islander patients exhibited the highest discrepancy at 14.6% and 12.0% fewer cases, respectively, compared with 8.6% and 6.9% for White and Black patients. Our results highlight the importance of targeting health resources toward vulnerable populations in an effort to address accumulated cases of uterine cases after the pandemic.

Guideline-Concordant Surveillance After Treatment for High-Grade Cervical Dysplasia

OBJECTIVE: To quantify how many patients treated for high-grade cervical dysplasia completed guideline-concordant surveillance. METHODS: We retrospectively analyzed patients aged 30–65 treated for high-grade cervical dysplasia (cervical intraepithelial neoplasia 2 or worse) at two PROSPR II METRICS (Population-based Research to Optimize the Screening Process Multi-level Optimization of the Cervical Cancer Screening Process in Diverse Settings & Populations sites) (Massachusetts General Brigham, Parkland Health) from 2010 to 2019. The primary outcome was receipt of two negative co-tests after treatment within 30 months (allowing 6-month scheduling leeway). RESULTS: Among 3,146 patients treated for high-grade dysplasia, most were aged 30–39 years (Massachusetts General Brigham 58.9%, Parkland Health 60.9%) and had no or few known comorbidities (Massachusetts General Brigham 81.2%, Parkland Health 85.6%). Race and ethnicity, insurance status, and socioeconomic status reflected broader patient population demographics. Only half of the patients (45.5%) completed two surveillance co-tests after treatment within 30 months (Massachusetts General Brigham 55.3%, Parkland Health 40.6%), among whom a third received at least one subsequent abnormal co-test result (Massachusetts General Brigham 30.9%, Parkland Health 31.6%). Patients who completed two co-tests were under observation longer than those who did not complete two co-tests (median Massachusetts General Brigham 64.9 months vs 33.1 months, median Parkland Health 63.9 months vs 41.8 months). Among patients who completed two co-tests, the timing of surveillance co-testing was largely concordant with guidelines (median [interquartile range] time to first co-test: Massachusetts General Brigham 6.4 [5.1–9.2] months, Parkland Health 10.1 [6.6–12.6] months; median [interquartile range] time between first and second co-test: Massachusetts General Brigham 8.5 [6.0–12.6] months, Parkland Health 12.0 [8.0–13.5] months). Overall, 16 patients (0.5%) were diagnosed with cervical cancer after treatment for high-grade dysplasia (median [interquartile range] time from treatment to cancer diagnosis 14.9 [3.8–45.9] months). CONCLUSION: Approximately half of patients did not receive guideline-concordant surveillance after treatment for high-grade dysplasia, and one-third had a subsequent abnormal co-test result. Patients with high-grade cervical dysplasia are at elevated risk of subsequent abnormalities and should continue to be closely monitored. Additional systematic monitoring is needed to ensure guideline-compliant surveillance after dysplasia treatment.

Decline in Rate of Radical Hysterectomies Performed by Gynecologic Oncologists in the United States

Trends in cervical cancer epidemiology and physician workforces have converged to make radical hysterectomy an increasingly rare procedure for gynecologic oncologists practicing in the United States. Using data from the National Cancer Database and the Centers for Disease Control and Prevention's United States Cancer Statistics and published gynecologic oncology workforce data, we assessed trends in radical hysterectomy performed in the United States from 2004 to 2020. Over this period, the annual rate of radical hysterectomies per gynecologic oncologist declined significantly, by an average of 6.9% per year (95% CI, 6.4–7.5), corresponding to a decrease from 4.5 to 1.5 cases per oncologist per year. The increasing rarity of radical hysterectomy may pose a challenge to those seeking to acquire and maintain competency in this complex operation.

Incidence of Vaginal Intraepithelial Neoplasia After Hysterectomy for Cervical Cancer or Cervical Intraepithelial Neoplasia

OBJECTIVE: To investigate the incidence of vaginal intraepithelial neoplasia (VAIN) 1+ in patients after hysterectomy for cervical intraepithelial neoplasia (CIN) or cervical cancer. DATA SOURCES: A systematic search was conducted in PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials from inception to January 2025. METHODS OF STUDY SELECTION: We identified 7,234 studies, 48 of which were included in the meta-analysis. The primary outcome was the incidence of pathologically confirmed VAIN 1+ (VAIN 1, 2, or 3 or vaginal cancer) in patients after hysterectomy for CIN or cervical cancer; the secondary outcome was the clinicopathologic characteristics of these patients. Single-proportion meta-analysis was performed to estimate the incidence and 95% CIs of VAIN 1+. TABULATION, INTEGRATION, AND RESULTS: A total of 18,959 patients who underwent hysterectomy for CIN or cervical cancer were included. The overall pooled incidence of VAIN 1+ was 2.7% (95% CI, 1.8–3.7%). The incidences of VAIN and vaginal cancer were 2.7% (95% CI, 1.7–3.7%) and 0.3‰ (95% CI, 0.0–1.0‰), respectively. The incidence of VAIN increased gradually in more recent studies compared with studies published before 2000. CONCLUSION: Nearly 3 of every 100 women develop VAIN 1+ after hysterectomy for CIN or cervical cancer. The rate of vaginal dysplasia has significantly increased over time. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42023433781.

Detection of Human Papillomavirus DNA on Red Blood Cells in Patients With Cervical Cancer

Red blood cells (RBCs) have the potential to bind and harbor viral DNA, providing a novel approach to detecting human papillomavirus (HPV). Red blood cells incubated with fluorescently labeled HPV CpG acquired HPV DNA in a concentration-dependent manner. Red blood cells incubated with HPV-positive cervical cancer cells (CaSki cell line) acquired HPV 16 DNA detected by quantitative polymerase chain reaction (PCR). Consistent with these results, HPV 16 DNA was detected by quantitative PCR on RBCs from five patients with cervical cancer or dysplasia but not on healthy control RBCs. Detection of HPV 16 DNA on RBCs from patients with cervical cancer underscores the potential of RBC-bound DNA as a substrate for future blood-based HPV screening.

Ovarian Cancer Is Not So Silent

Uterine Leiomyomas and Reproduction

There is a prevailing opinion by gynecologists, much of it based on expert opinion or anecdotal evidence, that myomas are detrimental to pregnancy. Newer data challenge much of this dogma, but incorrect assumptions remain. Although not impeccable, multiple data address the correlation between myomas and reproduction, and some emerging evidence addresses surgical removal of these myomas and subsequent outcomes. A thorough literature search was performed, and the amassed data were analyzed to answer some of our most important queries about the role that myomas play in pregnancy and delivery. Uterine leiomyomas ultimately decrease in size during late pregnancy and postpartum. Spontaneous abortion rates are similar in women with and without leiomyomas. The data addressing leiomyoma effects on preterm prelabor rupture of membranes, placental abruption, cesarean delivery, and postpartum hemorrhage rates are conflicting, but the best evidence does not show a significant correlation compared with women without myomas. Preterm delivery rates are elevated in women with leiomyomas. Myomectomy does not decrease preterm deliveries and may increase this risk. Women with myomectomies have increased elective cesarean delivery rates and more blood loss at delivery compared with women with leiomyomas in situ.

Survival After Simple Compared With Radical Hysterectomy for Patients With Early-Stage Cervical Cancer

OBJECTIVE: To assess the effect on overall survival of simple hysterectomy with lymph node staging compared with radical hysterectomy with lymph node staging for patients with early-stage cervical cancer. METHODS: We conducted a retrospective cohort study of patients in the National Cancer Database diagnosed with early cervical carcinoma of 2 cm or smaller (stage IA1 with lymphovascular space invasion through IIA1, International Federation of Gynecology and Obstetrics staging) from 2010 to 2019. After 1:1 propensity score matching, we compared patients who underwent simple hysterectomy with lymph node staging and those with radical hysterectomy with lymph node staging. The variables used for matching were age, tumor size, race and ethnicity, lymphovascular space invasion, year of diagnosis, Charlson–Deyo comorbidity score, histology, and surgical approach. The primary outcome was overall survival at the end of follow-up. Secondary outcomes included 30-day readmission rate and 30- and 90-day mortality rates. RESULTS: In total, 4,167 patients met the inclusion criteria, of whom 2,637 patients (63.3%) underwent radical hysterectomy and lymph node staging and 1,530 patients (36.7%) underwent simple hysterectomy and lymph node staging. After propensity score matching, 1,529 patients in each group were included. There was no statistically significant difference in overall survival between patients who underwent simple hysterectomy and those who underwent radical hysterectomy (hazard ratio 1.25, 95% CI, 0.91–1.73, P=.17). Subgroup analysis by histology, lymphovascular space invasion, tumor size, and surgical approach did not reveal statistically significant differences in overall survival according to hysterectomy type. The hysterectomy groups also did not significantly differ in 30-day readmission rate (4.6% vs 4.2%, P=.73), 30-day mortality rate (0.1% vs 0%, P=.14), or 90-day mortality rate (0.1% vs 0.1%, P=.93). CONCLUSION: Patients with low-risk cervical cancer could undergo less radical surgery without a negative effect on their oncologic outcomes.

Compliance Rate With Triage Test and Treatment for Participants Screening Positive in Cervical Cancer Screening Programs

OBJECTIVE: To assess the rates of adherence to triage testing after positive screening results and referral to treatment for precancerous lesions in global cervical cancer screening programs. DATA SOURCES: We searched three electronic databases (Medline, EMBASE, and Web of Science) for articles published in the English language from January 1, 2018, to December 31, 2023. We included studies reporting the compliance rate of triage testing and precancer treatment in cervical cancer screening programs. ClinicalTrials.gov was reviewed, and no more studies were identified. METHODS OF STUDY SELECTION: The combined search strategies identified 1,673 titles, of which 858 titles and abstracts were screened and 113 full-text articles were assessed for eligibility. A total of 33 studies met the inclusion criteria and were included in the meta-analysis. TABULATION, INTEGRATION, AND RESULTS: Thirty-three studies were included in the systematic review and meta-analysis. The average compliance rate for women screening positive was 77.1% for triage testing and 69.4% for referral to treatment. Compliance varied by country income level, screening guideline approach, and target population. CONCLUSION: The current compliance rate was lower than the 90% target set by the World Health Organization's global strategy to eliminate cervical cancer. Inadequate follow-up of participants screening positive revealed a gap between the screening program and clinical care.

Human Papillomavirus Vaccination in the Postpartum Period

OBJECTIVE: To assess whether routine postpartum human papillomavirus (HPV) vaccination is acceptable and feasible and to identify key themes and strategies that can be used to increase postpartum HPV vaccination rates. DATA SOURCES: PubMed and ClinicalTrials.gov were queried from inception to July 2024 for postpartum and HPV vaccination. Studies were limited to human subjects and the English language. METHODS OF STUDY SELECTION: Screening was performed for studies of any method that evaluated HPV vaccination in the postpartum period (N=60). Only original research that reported either uptake or acceptability of the HPV vaccine was included. Thirty-nine studies were eliminated after abstract review because they did not meet the inclusion criteria. TABULATION, INTEGRATION, AND RESULTS: Nine studies were categorized according to the primary aim of the study (defining the problem, assessing patient perspectives, or testing interventions to increase vaccination) and demonstrated that postpartum HPV vaccination programs can significantly increase HPV vaccination rates and are feasible and acceptable to patients. CONCLUSION: Incorporating HPV vaccination into standard postpartum care provides an opportunity to reach vulnerable patient populations, reduces cost for patients, and has the ability to prevent HPV-related cancers.

Barbed Sutures Compared With Conventional Sutures During Laparoscopic Myomectomy

OBJECTIVE: To accumulate the currently available literature on the safety and efficacy of the use of knotless barbed sutures for the reconstruction of the uterine wall during laparoscopic myomectomy based on comparison with traditional suture studies. DATA SOURCES: We searched PubMed/Medline, Scopus, ClinicalTrials.gov, and Google Scholar up to February 29, 2024. METHODS OF STUDY SELECTION: Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines and PICO criteria, we included all English-language, full-text articles that evaluated the perioperative outcomes of patients who had laparoscopic myomectomy and repair of the uterine wall defect with either barbed or traditional (extracorporeal or intracorporeal sutures). TABULATION, INTEGRATION, AND RESULTS: The application of barbed sutures resulted in significantly reduced operative time (2,111 patients, mean difference −12.04 minutes, 95% CI, −16.94 to −7.14, P<.001). This was also reflected when suturing time was separately analyzed (437 patients, mean difference −6.04 minutes, 95% CI, −7.43 to −4.65, P<.001) The mean difference in hemoglobin levels before and after surgery was significantly lower in the barbed suture group (1,277 patients, mean difference −0.40 g/dL, 95% CI, −0.72 to −0.09, P<.01) This was also observed in case of estimated blood loss, which was found to be lower in the barbed suture group (1,823 patients, mean difference −47.22 mL, 95% CI, −78.54 to −15.90, P=.003). Finally, the barbed suture group presented lower transfusion rates (1,217 patients, odds ratio 0.43, 95% CI, 0.19–1.00, P=.05). Concerning visual analog scale (VAS) score as evaluated by the surgeons for surgical difficulty, the control group proved to be more technically challenging compared with the barbed sutures group (184 patients, mean difference −1.66 95% CI, −2.37 to −0.94, P<.001). The VAS score for pain at 24 hours postoperatively, postoperative complication rates, and length of hospital stay were similar for both groups. Regarding reproductive outcomes, there was no difference in pregnancy, live birth, and birth complication rates. CONCLUSION: The use of barbed sutures during laparoscopic myomectomy presents many clinical benefits for the patient and the surgeon in terms of shorter operative and suturing time, less estimated blood loss, and ease of use. This pioneer technology may contribute to the expansion of laparoscopy on more complex myomectomies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42023477304.

Intramural Leiomyomas and Fertility

OBJECTIVE: To evaluate fertility outcomes based on size and number of intramural leiomyomas and outcomes after removal. DATA SOURCES: Online searches: MEDLINE, ClinicalTrials.gov, PubMed, Cochrane Library, and PROSPERO Library from 1994 to 2023. METHODS OF STUDY SELECTION: A total of 5,143 studies were identified, with inclusion of 13 study groups. TABULATION, INTEGRATION AND RESULTS: Outcomes for size and number of leiomyomas were reported with clinical pregnancy rates and ongoing pregnancy or live-birth rates. In data sets with maximum leiomyoma diameters of less than 6 cm for study inclusion, women with leiomyomas smaller than 3 cm had lower clinical pregnancy rates than women without leiomyomas, with an odds ratio (OR) of 0.53 (95% CI, 0.38–0.76) and, for ongoing pregnancy or live-birth rates, an OR of 0.59 (95% CI, 0.41–0.86). The ORs for clinical pregnancy rates in women with intermediately-sized leiomyomas (those between 3 cm and 6 cm) were lower than in women without leiomyomas, with an OR at 0.43 (95% CI, 0.29–0.63) and, for ongoing pregnancy or live-birth rates, an OR at 0.38 (95% CI, 0.24–0.59). In data sets without exclusion for women with larger-sized leiomyomas, clinical pregnancy rates were lower for those with leiomyomas smaller than 5 cm compared with those without leiomyomas, with an OR of 0.75 (95% CI, 0.58–0.96). Women with leiomyomas larger than 5 cm showed no differences in clinical pregnancy rate compared with women without leiomyomas, with an OR of 0.71 (95% CI, 0.32–1.58). Although women with a single leiomyoma in any location had no differences in outcomes, those with more than one leiomyoma had lower clinical pregnancy rates and ongoing pregnancy or live-birth rates, with an OR of 0.62 (95% CI, 0.44–0.86) and 0.57 (95% CI, 0.36–0.88), respectively. The clinical pregnancy rate for women undergoing myomectomy for intramural leiomyomas was no different than those with intramural leiomyomas in situ, with an OR of 1.10 (95% CI, 0.77–1.59). CONCLUSION: Even small intramural leiomyomas are associated with lower fertility; removal does not confer benefit. Women with more than one leiomyoma in any location have reduced fertility.

Association of Clinical Trial Participation With Improved Overall Survival for Recurrent, Platinum-Resistant Ovarian Cancer

OBJECTIVE: To investigate whether clinical trial participation is associated with overall survival in patients with platinum-resistant ovarian cancer. METHODS: An IRB-approved, retrospective, single-institution cohort study was performed in patients with platinum-resistant ovarian cancer from January 1, 2009, to December 31, 2017. Platinum resistance was defined as progression within 6 months after completion of platinum chemotherapy. Patients were divided into two cohorts: 1) clinical trial participants for platinum-resistant ovarian cancer or 2) standard of care. The association of trial participation with overall survival from the date of platinum resistance was assessed with univariate and multivariable models. RESULTS: Of 305 eligible patients with recurrent platinum-resistant ovarian cancer, 46 (15.1%) were clinical trial participants. There were no significant differences in age (61.2 years vs 63.3 years, P=.21), body mass index (27.5 vs 27.6, P=.90), race (P=.61), medical comorbidities (P>.05), or performance status (P=.07) for clinical trial participants compared with those receiving standard of care. The majority underwent primary cytoreduction (76.1% vs 69.1%, P=.34) with no differences in residual disease (P=.43) for clinical trial participants compared with those receiving standard of care. There was no difference in poly-ADP-ribose polymerase inhibitor (21.7% vs 15.1%, P=.26) or bevacizumab (22.2% vs 32.1%, P=.31) use for clinical trial participants compared with those receiving standard of care. On multivariable analysis controlling for comorbidities, stage, and germline mutational status, clinical trial participation was associated with significantly improved overall survival from the date of platinum resistance compared with standard of care (13.8 months vs 10.5 months, adjusted hazard ratio 1.46, 95% CI 1.04–2.05, P=.028). CONCLUSIONS: In this retrospective cohort of patients with platinum-resistant ovarian cancer, clinical trial participation was associated with improved overall survival compared with standard of care therapies. Availability and participation in clinical trials should be prioritized in patients with recurrent, platinum-resistant ovarian cancer.

Diagnosis and Management of Cervical Squamous Intraepithelial Lesions in Pregnancy and Postpartum

Perinatal care provides important health care opportunities for many individuals at risk for cervical cancer. Pregnancy does not alter cervical cancer screening regimens. ASCCP risk-based management has a colposcopy threshold of a 4% immediate risk of cervical intraepithelial neoplasia (CIN) 3 or cancer, but the actual risk can be considerably higher based on current and past screening results. Improving cervical cancer outcomes with diagnosis during pregnancy rather than postpartum and facilitating further evaluation and treatment postpartum for lesser lesions are the perinatal management goals. Although colposcopy indications are unchanged in pregnancy, some individuals with lower risk of CIN 2–3 and reliable access to postpartum evaluation may defer colposcopy until after delivery. Cervical intraepithelial neoplasia diagnosed in pregnancy tends to be stable, with frequent regression postpartum, though this is not universal. Colposcopic inspection during pregnancy can be challenging. Although biopsies in pregnancy are subjectively associated with increased bleeding, they do not increase complications. Endocervical curettage and expedited treatment are unacceptable. Treatment of CIN 2–3 in pregnancy is not recommended. Excisional biopsies in pregnancy are reserved for suspicion of malignancy that cannot be confirmed by colposcopic biopsy and when excisional biopsy results would alter oncologic or pregnancy care. Surveillance of high-grade lesions in pregnancy uses human papillomavirus-based testing, cytology, and colposcopy, with biopsy of worsening lesions every 12–24 weeks from diagnosis until postpartum evaluation. Mode of delivery does not definitively affect persistence of CIN postpartum. Postpartum care may involve a full colposcopic evaluation or expedited excisional procedure if indicated.

Trends in Uterine Cancer Mortality in the United States: A 50-Year Population-Based Analysis

Uterine Myomas: An Overview of Development, Clinical Features, and Management

Uterine fibroids are the most common benign tumors of the uterus among women of reproductive age, disproportionally affecting non-Hispanic Black women compared to other races and ethnicities. This report is an update of a 2011 MSMR report that examined uterine fibroids among female active component service members in the U.S. Armed Forces from 2001 to 2010. Incident uterine fibroids were identified for this report from inpatient and outpatient medical encounter data from 2011 to 2022. Health care burden was estimated utilizing uterine fibroid-related inpatient and outpatient diagnostic and procedure codes. Crude incidence rates and incidence rate ratios were calculated to compare rate differences between subpopulations. A total of 16,046 new uterine fibroid cases were identified, with an incidence rate of 63.5 cases per 10,000 person-years (95% confidence interval: 62.5-64.5). The highest incidence rates were observed among service women 40 years and older, non-Hispanic Black women, and those who served in the Army. Health care burden analysis showed that, even with increases in medical encounters and individuals affected, the numbers of hospital bed days declined over time. The decline in uterine fibroid-related hospital bed days could be attributed to early diagnoses and minimally-invasive treatments. Continued promotion of uterine fibroid awareness can potentially help further reduce uterine fibroid-related impacts on military readiness.

An Update on Prenatal Diethylstilbestrol Exposure and High-Grade Squamous Intraepithelial Lesions of the Lower Genital Tract

Women with prenatal diethylstilbestrol exposure are excluded from less frequent cervical cancer screening because of their increased neoplasia risk. We report the results of a prospective follow-up study of prenatal diethylstilbestrol exposure and lower genital tract high-grade (grade 2 or higher) squamous intraepithelial lesions (HSIL). The age-adjusted risk of HSIL among diethylstilbestrol-exposed women (n=4,062) was higher than among the diethylstilbestrol unexposed (n=1,837) through age 44 years (hazard ratio 2.03, 95% CI, 1.31–3.14) but not age 45 years or older. Elevated HSIL risk remained higher in diethylstilbestrol-exposed women, after accounting for frequency of cervical cancer screening. Compared with unexposed women, HSIL risk was higher among women with earlier gestational and high-dose diethylstilbestrol exposure. These data confirm the appropriateness of more frequent screening among diethylstilbestrol-exposed women through age 44 years. Whether those aged 45 years or older should continue to have increased screening will require careful weighing of possible risks and benefits.

Pregnancy Outcomes After Laparoscopic Radiofrequency Ablation of Uterine Leiomyomas Compared With Myomectomy

OBJECTIVE: To compare pregnancy outcomes after laparoscopic radiofrequency ablation and myomectomy. METHODS: The ULTRA (Uterine Leiomyoma Treatment With Radiofrequency Ablation) study is an ongoing multicenter prospective cohort study with longitudinal follow-up up to 5 years comparing outcomes of radiofrequency ablation with myomectomy in premenopausal women older than age 21 years with symptomatic uterine leiomyomas. Participants were queried every 6 months after surgery to assess the incidence of pregnancy and pregnancy outcomes. RESULTS: Among 539 women enrolled in ULTRA, a total of 37 participants (mean age at first pregnancy 35.0±4.7 years) conceived 43 times as of March 2023 (22 radiofrequency ablation, 21 myomectomy). The average length of follow-up time after all procedures was 2.5±1.0 years. The baseline miscarriage rate in the study population was 33.3%. In participants who underwent radiofrequency ablation, 9 of 22 pregnancies (40.9%, 95% CI, 20.3–61.5%) ended in first-trimester miscarriage, 11 resulted in live births (50.0%, 95% CI, 29.1–70.9%), one resulted fetal death at 30 weeks of gestation, and one resulted in uterine rupture during miscarriage treatment with misoprostol 10 weeks after radiofrequency ablation. Among the live births in the radiofrequency ablation group, 45.5% were by vaginal delivery. In the myomectomy group, 9 of 21 pregnancies (42.9%, 95% CI, 21.7–64.0%) ended in first-trimester miscarriage and 12 resulted in live births (57.1%, 95% CI, 36.0–78.3%). There were no significant differences in the likelihood of live birth or miscarriage between the study groups. CONCLUSION: Full-term pregnancy and vaginal delivery are achievable after radiofrequency ablation of leiomyomas. However, in this interim analysis, the miscarriage rate in both radiofrequency ablation and myomectomy groups was higher than expected for women in this age group. Long-term data collection in the ongoing ULTRA study aims to further understand pregnancy outcomes after radiofrequency ablation compared with myomectomy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT0210094.

Changes in Bone Density in Carriers of BRCA1 and BRCA2 Pathogenic Variants After Salpingo-Oophorectomy

OBJECTIVE: To evaluate the effect of risk-reducing salpingo-oophorectomy (RRSO) on change in bone mineral density (BMD) in women aged 34–50 years with pathogenic variants in BRCA1 or BRCA2 (BRCA1/2). METHODS: The PROSper (Prospective Research of Outcomes after Salpingo-oophorectomy) study is a prospective cohort of women aged 34–50 years with BRCA1 or two germline pathogenic variants that compares health outcomes after RRSO to a non-RRSO control group with ovarian conservation. Women aged 34–50 years, who were planning either RRSO or ovarian conservation, were enrolled for 3 years of follow-up. Spine and total hip BMD were measured by dual-energy X-ray absorptiometry (DXA) scans obtained at baseline before RRSO or at the time of enrollment for the non-RRSO group, and then at 1 and 3 years of study follow-up. Differences in BMD between the RRSO and non-RRSO groups, as well as the association between hormone use and BMD, were determined by using mixed effects multivariable linear regression models. RESULTS: Of 100 PROSper participants, 91 obtained DXA scans (RRSO group: 40; non-RRSO group: 51). Overall, total spine, and hip BMD decreased significantly from baseline to 12 months after RRSO (estimated percent change −3.78%, 95% CI −6.13% to −1.43% for total spine; −2.96%, 95% CI −4.79% to −1.14% for total hip) and at 36 months (estimated percent change −5.71%, 95% CI −8.64% to −2.77% for total spine; −5.19%, 95% CI −7.50% to −2.87% for total hip. In contrast, total spine and hip BMD were not significantly different from baseline for the non-RRSO group. The differences in mean percent change in BMD from baseline between the RRSO and non-RRSO groups were statistically significant at both 12 and 36 months for spine BMD (12-month difference −4.49%, 95% CI −7.67% to −1.31%; 36-month difference −7.06%, 95% CI −11.01% to −3.11%) and at 36 months for total hip BMD (12-month difference −1.83%, 95% CI −4.23% to 0.56%; 36-month difference −5.14%, 95% CI −8.11% to −2.16%). Across the study periods, hormone use was associated with significantly less bone loss at both the spine and hip within the RRSO group compared with no hormone use (P<.001 at both 12 months and 36 months) but did not completely prevent bone loss (estimated percent change from baseline at 36 months −2.79%, 95% CI −5.08% to −0.51% for total spine BMD; −3.93%, 95% CI −7.27% to −0.59% for total hip BMD). CONCLUSION: Women with pathogenic variants in BRCA1/2 who undergo RRSO before the age of 50 years have greater bone loss after surgery that is clinically significant when compared with those who retain their ovaries. Hormone use mitigates, but does not eliminate, bone loss after RRSO. These results suggest that women who undergo RRSO may benefit from routine screening for BMD changes to identify opportunities for prevention and treatment of bone loss. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01948609.

Secondary Cytoreductive Surgery With Hyperthermic Intraperitoneal Chemotherapy for Advanced or Recurrent Mucinous Ovarian Cancer

BACKGROUND: Advanced or recurrent primary mucinous ovarian cancer is typically incurable and associated with short progression-free and overall survival when treated with standard chemotherapy. Novel approaches are desperately needed for women with this disease. CASES: Two patients with advanced or recurrent primary mucinous ovarian cancer were treated with secondary cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC). No additional chemotherapy was administered postoperatively. Both patients achieved a complete and durable response, with no evidence of recurrence at 21 and 27 months, respectively, after CRS with HIPEC. CONCLUSION: Secondary CRS with HIPEC represents a potential therapeutic option for women with recurrent primary mucinous ovarian cancer.

Hyperthermic Intraperitoneal Chemotherapy and Interval Debulking Surgery in Conjunction With Elective Cesarean Delivery

BACKGROUND: Ovarian cancer is rare during pregnancy. For patients beyond 20 weeks of gestation who choose to continue the pregnancy, neoadjuvant chemotherapy may be initiated, followed by interval debulking surgery. Hyperthermic intraperitoneal chemotherapy (HIPEC) may be used with interval debulking surgery for stage III epithelial ovarian cancer, but data are lacking on its administration in the peripartum period. CASE: We illustrate the case of a 40-year-old patient diagnosed with stage III epithelial ovarian cancer at 27 weeks of gestation who underwent neoadjuvant chemotherapy followed by cesarean delivery at term along with interval debulking surgery and HIPEC. The intervention was well tolerated and resulted in the birth of a healthy neonate. The postoperative period was unremarkable, and the patient is disease-free after 22-months of follow-up. CONCLUSION: We demonstrate the feasibility of peripartum HIPEC. Optimal oncologic care should not be jeopardized by the peripartum state of an otherwise healthy patient.

Postpartum Opportunistic Salpingectomy Compared With Bilateral Tubal Ligation After Vaginal Delivery for Ovarian Cancer Risk Reduction

OBJECTIVE: To compare the cost effectiveness of opportunistic salpingectomy and bilateral tubal ligation for sterilization immediately after vaginal delivery. METHODS: A cost-effectiveness analytic decision model was used to compare opportunistic salpingectomy with bilateral tubal ligation during vaginal delivery admission. Probability and cost inputs were derived from local data and available literature. Salpingectomy was assumed to be performed with a handheld bipolar energy device. The primary outcome was the incremental cost-effectiveness ratio (ICER) in 2019 U.S. dollars per quality-adjusted life-year (QALY) at a cost-effectiveness threshold of $100,000/QALY. Sensitivity analyses were performed to determine the proportion of simulations in which salpingectomy would be cost effective. RESULTS: Opportunistic salpingectomy was more cost effective than bilateral tubal ligation with an ICER of $26,150/QALY. In 10,000 patients desiring sterilization after vaginal delivery, opportunistic salpingectomy would result in 25 fewer ovarian cancer cases, 19 fewer ovarian cancer deaths, and 116 fewer unintended pregnancies than bilateral tubal ligation. In sensitivity analysis, salpingectomy was cost effective in 89.8% of simulations and cost saving in 13% of simulations. CONCLUSION: In patients undergoing sterilization immediately after vaginal deliveries, opportunistic salpingectomy is more cost effective and may be more cost saving than bilateral tubal ligation for reducing ovarian cancer risk.

Concurrent Surgery for Locoregional Gynecologic Cancers and Pelvic Floor Disorders in a Population of Patients With Medicare Insurance

OBJECTIVE: To estimate the rate of concurrent surgery for locoregional gynecologic cancer and pelvic organ prolapse–urinary incontinence (POP–UI) and to assess the rate of surgery for POP–UI within 5 years for those who did not undergo concurrent surgery. METHODS: This is a retrospective cohort study. The SEER-Medicare data set was used to identify cases of local or regional endometrial, cervical, and ovarian cancer diagnosed from 2000 to 2017. Patients were followed up for 5 years from diagnosis. We used χ2 tests to identify categorical variables associated with having a concurrent POP–UI procedure with hysterectomy or within 5 years of hysterectomy. Logistic regression was used to calculate odds ratios and 95% CIs adjusted for variables statistically significant (α=.05) in the univariate analyses. RESULTS: Of 30,862 patients with locoregional gynecologic cancer, only 5.5% underwent concurrent POP–UI surgery. Of those with a preexisting diagnosis related to POP–UI, however, 21.1% had concurrent surgery. Of the patients who had a diagnosis of POP–UI at the time of initial surgery for cancer and who did not undergo concurrent surgery, an additional 5.5% had a second surgery for POP–UI within 5 years. The rate of concurrent surgery remained constant over the time period (5.7% in 2000 and 2017) despite an increase in the frequency of POP–UI diagnosis in the same time frame. CONCLUSION: The rate of concurrent surgery for patients with an early-stage gynecologic cancer and POP–UI–associated diagnosis in women older than age 65 years was 21.1%. Of women who did not undergo concurrent surgery but had a diagnosis of POP–UI, 1 in 18 underwent surgery for POP–UI within 5 years of their index cancer surgery. Dedicated efforts must be made to identify patients who would most benefit from concurrent cancer and POP–UI surgery in those with locoregional gynecologic cancers and pelvic floor disorders.

Concurrent Minimally Invasive Gynecologic Procedures at the Time of Laparoscopic Cholecystectomy

In this cross-sectional study including 1,722,479 women who underwent laparoscopic cholecystectomy between January 2016 and December 2019 identified in the Healthcare Cost and Utilization Project's Nationwide Ambulatory Surgery Sample, the prevalence rate of gynecologic diagnoses was 11.3 per 1,000. Among presumed elective laparoscopic cholecystectomy, the highest performance rate of concurrent gynecologic procedure per gynecologic diagnosis was laparoscopic adnexectomy among patients with benign ovarian tumor (652/1,000 diagnoses), followed by laparoscopic adnexectomy for endometrioma (386/1,000 diagnoses) and cervical conization for cervical carcinoma in situ (304/1,000 diagnoses). The measured surgical morbidity rates for patients who had concurrent gynecologic surgery and those who did not were 2.8 per 1,000 and 1.9 per 1,000, respectively (adjusted odds ratio 1.39, 95% CI 0.75–2.59). These results suggest that minimally invasive gynecologic surgeries are being performed at the time of outpatient laparoscopic cholecystectomy in the United States.

Human Papillomavirus Detectability and Cervical Cancer Prognosis

OBJECTIVE: To evaluate whether testing positive for human papillomavirus (HPV) before treatment is associated with cervical cancer recurrence and disease-free, cancer-specific, and overall survival and to report the relationship of HPV to cervical cancer histology, stage, grade, tumor size, lymph node involvement, and treatment response. DATA SOURCES: EMBASE and MEDLINE were searched from inception to January 27, 2022, with the use of MeSH terms and keywords relating to cervical cancer, HPV, and prognosis. ClinicalTrials.gov was not searched because of the nature of our review question. METHODS OF STUDY SELECTION: Studies must have assessed HPV DNA or RNA in cervical pretreatment biopsies or cells from 20 or more patients with invasive cervical cancer followed up for any length of time and reported the effect of testing positive or negative for HPV on cervical cancer recurrence, disease-free survival, cancer-specific survival, or overall survival. We extracted data on HPV-detection methods, patient and tumor characteristics, and clinical outcomes. TABULATION, INTEGRATION, AND RESULTS: Hazard ratios (HRs) and 95% CIs were pooled with a random-effects model. Meta-regression was performed to explore heterogeneity. Of 11,179 titles or abstracts and 474 full-text articles reviewed, 77 studies were included in the systematic review. Among these 77 studies, 30 reported on the relationship of HPV status to histology, 39 to cancer stage, 13 to tumor grade, 17 to tumor size, 23 to lymph node involvement, and four to treatment response. Testing positive for HPV was associated with better disease-free survival (HR 0.38, 95% CI 0.25–0.57; 15 studies with 2,564 cases), cancer-specific survival (HR 0.56, 95% CI 0.44–0.71; nine studies with 1,398 cases), and overall survival (HR 0.59, 95% CI 0.47–0.74; 36 studies with 9,169 cases), but not recurrence (HR 0.59, 95% CI 0.33–1.07; eight studies with 1,313 cases). Meta-regression revealed that the number of cases, tumor grade, specimen type, gene target, and HPV prevalence together explained 73.8% of the between-study heterogeneity. CONCLUSION: This review indicates that HPV detectability in cervical cancer is associated with a better clinical prognosis. SYSTEMATIC REVIEW REGISTRATION: https://osf.io/dtyeb.

Primary Human Papillomavirus Testing and Other New Technologies for Cervical Cancer Screening

Cervical cancer screening has saved the lives of millions in regions where routine gynecologic care is readily accessible. As screening continues to evolve away from cervical cytology to primary human papillomavirus (HPV) testing, robust prospective cohort data have allowed for precise risk stratification and improved our ability to identify those at greatest risk of high-grade dysplasia and decrease unnecessary diagnostic procedures. New technologies such as p16/Ki-67 dual stain testing and HPV methylation panels, which offer comparable performance to co-testing and can be developed into high-throughput workflows, could lead to a fully molecular Pap test. Self-sampling in the United States, where the initial screen can be done in the home, in conjunction with new screening technologies, may decrease the existing hurdles of routine cervical cancer screening. Implementation barriers include issues with workflow, workforce, and cost. These need to be addressed to achieve an improved and more equitable cervical cancer screening program in the United States.

Timing of Colposcopy and Risk of Cervical Cancer

OBJECTIVE: To quantify the association between time to colposcopy and risk of subsequent cervical cancer. METHODS: A longitudinal analysis of patients aged 21–79 years with an abnormal cervical cancer test result from health care systems in Texas, Massachusetts, and Washington was performed. The outcome was a cervical cancer diagnosis 12 months or more after the abnormal result. The primary analysis compared receipt of colposcopy within 3 months (91 days or less) with receipt of colposcopy at 3–12 months (92–365 days) and no colposcopy within 12 months of the abnormal test result; post hoc analyses compared colposcopy within 12 months (365 days or less) with no colposcopy within 12 months. Associations were assessed with multivariable Cox proportional hazards regression controlling for age, risk status, result severity, and health care system. RESULTS: Of 17,541 patients, 53.3% of patients received colposcopy within 3 months, 22.2% received colposcopy in 3–12 months, and 24.6% had no colposcopy within 12 months. One hundred forty-seven patients were diagnosed with cervical cancer within 12 months and removed from subsequent analyses. Sixty-five patients (0.4%) were diagnosed with cervical cancer more than 1 year (366 days or more) after the abnormal Pap or human papillomavirus test result. The risk of cervical cancer detection more than 1 year after the abnormal test result was not different in patients who received colposcopy within 3–12 months (hazard ratio [HR] 1.07, 95% CI 0.54–2.12) and higher among patients with no colposcopy within 12 months (HR 2.34, 95% CI 1.33–4.14) compared with patients who had colposcopy within 3 months. Post hoc analyses showed that the risk of cervical cancer diagnosis was 2.29-fold higher among those without colposcopy within 12 months compared with those who received colposcopy within 12 months (95% CI 1.37–3.83); among patients with high-grade cytology results, the risk of cervical cancer detection among those without colposcopy within 12 months was 3.12-fold higher compared with those who received colposcopy within 12 months (95% CI 1.47–6.70). CONCLUSION: There was no difference in cervical cancer risk at more than 1 year between patients who received colposcopy within 3 months compared with those who received colposcopy within 3–12 months of an abnormal result. Patients who did not receive colposcopy within 12 months of an abnormal result had a higher risk of subsequent cervical cancer compared with those who received a colposcopy within 12 months.

Large Publication Gap for Gynecologic Cancers in High–Impact Factor Journals

OBJECTIVE: To analyze research publication trends in high–impact factor journals, comparing gynecologic cancers with other cancers from 2000 to 2018. METHODS: Abstracts from the 55 journals with the highest impact factors, as measured by Clarivate, from 2000 to 2018 were extracted from PubMed. We developed an algorithm to search the title of the abstract to determine whether the abstract was about cancer and to identify the cancer type. The algorithm was validated against the gold standard of human review in 1,143 abstracts. Article proportion was compared with site-specific incidence, mortality, and lethality from the National Cancer Institute’s Surveillance, Epidemiology and End Results database using scatterplots and nonparametric Wilcoxon signed-rank test. RESULTS: We identified 128,377 articles; 31,045 (24.1%) were about cancer and 1,189 (3.8%) were about gynecologic cancers. Gynecologic cancers (ovarian, cervical, and uterine) were all poorly represented in high–impact factor journals compared with their incidence, mortality, and lethality. Ovarian, uterine, and cervical cancers ranked in the bottom half of Article-to-Lethality scores (P<.01 for all comparisons). Analyses of the trends for gynecologic cancers over the past 18 years showed no change over time in Article-to-Lethality scores. Comparison of rankings by lethality with rankings by funding indicates relative underfunding of the gynecologic cancers. CONCLUSION: Research publications in high–impact factor journals by cancer site are not proportionate with individual cancer burden on society. Gynecologic cancers are significantly underrepresented in research publications relative to their disease burden, indicating a disparity that persists over the past 18 years. Relative underfunding of gynecologic cancers likely contributes to this publication gap.

Assessment of Human Papillomavirus Non-16/18, Type-Specific Risk for Cervical Intraepithelial Neoplasia Grade 3 or Worse Among Women With Cervical Atypical Glandular Cells

OBJECTIVE: To evaluate the risk for cervical intraepithelial neoplasia grade 3 (CIN 3) or worse (including adenocarcinoma in situ [AIS] and invasive cervical cancer) associated with non-16/18 human papillomavirus (HPV) types (other HPV) among women with atypical glandular cells (AGC) in cervical cytology. METHODS: This population-based cohort study evaluates the risk of CIN 3 or worse associated with other HPV types. Human papillomavirus genotyping was performed on Pap tests collected in Sweden from 341 women with AGC that were positive for other HPV types from February 17, 2014, to December 31, 2018. The women were followed for histopathologic outcomes using comprehensive registry linkages until December 31, 2019. Cumulative incidence proportions of CIN 3 or worse by specific HPV type were calculated using 1-minus Kaplan-Meier function. Hazard ratios (HRs) for CIN 3 or worse were generated using multivariate Cox regression. RESULTS: Of 341 women, 134 (39.3%) had CIN 3–AIS, but there were only five (1.5%) women in the cohort with invasive cervical cancer. Human papillomavirus 45 preceded 80.0% of invasive cervical cancer cases. Among women positive for HPV33, 82.9% (95% CI 58.0–97.3%) had CIN 3 or worse during follow-up. Positivity for HPV31 conferred the highest HR for CIN 3 or worse relative to other types, both in primary cytology and primary HPV screening (HR 2.71, 95% CI 1.47–5.00 and HR 3.41, 95% CI 1.95–5.96, respectively). CONCLUSION: Among non-16/18 HPV types in AGC, HPV31 and 33 had the highest risk for CIN 3 or worse, whereas most of the women with invasive cancer were positive for HPV45. Extended HPV genotyping may be helpful for the management of AGC.

Neovaginal Human Papillomavirus Prevalence in Transfeminine Individuals

OBJECTIVE: To assess the prevalence of high-risk human papillomavirus (hrHPV) and human papillomavirus (HPV)–associated abnormalities in the neovaginas of postvaginoplasty transfeminine patients to inform potential HPV-screening guidelines for this patient population. DATA SOURCES: MEDLINE, ClinicalTrials.gov, the Cochrane Library, Scopus, and Google Scholar were searched through September 30, 2022. METHODS OF STUDY SELECTION: The population included transfeminine individuals who had undergone vaginoplasty with an outcome of subsequent positive HPV diagnosis or HPV-related lesions. Randomized clinical trials, cohort studies, cross-sectional studies, and case reports available in English were included in the analysis. Identified articles were doubly screened, and accepted articles were doubly extracted. TABULATION, INTEGRATION, AND RESULTS: Of 59 abstracts identified, 30 were screened for eligibility, of which 15 met the criteria for review. Included studies were assessed for vaginoplasty procedure type, time elapsed between vaginoplasty and HPV testing, HPV type, location and manner of sample collection, method of HPV diagnosis, and classification and location of HPV-associated neovaginal lesions. Studies were assigned a grade of evidence of very low, low, moderate, or high based on study design, precision, directness, and risk of bias. Prevalence of neovaginal hrHPV ranged from 8.3% to 20% in identified studies, and per-study prevalence of HPV-related neovaginal abnormalities ranged from 0% to 8.3% in patients. CONCLUSION: The current body of research demonstrates that, after vaginoplasty, transfeminine individuals may develop neovaginal HPV infection with associated cytologic abnormalities or grossly apparent lesions. In some included studies, neovaginal HPV-associated lesions were highly advanced before they were identified. A small number of studies assessed neovaginal HPV prevalence in transfeminine individuals, with hrHPV prevalence ranging from 8.3% to 20%. However, broader conclusions about neovaginal HPV prevalence are limited by a lack of high-grade evidence in the existing literature. More rigorous prevalence research is needed to inform preventative care guidelines for transfeminine individuals at risk of developing HPV-related neovaginal complications. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42022379977.

Clinical Effects of Early or Surgical Menopause

Increasing numbers of women experience early menopause due in part to surgical treatment for benign gynecologic disorders and the rise in risk-reducing bilateral salpingo-oophorectomy in women with BRCA mutations. Unfortunately, the adverse health consequences of early loss of ovarian function accelerate the menopausal state and affect multiple systems, including cardiovascular, neurologic, bone, and connective tissue, and affect quality of life owing to vasomotor symptoms, mood, sleep, and sexual function. Yet many clinicians and women remain reluctant to use hormone therapy because of the Women's Health Initiative's adverse findings, even though they are not applicable to women with early menopause. This review examines the effects of early menopause and highlights the critical role of hormone therapy in this population.

Guideline-Discordant Care in Early-Stage Vulvar Cancer

OBJECTIVE: To describe the use of National Comprehensive Cancer Network guideline-concordant inguinofemoral lymph node (LN) evaluation in individuals with early-stage vulvar cancer. METHODS: This retrospective cohort study identified patients with T1b and T2 vulvar squamous cell carcinoma diagnosed between 2012 and 2018 using the National Cancer Database. Factors associated with LN evaluation were examined using logistic regression analyses, adjusting for patient, disease, and facility-level characteristics. Kaplan-Meier survival analysis using log rank test and Cox regression was performed for the entire cohort and a subgroup of older patients, defined as individuals aged 80 years or older. RESULTS: Of the 5,685 patients with vulvar cancer, 3,756 (66.1%) underwent guideline-concordant LN evaluation. In our adjusted model, age 80 years or older (odds ratio [OR], 0.30; 95% CI 0.22–0.42) and Black race (OR 0.72; 95% CI 0.54–0.95) were associated with lower odds of LN evaluation. High-volume hospitals were associated with increased odds of LN evaluation compared with low-volume hospitals (OR 1.62; 95% CI 1.28–2.05). Older individuals who did not undergo LN evaluation had significantly worse overall survival than those with pathologically negative LNs (hazard ratio [HR] 0.45; 95% CI 0.37–0.55) and similar overall survival as those with pathologically positive LNs (HR 1.05; 95% CI 0.77–1.43). CONCLUSION: Guideline-concordant LN evaluation for early-stage vulvar squamous cell carcinoma is low. Lower utilization is associated with older age, Black race, and care at a low-volume hospital.

Combining Ultrasonography and Endometrial Aspiration as a One-Stop Screening for Endometrial Neoplasia

OBJECTIVE: To assess the performance of simultaneous endometrial aspiration and sonohysterography to screen for endometrial cancer or hyperplasia in women aged 50 years or older. METHODS: We conducted a prospective study from February 2014 to October 2020 at the ultrasound unit of a large urban academic medical center. The study included 1,635 women aged 50 years or older referred for endometrial evaluation, with follow-up through January 2021. Participants underwent saline infusion sonohysterography combined with ultrasound-guided endometrial aspiration. The primary outcome measured was a diagnosis of endometrial cancer or hyperplasia within 1 year from screening. The diagnostic accuracy of the combined evaluation method, including sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), was assessed. RESULTS: Of 1,170 women who completed the study protocol, 82 (7.0%) had endometrial cancer and 42 (3.6%) had endometrial hyperplasia. Of all patients who developed cancer during the follow-up period, 85.5% were diagnosed within 1 year after evaluation. The application of simultaneous endometrial aspiration and sonohysterography together demonstrated a sensitivity of 99.1%, specificity of 24.9%, PPV of 11.8%, and NPV of 99.6%. Using a theoretical sequential approach, assuming an endometrial aspiration is performed only in patients determined to be high risk by sonohysterography, demonstrated a sensitivity of 93.4%, specificity of 99.9%, PPV of 99.0%, and NPV of 99.3%. CONCLUSION: Simultaneous endometrial aspiration and sonohysterography is an effective one-stop outpatient screening tool for detecting endometrial cancer and hyperplasia in women aged 50 years or older. With the integration of two screening modalities into a single procedure, simultaneous endometrial aspiration and sonohysterography may overcome the limitations inherent in each of the currently recommended methods individually, potentially improving patient prognosis and streamlining the diagnostic process.

Fertility-Sparing Treatment for Early-Stage Cervical, Ovarian, and Endometrial Malignancies

Approximately 20% of gynecologic malignancies are diagnosed in reproductive-aged women, and standard-of-care surgical treatment often precludes future fertility. In early-stage disease, shared decision making about fertility-sparing medical and surgical approaches may give well-selected patients the opportunity to pursue their family-building goals without compromising long-term survival. Although future fertility is an important consideration for young women with cancer, rates of fertility-sparing procedures remain low. Moreover, because data on pregnancy rates and outcomes after fertility-sparing treatments are limited, it is challenging to counsel patients on realistic expectations. This review examines the critical oncologic outcomes of fertility-sparing approaches in early-stage gynecologic malignancies and highlights pregnancy outcomes in this population.

Ovarian Cancer After Prophylactic Salpingectomy in a Patient With Germline BRCA1 Mutation

BACKGROUND: Women with germline BRCA1 or BRCA2 mutations have a lifetime risk of ovarian cancer of up to 46%. Opportunistic salpingectomy has been advocated as a risk-reducing strategy owing to increasing recognition of tubal origin, yet evidence of efficacy in this high-risk population is limited. CASE: This is the case of a woman with a BRCA1 mutation who underwent prophylactic mastectomy and bilateral salpingectomy with ovarian retention before the age of 40 years. She did not undergo oophorectomy and subsequently developed stage IV high-grade serous ovarian cancer 4 years after her initial surgery. CONCLUSION: More research is needed to determine the role of prophylactic salpingectomy with delayed oophorectomy, optimal timing of completion oophorectomy, and the risks and benefits compared with up-front risk-reducing salpingo-oophorectomy.

Too Good to Be True

Association of the Affordable Care Act With Ovarian Cancer Care

OBJECTIVE: To estimate how implementation of the 2010 Affordable Care Act (ACA) might be associated with stage at diagnosis and time to treatment for women with ovarian cancer. METHODS: We conducted a retrospective cohort study using difference-in-differences analysis comparing stage at diagnosis and time to treatment before and after implementation of the ACA among women with ovarian cancer aged 21–64 years (exposure group) compared with women aged 65 years or older (control group). Using 2004–2015 data from the National Cancer Database, outcomes were analyzed overall and by insurance type and race, adjusting for urban-rural, income and education level, comorbidities, distance traveled for care, region, and care at an academic center. RESULTS: A total of 39,999 ovarian cancer cases prereform and 36,564 postreform were identified for women aged 21–64 years compared with 31,290 cases prereform and 29,807 postreform for women aged 65 years or older. The ACA was associated with increased early-stage diagnosis detection for women aged 21–64 years compared with women 65 and older (difference-in-differences 1.4%, 95% CI 0.4–2.4). The ACA was associated with more women receiving treatment within 30 days of ovarian cancer diagnosis (2.3%, 95% CI 1.7–3.0). Among women with public insurance, the ACA was associated with a significant improvement in early-stage diagnosis and receipt of treatment within 30 days of diagnosis (difference-in-differences 2.7%, 95% CI 1.0–4.5, difference-in-differences 2.5%, 95% CI 1.2–3.8). Improvements in time to treatment were seen across race and income groups. CONCLUSION: Implementation of the ACA was associated with earlier ovarian cancer stage at detection and treatment within 30 days of diagnosis.

Ovarian Cancer Care in the Affordable Care Act Era

Delay in Care for Gynecologic Oncology Patients With Limited English Proficiency

OBJECTIVE: To evaluate referral patterns and care delay for the growing population of patients with limited English proficiency (LEP) who seek treatment with gynecologic oncologists. METHODS: This is a retrospective cohort study of all patients seen by gynecologic oncologists at a National Cancer Institute–designated cancer center from 2013 to 2024 (referral cohort). Our primary outcome was the time to receipt of first treatment after the initial referral, by LEP status (among patients receiving treatment with a gynecologic oncologist—the treatment cohort) and with delay categorized using 4- and 6-week cutoffs. We compared referral patterns and sociodemographic, clinical, and temporal data by LEP status , defined as documented need for an interpreter. We employed χ 2 tests for categorical variables and two-sided t tests or Mann-Whitney U tests for continuous variables. Multivariable linear regression was performed. RESULTS: Of 9,915 patients seen for consultation, 5.8% (n=573) had LEP. Patients with LEP were significantly more likely to have referrals originating from the emergency department (6.5% vs 1.0%, P <.001), require multiple referrals to a gynecologic oncologist before initial consultation (9.4% vs 5.1%, P <.001), and be referred to other obstetrics and gynecology specialties before reaching gynecologic oncology (15.9% vs 8.7%, P <.001). Of 5,329 patients who received treatment with gynecologic oncologists, those with LEP were more likely to experience delays in receiving treatment after the initial diagnosis-related referral (63.2% with LEP vs 52.4% without LEP waiting more than 4 weeks, P <.001; 43.5% with LEP vs 35.7% without LEP waiting more than 6 weeks, P <.001). The time from consultation to treatment did not differ by language status. After adjusting for race, insurance status, and ethnicity, the time from referral to treatment remained 16.0% longer for patients with LEP. CONCLUSION: In this large, diverse cohort, patients with LEP experienced inequitable, cumulative health care delays. Inefficient referral patterns created delay before initial gynecologic oncology consultation.

Outcomes of the First Pregnancy After Fertility-Sparing Surgery for Early-Stage Cervical Cancer

OBJECTIVE: To evaluate outcomes of the first pregnancy after fertility-sparing surgery in patients with early-stage cervical cancer. METHODS: We performed a population-based study of women aged 18–45 years with a history of stage I cervical cancer reported to the 2000–2012 California Cancer Registry. Data were linked to the OSHPD (California Office of Statewide Health Planning and Development) birth and discharge data sets. We included patients with cervical cancer who conceived at least 3 months after a fertility-sparing surgery, which included cervical conization or loop electrosurgical excision procedure. Those undergoing trachelectomy were excluded. The primary outcome was preterm birth. Secondary outcomes included growth restriction, neonatal morbidity, stillbirth, cesarean delivery, and severe maternal morbidity. We used propensity scores to match similar women from two groups in a 1:2 ratio of case group participants to control group participants: population individuals without cancer and individuals with cervical cancer (women who delivered before their cervical cancer diagnosis). Wald statistics and logistic regressions were used to evaluate outcomes. RESULTS: Of 4,087 patients with cervical cancer, 118 (2.9%) conceived after fertility-sparing surgery, and 107 met inclusion criteria and were matched to control group participants. Squamous cell carcinoma was the most common histology (63.2%), followed by adenocarcinoma (30.8%). Patients in the case group had higher odds of preterm birth before 37 weeks of gestation compared with both control groups (21.5% vs 9.3%, odds ratio [OR] 2.7, 95% CI 1.4–5.1; 21.5% vs 12.7%, OR 1.9, 95% CI 1.0–3.6), but not preterm birth before 32 weeks. Neonatal morbidity was more common among the patients in the case group relative to those in the cervical cancer control group (15.9% vs 6.9%, OR 2.5, 95% CI 1.2–5.5). There were no differences in rates of growth restriction, stillbirth, cesarean delivery, and maternal morbidity. CONCLUSION: In a population-based cohort, patients who conceived after surgery for cervical cancer had higher odds of preterm delivery compared with control groups.

Complete Response to Combination Nivolumab and Ipilimumab in Recurrent Neuroendocrine Carcinoma of the Cervix

BACKGROUND: Small cell neuroendocrine carcinoma of the cervix is a rare, aggressive tumor treated with a combination of surgery, chemotherapy, and radiation. Survival rates are poor, and innovative therapies are needed. CASE: A 52-year-old woman was diagnosed with small cell neuroendocrine carcinoma of the cervix. Over a 10-year period, she was treated with six different systemic therapeutic regimens, underwent planned hysterectomy with bilateral salpingo-oophorectomy, and received radiation to the pelvis and brain. After a second recurrence of disease, she was treated with a combination of nivolumab and ipilimumab and experienced a complete and durable response. CONCLUSION: The combination of nivolumab and ipilimumab may represent a promising new treatment option for recurrent small cell neuroendocrine carcinoma of the cervix.

Associated Trends in Obesity and Endometrioid Endometrial Cancer in the United States

OBJECTIVE: To evaluate the correlation in temporal trends in obesity and endometrioid endometrial cancer incidence in the United States using two comprehensive national databases. METHODS: This is a cohort study in which data on endometrioid endometrial cancer were obtained from the U.S. Cancer Statistics from 2001 to 2018 and corrected for hysterectomy and pregnancy. Data on obesity were collected from the NHANES (National Health and Nutrition Examination Survey) database from 1988 to 2018. Average annual percentage changes (AAPCs) were used to describe trends. Pearson correlation coefficients (r) were calculated to examine the relationship between trends. SEER*Stat 8.3.9.2 and joinpoint regression program 5.2.0 were used for statistical analysis. RESULTS: From U.S. Cancer Statistics data, 586,742 cases of endometrioid cancer were identified from 2001 to 2018. The average annual increase in endometrioid cancer was as follows: Hispanic 1.37% (95% CI, 1.14–1.60, P<.001), Black 1.30% (95% CI, 1.04–1.57, P<.001), and White −0.17 (95% CI, −0.91 to 0.58, P=.656). Women aged 20–29 years had a 4.48% annual increase (95% CI, 3.72–5.25, P<.001) and women aged 30–39 years had a 3.00% annual increase in rates (95% CI, 2.65–3.36, P<.001). According to the NHANES data, the prevalence of obesity in 2018 in adult women was as follows: Black 56.80%, Hispanic 44.10%, and White 40.90%. An examination of trends by age showed that women aged 20–29 years had the highest annual rise in obesity compared with other age groups (AAPC 7.36%, 95% CI, 4.0–10.8, P<.05). Strong and statistically significant correlations between endometrioid cancer and obesity trends were noted for Black (r=0.78, P=.01) and Hispanic (r=0.91, P<.001) women, as well as women aged 20–29 years (r=0.72, P=.03) and 30–39 years (r=0.88, P=.001). CONCLUSION: The current data demonstrate a temporal association between the increasing incidence of obesity and endometrioid endometrial cancer, and this effect disproportionately affects younger women and Black and Hispanic women.

Diagnosis Shift in Site of Origin of Tubo-Ovarian Carcinoma

OBJECTIVE: To assess population-level trends, characteristics, and outcomes of high-grade serous tubo-ovarian carcinoma in the United States. METHODS: This retrospective cohort study queried the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. The study population was 27,811 patients diagnosed with high-grade serous tubo-ovarian carcinoma from 2004 to 2020. The exposure was the primary cancer site (ovary or fallopian tube). Main outcome measures were temporal trends, clinical characteristics, and overall survival associated with primary cancer site assessed in multivariable analysis. RESULTS: The study population comprised 23,967 diagnoses of high-grade serous ovarian carcinoma and 3,844 diagnoses of high-grade serous fallopian tubal carcinoma. The proportion of diagnoses of high-grade serous fallopian tubal carcinoma increased from 365 of 7,305 (5.0%) in 2004–2008 to 1,742 of 6,663 (26.1%) in 2017–2020. This increase was independent in a multivariable analysis (adjusted odds ratio [aOR] vs 2004–2008, 2.28 [95% CI, 1.98–2.62], 3.27 [95% CI, 2.86–3.74], and 6.65 [95% CI, 5.84–7.57] for 2009–2012, 2013–2016, and 2017–2020, respectively). This increase in high-grade serous fallopian tubal carcinoma was seen across age groups (4.3–5.8% to 22.7–28.3%) and across racial and ethnic groups (4.1–6.0% to 21.9–27.5%) (all P for trend <.001). Among the cases of tumors smaller than 1.5 cm, the increase was particularly high (16.9–67.6%, P for trend <.001). Primary-site tumors in the high-grade serous fallopian tubal carcinoma group were more likely to be smaller than 1.5 cm (aOR 8.26, 95% CI, 7.35–9.28) and unilateral (aOR 7.22, 95% CI, 6.54–7.96) compared with those in high-grade serous ovarian carcinoma. At the cohort level, the diagnosis shift to high-grade serous fallopian tubal carcinoma was associated with narrowing differences in survival over time between the two malignancy groups: adjusted hazard ratio 0.84 (95% CI, 0.74–0.96), 0.91 (95% CI, 0.82–1.01), 1.01 (95% CI, 0.92–1.12), and 1.12 (95% CI, 0.98–1.29) for 2004–2008, 2009–2012, 2013–2016, and 2017–2020, respectively. CONCLUSION: This population-based assessment suggests that diagnoses of high-grade serous tubo-ovarian carcinoma in the United States have been rapidly shifting from high-grade serous ovarian to fallopian tubal carcinoma in recent years, particularly in cases of smaller, unilateral tumors.

Creating Breast and Gynecologic Cancer Guidelines for Transgender Patients With BRCA Mutations

More than 1.5 million individuals in the United States identify as transgender. Transgender individuals have lower rates of health care utilization and higher rates of health care discrimination than cisgender patients. With a growing interest in providing comprehensive and compassionate care to the transgender community, there has been a concurrent increase in research on transgender health. However, lack of long-term data limits understanding the effects of hormone therapy on cancer risk factors in this population. This is particularly relevant for patients with hormonally mediated cancers and those at elevated risk from hereditary breast and ovarian cancer syndromes. Few cancer-screening and management guidelines currently exist for this population. Specific practices guided by the nuances of gender identity and gender-affirming care are essential to improve clinical management and to avoid further alienating a population that is already marginalized from the health care system. This commentary summarizes screening, management, and surveillance strategies devised for cisgender patients to offer corresponding recommendations tailored for transgender BRCA mutation carriers. In doing so, it highlights critical unanswered questions pertaining to the care of these patients. To address these questions, we must prioritize this population and adopt more inclusive frameworks in medicine and research.

Intraoperative Rupture of the Ovarian Capsule in Early-Stage Ovarian Cancer

OBJECTIVE: To examine the effects of intraoperative ovarian capsule rupture on progression-free survival and overall survival in women who are undergoing surgery for early-stage ovarian cancer. DATA SOURCES: MEDLINE using PubMed, EMBASE (Elsevier), ClinicalTrials.gov, and Scopus (Elsevier) were searched from inception until August 11, 2020. METHODS OF STUDY SELECTION: High-quality studies reporting survival outcomes comparing ovarian capsule rupture to no capsule rupture among patients with early-stage epithelial ovarian cancer who underwent surgical management were abstracted. Study quality was assessed with the Newcastle-Ottawa Scale, and studies with scores of at least 7 points were included. TABULATION, INTEGRATION, AND RESULTS: The data were extracted independently by multiple observers. Random-effects models were used to pool associations and to analyze the association between ovarian capsule rupture and oncologic outcomes. Seventeen studies met all the criteria for inclusion in the meta-analysis. Twelve thousand seven hundred fifty-six (62.6%) patients did not have capsule rupture and had disease confined to the ovary on final pathology; 5,532 (33.7%) patients had intraoperative capsule rupture of an otherwise early-stage ovarian cancer. Patients with intraoperative capsule rupture had worse progression-free survival (hazard ratio [HR] 1.92, 95% CI 1.34–2.76, P<.001), with moderate heterogeneity (I2=41%, P=.07) when compared with those without capsule rupture. Pooled results from these studies showed a worse overall survival (HR 1.48, 95% CI 1.15–1.91, P=.003), with moderate heterogeneity (I2=53%, P=.02) when compared with patients without intraoperative capsule rupture. This remained significant in a series of sensitivity analyses. CONCLUSION: This systematic review and meta-analysis of high-quality observational studies shows that intraoperative ovarian capsule rupture results in decreased progression-free survival and overall survival in women with early-stage ovarian cancer who are undergoing initial surgical management. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42021216561.

Outcomes of the First Pregnancy After Fertility-Sparing Surgery for Early-Stage Ovarian Cancer

OBJECTIVE: To evaluate the outcomes of the first pregnancy after fertility-sparing surgery in patients treated for early-stage ovarian cancer. METHODS: We performed a retrospective study of women aged 18–45 years with a history of stage IA or IC ovarian cancer reported to the California Cancer Registry for the years 2000–2012. These data were linked to the 2000–2012 California Office of Statewide Health Planning and Development birth and discharge data sets to ascertain oncologic characteristics and obstetric outcomes. We included in the case group ovarian cancer patients who conceived at least 3 months after fertility-sparing surgery. The primary outcome was preterm birth, and only the first pregnancy after cancer diagnosis was considered. Secondary outcomes included small-for-gestational-age (SGA) neonates, neonatal morbidity (respiratory support within 72 hours after birth, hypoxic-ischemic encephalopathy, seizures, infection, meconium aspiration syndrome, birth trauma, and intracranial or subgaleal hemorrhage), and severe maternal morbidity as defined by the Centers for Disease Control and Prevention. Propensity scores were used to match women in a 1:2 ratio for the case group and the control group. Wald statistics and logistic regressions were used to evaluate outcomes. RESULTS: A total of 153 patients who conceived after fertility-sparing surgery were matched to 306 women in a control group. Histologic types included epithelial (55%), germ-cell (37%), and sex-cord stromal (7%). Treatment for ovarian cancer was not associated with preterm birth before 37 weeks of gestation (13.7% vs 11.4%; odds ratio [OR] 1.23, 95% CI 0.69–2.20), SGA neonates (birth weight less than the 10th percentile: 11.8% vs 12.7%; OR 0.91, 95% CI 0.50–1.66), severe maternal morbidity (2.6% vs 1.3%; OR 2.03, 95% CI 0.50–8.25), or neonatal morbidity (both 5.9% OR 1.00, 95% CI 0.44–2.28). CONCLUSION: Patients who conceived at least 3 months after surgery for early-stage ovarian cancer did not have an increased risk of adverse obstetric outcomes.

Controversies in Hereditary Cancer Management

Personalized management of patients at risk ideally should involve a multidisciplinary team of not only genetic counselors and surgeons, but also women's health or menopause specialists, knowledgeable psychologists, and primary care providers or obstetrician–gynecologists aware of the risks and fears “previvors” (survivors of a predisposition to cancer who have not had the disease) face as well as the issues that are common postoperatively. Identification of patients at risk for hereditary cancer, understanding of current genetic testing modalities and potential results, knowledge about screening and prevention including timing of surveillance, preventive medication and risk-reducing surgeries, understanding limitations and comorbidities associated with these risk management strategies and long-term psychological support are all important in hereditary cancer management. We describe issues surrounding the identification of the high-risk patient, universal testing in breast and ovarian cancer, and testing in special populations. We describe a simplified approach to understanding and communicating genetic testing results and nuances of testing including direct-to-consumer testing. We highlight concerns surrounding breast cancer screening during pregnancy and lactation. A framework for practical management and counseling of women who opt for risk-reducing salpingo-oophorectomy or risk-reducing mastectomy or both is provided. We provide an in-depth discussion of questions that arise in relation to timing of surgery, fertility preservation, management of menopausal symptoms, and surgical technique. Alternative choices in women who choose to delay bilateral salpingo-oophorectomy are reviewed. Finally, the psychosocial effects of carrying a genetic mutation and the issues that women face when undergoing to risk-reducing surgery including adjustment, sexuality issues, and cosmesis are addressed.

Association of the Affordable Care Act's Medicaid Expansion With 1-Year Survival Among Patients With Ovarian Cancer

OBJECTIVE: The Affordable Care Act's (ACA) 2014 Medicaid expansion is associated with gains in insurance and early-stage diagnosis among patients with gynecologic cancer, but its association with mortality remains unknown. This study aims to assess whether the ACA's Medicaid expansion was associated with improved survival among patients with ovarian cancer. METHODS: In this retrospective cohort study of patients with newly diagnosed ovarian cancer, we compared 1-year survival before and after 2014 Medicaid expansion in patients aged 40–64 years in Medicaid expansion states (intervention group) to patients aged 40–64 years in non–Medicaid expansion states using a difference-in-difference analysis. Results were adjusted for age, comorbidities, treatment at an academic center, and variables associated with Medicaid insurance status (race, income, high-school education, distance traveled for care, and living in a rural area). RESULTS: Our sample included 19,558 patients with ovarian cancer: 9,013 in Medicaid expansion states and 10,545 in nonexpansion states. The ACA's Medicaid expansion was associated with increased 1-year survival among patients in expansion states compared with nonexpansion states (adjusted difference-in-difference 2.2%, 95% CI 0.4–4.1). After adding stage at diagnosis, the mortality difference between expansion and nonexpansion states was no longer evident. Medicaid expansion was associated with a significant improvement in 1-year survival for White patients (2.4%, 95% CI 0.4–4.4), but the difference was not significant for Black patients (1.3%, 95% CI −5.7 to 8.2) or rural patients (9.5%, 95% CI −8.0 to 26.9). CONCLUSION: The ACA's Medicaid expansion was associated with improvements in 1-year survival among patients with ovarian cancer, which was mediated by an earlier stage at diagnosis. Continued insurance expansion to nonexpansion states may improve survival and reduce disparities for patients with ovarian cancer.

Cost Effectiveness of Salpingectomy Compared With Vasectomy for Permanent Contraception

OBJECTIVE: To evaluate the cost effectiveness of salpingectomy compared with vasectomy for couples seeking permanent contraception. METHODS: We developed a decision tree model that used TreeAge to evaluate the cost effectiveness of vasectomy compared with salpingectomy for a hypothetical cohort of 800,000 people, the number of male and female patients who undergo permanent contraception procedures in the United States annually. Effectiveness was expressed in quality-adjusted life-years (QALYs), and the willingness-to-pay (WTP) threshold was set to $100,000 per QALY gained or lost. We derived costs, probabilities, and utilities from the literature, and estimated the incremental cost-effectiveness ratio (ICER) between the two strategies. We completed a probabilistic sensitivity analysis with 10,000 simulations and created a cost-effectiveness acceptability curve for WTP thresholds from $0 to $200,000. Secondary outcomes included the number of unintended pregnancies, ovarian cancer cases, and ovarian cancer deaths. RESULTS: Salpingectomy was not a cost-effective strategy, with an ICER of $143,769 per QALY gained compared with vasectomy. Probabilistic sensitivity analysis showed that the chance of vasectomy being cost effective was 81.5% but decreased to 14.7% with a WTP threshold of $200,000. Annually, salpingectomy was associated with 1,215 fewer unintended pregnancies, 6,085 fewer ovarian cancer cases, and 4,921 fewer ovarian cancer deaths compared with vasectomy. CONCLUSION: Salpingectomy is not cost effective compared with vasectomy at a WTP threshold of $100,000, despite lower unintended pregnancy rates and societal ovarian cancer burden. Shared decision making, including a discussion of the long-term health benefits of salpingectomy, is important for couples deciding on permanent contraception procedures.

Association of Physician Densities and Gynecologic Cancer Outcomes in the United States

OBJECTIVE: To evaluate whether there is an association between county-level obstetrician–gynecologist (ob-gyn) and primary care physician (PCP) densities and gynecologic cancer outcomes in the United States. METHODS: A retrospective cohort study of gynecologic cancers (uterine, ovarian, and cervical) in the Surveillance, Epidemiology, and End Results (SEER) database was performed from 2005 to 2018. County-level demographics were abstracted from the SEER database, population density from the United States Census Bureau, and physician density (ob-gyns and PCPs/100,000 females) from the Area Health Resources File. Backward stepwise regression models were used. RESULTS: Final analysis included 113,938 patients for stage at diagnosis analysis and 98,573 patients for 5-year survival analysis. Uterine, ovarian, and cervical cancers represented 60.0%, 25.0%, and 15.0% of patients, respectively. Most counties (57%) were nonmetropolitan and had a mean ob-gyn density of 8 per 100,000 females and a mean PCP density of 89 per 100,000 females. Multivariate analysis showed that increasing PCP density was associated with earlier stage at diagnosis (95% CI −6.27 to −0.05; P<.05) and increased 5-year survival rates in cervical cancer (95% CI 0.03–0.09; P<.05). Obstetrician–gynecologist density was not found to affect stage or survival outcomes for uterine or ovarian cancer. Analysis of sociodemographic factors for cervical cancer showed that median household income was negatively correlated with stage (P=.01) and that the percentage of those with bachelor’s degrees and metropolitan status were positively correlated with 5-year survival rates (P<.01). For uterine cancer, the percentage of Black females was positively correlated with stage (P<.01) and negatively correlated with 5-year survival rates (P<.01). CONCLUSION: Increasing PCP density, but not ob-gyn density, is associated with earlier stage at diagnosis and improved 5-year survival rates in cervical cancer. County-level sociodemographic factors, including population diversity, metropolitan status, educational attainment, and household income, were also correlated with outcomes across all cancer types. Targeting PCP supply and education in lower density counties may improve population-based care for cervical cancer.

Screening for High-Risk Human Papillomavirus Using Passive, Self-Collected Menstrual Blood

OBJECTIVE: To assess concordance and acceptability of a modified menstrual pad compared with a clinician-collected high-risk human papillomavirus (HPV) sample. METHODS: This was a prospective observational study. Women presenting for either cervical cancer screening or with a history of high-risk HPV positivity were eligible. Three samples were requested from participants: 1) clinician-collected cervical specimens; 2) self-collected vaginal swabs; and 3) a modified menstrual pad, which was taken home for use during the next menstruation. All samples were processed using the Cobas HPV test. Menstrual pad dried blood spots were eluted, then similarly processed. RESULTS: Of 153 women enrolled in the study, 106 provided menstrual pad samples and clinician-collected cervical specimens for high-risk HPV analysis. For samples in which the interval between the clinician-collected specimen and the menstrual pad sample was less than 2 months, the concordance was 94% (95% CI 83–98). For women who tested positive for high-risk HPV who presented for general screening and those with more than cervical intraepithelial neoplasia 2, menstrual pad and clinician-collected specimen agreement was 100% (95% CI 32.5–100). Among participants, 22.9% expressed discomfort with the self-collected vaginal swabs and opted out of collection. Overall, 94.0% of participants preferred the menstrual pad over clinician-collected sampling. Twelve patients were found to be positive for HPV on the menstrual pad sample but negative on the clinician-collected specimen. CONCLUSION: Among women who tested positive for HPV, the menstrual pad showed highly concordant results compared with clinician-collected sampling. This collection approach shows promise for integration into cervical cancer prevention programs.

Temporal Trends in Cervical Cancer Screening Practices and Associated Downstream Abnormalities and Procedures Among Women With Insurance in the United States

OBJECTIVE: To examine temporal trends in cervical cancer screening practices and associated downstream abnormalities and procedures. METHODS: Women aged 18–64 years with commercial insurance or Medicaid insurance from 2008 to 2019 were identified using the IBM MarketScan databases. The annual rates of screening overall and by type of test (cytology, co-testing, or primary human papillomavirus testing) were examined. Downstream abnormal cytologic and histologic test results, colposcopies, and excisional procedures were examined, and rates were reported for the population of eligible patients with continuous insurance and for those who underwent screening. Changes over time in testing and outcomes were compared using χ2 tests and Spearman's correlation. RESULTS: From 2008 to 2019, the annual screening prevalence decreased from 42.6% to 29.4% in women with commercial insurance (P<.001) and from 27.9% to 12.4% among women with Medicaid insurance (P<.001). In the cohort of women with commercial insurance, cytology usage decreased from 79.4% to 38.9% and co-testing increased from 20.1% to 59.6% (P<.001). Per 1,000 women screened, the rate of abnormal histologic and cytologic test results rose from 96 to 119 (P<.001) and colposcopies rose from 33 to 42 (P<.001); excisional procedures remained relatively constant. Per 1,000 eligible women, the rate of abnormal histologic and cytologic test results decreased from 41 to 35 (P<.001), colposcopies declined from 14 to 12, and excisional procedures decreased from 3 to 2. CONCLUSION: Human papillomavirus testing has been rapidly incorporated into cervical cancer screening and is associated with an increasing trend of downstream abnormalities and procedures among screened women but a declining trend at the population level.

Computer-Animated Relational Agents in Human Papillomavirus Vaccination Education

Known Benefits and Unknown Risks of Active Surveillance of Cervical Intraepithelial Neoplasia Grade 2

Cervical intraepithelial neoplasia grade 2 (CIN 2) is an equivocal diagnosis with high interobserver variation. Owing to high regression rates of 50%, many countries recommend active surveillance of CIN 2, especially in women younger than age 25–30 years, where regression rates are even higher (ie, 60%). Additionally, excisional treatment is associated with increased risk of reproductive harm, particularly preterm birth. Active surveillance typically consists of semi-annual follow-up visits for up to 2 years, including colposcopy and either cytology, testing for human papillomavirus, or both. Excisional treatment is recommended for progression or persistent disease after 2 years. Because active surveillance in younger women is relatively new, knowledge on subsequent risk of cervical cancer is limited. Considering human papillomavirus latency, women undergoing active surveillance might be at higher risk of cervical cancer than women undergoing excisional treatment. Furthermore, there are limited data describing preferences of women for the management of CIN 2, and it is also unclear how active surveillance may affect planning for future pregnancy. In this context, biomarkers for risk stratification of CIN 2 into either high or low probability of progression would allow for targeted treatment. Currently, immunohistochemical staining for p16 is used to clarify the histologic diagnosis, but whether it or other biomarkers can be used for risk-stratification in clinical management of women with CIN 2 remains unknown. In conclusion, active surveillance of CIN 2 needs further investigation, including understanding the long-term cervical cancer risk and evaluation of markers that may enable risk stratification of CIN 2.

Adjuvant Chemotherapy in Stage I Ovarian Clear Cell Carcinoma

OBJECTIVE: To investigate the treatment effect of adjuvant chemotherapy for stage I ovarian clear cell carcinoma. DATA SOURCES: We searched Cochrane, PubMed, International Standard Randomised Controlled Trial Number registry, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform, and Ichushi-Web to January 22, 2025. METHODS OF STUDY SELECTION: We included randomized controlled trials (RCTs) and non-RCTs that included more than 50 patients with stage I ovarian clear cell carcinoma. The primary and secondary outcomes were disease-free survival and overall survival, respectively. We performed a meta-analysis of the stage-adjusted hazard ratios (HRs) of adjuvant chemotherapy compared with placebo or no intervention. The substage-related heterogeneity of effects was also assessed. A meta-analysis of proportions was also conducted to assess 5-year disease-free survival and 5-year overall survival. Risk of bias was assessed with the Risk of Bias in Non-randomized Studies of Interventions tool. TABULATION, INTEGRATION, AND RESULTS: Because no RCTs reported HRs for the ovarian clear cell carcinoma subgroup, data from nine non-RCTs were analyzed. The pooled substage-adjusted HR for disease-free survival associated with use of chemotherapy was 0.47 (95% CI, 0.29–0.74) and that for overall survival was 0.66 (95% CI,0.43–1.00). Heterogeneity in the effect by substage was not evident for either disease-free survival ( P for subgroup difference=.91) or overall survival ( P =.60). The pooled 5-year disease-free survival was 0.80 (95% CI, 0.65–0.89) for stage I overall, 0.95 (95% CI, 0.47–1.0) for stage IA, and 0.61 (95% CI, 0.47–0.74) for stage IC. The estimated number needed to treat was 10.2 (95% CI, 5.8–18.6) for stage I overall, 40.8 (95% CI, 3.9–infinity) for stage IA, and 5.2 (95% CI, 3.9–7.8) for stage IC. CONCLUSION: Adjuvant chemotherapy improves disease-free survival and may prolong overall survival in patients with stage I ovarian clear cell carcinoma. Available evidence suggests that recurrence is reduced by approximately 50%. Treatment decisions should consider the baseline recurrence risks and absolute benefits. CLINICAL TRIAL REGISTRATION: PROSPERO, CRD42024562486.

Fertility-Sparing Treatments in Patients With Gynecologic Cancers

Fertility preservation is a critical consideration in the care of reproductive-aged patients with gynecologic cancers, yet referral to reproductive specialists remains low, indicating a gap between guidance and practice. We compared 28 clinical guidelines that addressed fertility-sparing management of endometrial, cervical, and ovarian cancers, and reviewed diagnostic workup, eligibility thresholds, surgical approaches, and surveillance protocols. Recommendations were synthesized into stage-specific pathways to delineate areas of consensus, highlight discrepancies, and map evidence gaps. There is broad agreement across multiple independent guidelines to support fertility-sparing treatment for carefully selected patients with: grade 1, stage IA endometrioid endometrial carcinoma; stage IA1–IB1 cervical tumors measuring less than 2 cm without high-risk features; and borderline ovarian tumors and most malignant germ cell tumors. Recommendations for higher stage disease and uncommon histologies, however, diverge and remain inconsistent. Overall guideline quality was moderate to high but frequently relied on limited evidence or expert opinion outside early-stage, low-risk conditions. Synthesizing current guidance clarifies areas where practice can be standardized and prospective data are needed. Embedding routine fertility counseling and referral into standardized pathways is an important step to improve uptake while maintaining oncologic safety and preserving fertility potential.

A Feasibility Study for Mapping Ovarian Sentinel Lymph Nodes

BACKGROUND: To evaluate four methods of injecting indocyanine green (ICG) around the adnexa and identify the optimal technique for ovarian sentinel lymph node (SLN) mapping. METHOD: Patients presenting for management of an adnexal mass were prospectively enrolled. Patients with peritoneal carcinomatosis were excluded. Four injection methods were evaluated: 1) intratubal, 2) paraovarian peritoneum, 3) infundibulopelvic (IP) ligament after resection of the adnexal mass, and 4) IP ligament before resection of the adnexal mass. Two mL of ICG was injected, and at least 10 minutes of transit time was allowed. The ipsilateral and contralateral pelvic and para-aortic lymph node beds were evaluated for ICG uptake. Retroperitoneal nodal resection was performed if indicated. EXPERIENCE: Forty patients were enrolled, 10 in each group. For method 1, 20.0% of SLNs mapped, all to the ipsilateral para-aortic lymph node bed. For method 2, 10.0% mapped, only to the ipsilateral para-aortic lymph node bed. For method 3, 50.0% mapped to the ipsilateral para-aortic lymph node bed (n=3), contralateral para-aortic lymph node bed (n=1), or ipsilateral pelvic lymph node bed (n=1). For method 4, 70.0% mapped to the ipsilateral para-aortic lymph node bed (n=5) or ipsilateral pelvic lymph node bed (n=2). Surgeons reported methods 1 and 2 as cumbersome, and excessive peritoneal staining made SLN identification difficult. No injection-related complications were reported. CONCLUSION: Injection of ICG into the IP ligament before or after adnexal mass resection led to similar rates of SLN mapping and was deemed feasible by surgeons. Only one SLN was identified contralateral to the adnexal mass, and all but three mapped to the para-aortic region. Injection into the IP ligament should be evaluated in patients with likely adnexal malignancy, including SLN resection.

Uterine Transposition for Fertility Preservation and Ovarian Conservation in Patients Undergoing Pelvic Radiotherapy

Because pelvic malignancies and their treatments often compromise reproductive potential, the need for effective fertility preserving strategies has become increasingly important. Although traditional options offer varying success, most do not aim to maintain uterine reproductive function. Uterine transposition is an innovative surgical technique designed to preserve fertility by safeguarding both the uterus and ovaries in patients undergoing pelvic radiotherapy. This approach involves temporarily repositioning the uterus and ovaries outside the radiation field, with reimplantation after treatment. Since its first successful use in 2015, uterine transposition has been used across different types of cancer and age groups, including prepubertal patients. Early clinical outcomes have been promising, with high rates of ovarian function preservation, menstrual resumption, and successful pregnancies, including spontaneous fertilizations. Additionally, the procedure has demonstrated an acceptable safety profile, with most complications being minor and manageable, although concerns remain regarding uterine ischemia and vascular integrity postreimplantation. The overall findings support its potential as a viable fertility preserving option. However, further research is necessary to refine patient selection, evaluate long-term reproductive outcomes and complications, and address challenges related to uterine perfusion and implantation.

Clinical Outcomes of Bilateral Oophorectomy Compared With Ovarian Preservation in Patients With Intravenous Leiomyomatosis Who Underwent Hysterectomy

OBJECTIVE: Intravenous leiomyomatosis is a rare, histologically benign yet biologically aggressive smooth muscle tumor. Previous studies have indicated that ovarian hormones may play a crucial role in the pathogenesis of intravenous leiomyomatosis. However, the question of whether the deprivation of ovarian estrogen, including bilateral oophorectomy, reduces tumor recurrence in intravenous leiomyomatosis remains unclear. METHODS: This retrospective cohort study, conducted across multiple centers in China from August 2003 to July 2023, focused on premenopausal patients with intravenous leiomyomatosis who underwent hysterectomy. Patients were categorized into either the bilateral oophorectomy group or the ovarian preservation group. The study compared disease-free survival (DFS) between these two groups. Univariate and multivariate analyses were employed to identify factors associated with DFS. RESULTS: The study included 219 patients, with 132 (60.3%) in the bilateral oophorectomy group and 87 (39.7%) in the ovarian preservation group. Generally, patients in the bilateral oophorectomy group were older, were more likely to have given birth, and had a higher proportion of extrauterine disease compared with those in the ovarian preservation group. Kaplan-Meier curves showed significantly lower recurrence rates in the bilateral oophorectomy group compared with the ovarian preservation group (P=.01). The cumulative recurrence rates at 3 years, 5 years, and 10 years were 0.8%, 2.6%, and 4.0%, respectively, in the bilateral oophorectomy group and 9.0%, 10.3%, and 14.0%, respectively, in the ovarian preservation group. Multivariate analysis for DFS demonstrated that ovarian preservation significantly increased the risk of tumor recurrence (adjusted hazard ratio 0.14, 95% CI, 0.04–0.52, P=.003). CONCLUSION: Simultaneous bilateral oophorectomy may reduce the risk of tumor recurrence for premenopausal women diagnosed with intravenous leiomyomatosis who undergo hysterectomy.

Conversion Rate for Robotic-Assisted Gynecologic Cancer Surgery

Our objective was to identify the rate of and reasons for conversion from robotic-assisted surgery to laparotomy for patients with gynecologic cancers. A retrospective analysis was conducted of all consecutive robotic surgeries for gynecologic cancers performed at a tertiary cancer center between December 2007 and December 2022. Data were stratified based on cancer type (endometrial, ovarian, cervical, and “other”) and body mass index (BMI). Reasons for conversion were categorized as specimen removal, anesthesia-related, organ or vessel injury, advanced metastatic disease, and equipment malfunction. The conversion rate was 2.4% (55/2,328) overall and 0.5% for endometrial cancer after excluding mini-laparotomies performed solely to remove large specimens. The predominant reason for conversion in ovarian cancer was disease invasion into surrounding structures not amenable to robotic resection. No association was found between conversion rates and BMI or age.

Canadian Management of Serous Tubal Intraepithelial Carcinoma

OBJECTIVE: To assess the management and outcomes of patients diagnosed with an isolated serous tubal intraepithelial carcinoma lesion across Canada. METHODS: This retrospective study included consecutive patients with an isolated serous tubal intraepithelial carcinoma lesion diagnosed between 2006 and 2020 at 15 Canadian centers. Cases underwent multicenter panel pathology review. RESULTS: Of 107 patients, 41 serous tubal intraepithelial carcinoma cases (38.3%) were identified at prophylactic surgery for germline pathogenic variants, 36 (33.6%) at surgery for suspicion of malignancy, and 30 (28.0%) at surgery for benign conditions. Treatment groups included observation (n=62, 57.9%), staging surgery (n=35, 32.7%), and adjuvant chemotherapy (n=10, 9.3%). Median follow-up was 55.5 months (interquartile range 30.26–82.07 months). Overall, nine patients developed high-grade serous carcinoma. The cumulative incidence of high-grade serous carcinoma was not significantly different between treatment groups (P=.181); however, no patient treated with chemotherapy developed high-grade serous carcinoma. The cumulative incidence of high-grade serous carcinoma was 1.1% (95% CI, 0.1–5.3%) at 2 years and 5.7% (95% CI, 1.8–13.1%) at 5 years. No significant predictive factors were found on univariate analysis. After multicenter pathology review of 59 cases (55.1%), consensus diagnosis was reached: 45 (76.3%) with serous tubal intraepithelial carcinoma, three (5.1%) with serous tubal intraepithelial lesion, seven (11.9%) with high-grade serous carcinoma, and two (3.4%) with normal tissue. Of the cases reviewed, only 1 of 45 patients (2.2%) with confirmed serous tubal intraepithelial carcinoma developed high-grade serous carcinoma at 73 months, indicating a 5-year cumulative incidence of cancer of 2.6% (95% CI, 0.2–11.7). CONCLUSION: Management of serous tubal intraepithelial carcinoma varied across centers. The 5-year cumulative incidence of high-grade serous carcinoma after isolated serous tubal intraepithelial carcinoma was 5.7%, consistent with recent literature. However, multicenter pathology review revealed initial underdiagnosed high-grade serous carcinoma, and 5-year cumulative incidence of high-grade serous carcinoma after confirmed serous tubal intraepithelial carcinoma decreased to 2.6%, underscoring the importance of diagnostic confirmation by expert pathologists to guide accurate management.

Menopausal Symptom Management in Patients After Risk-Reducing Oophorectomy

Patients with BRCA1/2 mutations face difficult decisions on pursuing risk-reducing (and lifesaving) surgery, especially because of concerns about the safety of menopausal hormone therapy and breast cancer risk. However, observational data suggest that systemic menopausal hormone therapy does not elevate breast cancer risk among patients with pathogenic mutations with intact breasts who have undergone risk-reducing bilateral salpingo-oophorectomy (BSO) before age 45 years. Accordingly, such individuals should be considered for menopausal hormone therapy to improve quality of life and to decrease health risks associated with premature menopause. Given emerging data on the potential of estrogen-only therapy to reduce breast cancer risk, clinicians caring for women with BRCA1/2 mutations could consider offering hysterectomy along with BSO as part of risk-reducing surgery.

Optimization of Timing for Risk-Reducing Salpingectomy and Oophorectomy

Most cases of ovarian cancer are diagnosed at an advanced stage, and long-term survival rates are low. Because no effective ovarian cancer screening has yet been developed, the primary focus to reduce ovarian cancer mortality is surgical prevention. For individuals with a significantly increased risk of ovarian cancer, risk-reducing bilateral salpingo-oophorectomy is highly effective, but uptake at the recommended age is suboptimal, likely because of concerns about premature menopause. Evidence suggests that many “ovarian” cancers originate in the distal fallopian tube, thus making bilateral salpingectomy after completion of childbearing with delayed oophorectomy an attractive but still unproven risk-reduction option for those who decline or are not yet ready for risk-reducing bilateral salpingo-oophorectomy. Two clinical trials (SOROCk [A Non-randomized Prospective Clinical Trial Comparing the Non-inferiority of Salpingectomy to Salpingo-oophorectomy to Reduce the Risk of Ovarian Cancer Among BRCA1 Carriers], NCT04251052; and TUBA-WISP2 [Tubectomy With Delayed Oophorectomy as an Alternative to Risk-Reducing Salpingo-oophorectomy in High-Risk Women to Assess the Safety of Prevention]; NCT04294927) are ongoing to determine whether bilateral salpingectomy with delayed oophorectomy is as effective as risk-reducing bilateral salpingo-oophorectomy to prevent ovarian cancer. The SOROCk trial is a national, prospective nonrandomized trial powered to test the hypothesis that bilateral salpingectomy with delayed oophorectomy is noninferior to risk-reducing bilateral salpingo-oophorectomy to reduce the incidence of ovarian cancer among people with deleterious germline BRCA1 mutations. Gynecologists and gynecologic oncologists in both community-based and academic practices may perform risk-reducing surgeries and have their patients participate in the SOROCk trial. We review key aspects of the SOROCk clinical trial and discuss how surgeons can partner with SOROCk clinical trial sites and facilitate their patients' participation to help answer this important clinical question. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT04251052.

Diagnostic Algorithms for Adnexal Masses in the Hands of a Novice Operator

OBJECTIVE: To compare the performance of four commonly used algorithms to differentiate benign from malignant adnexal masses when used by a novice operator. METHODS: Women with adnexal masses treated at Mayo Clinic, Rochester, Minnesota, in 2019 were identified retrospectively. Patients were included if they underwent surgery within 3 months of diagnosis or had at least 10 months of follow-up. A nonexpert operator (European Federation of Societies for Ultrasound in Medicine and Biology level I) classified each lesion using ADNEX (Assessment of Different Neoplasias in the Adnexa), two-step strategy (benign descriptors followed by ADNEX), O-RADS (Ovarian-Adnexal Reporting and Data System) 2019, and O-RADS 2022. The primary outcome measure was the area under the receiver operating characteristic curve (AUC) compared across the four algorithms. RESULTS: A total of 556 women were included in the analyses: 452 with benign and 104 with malignant masses. The AUCs of ADNEX, the two-step strategy, O-RADS 2019, and O-RADS 2022 were 0.90 (95% CI, 0.87–0.94), 0.91 (95% CI,0.88–0.94), 0.88 (95% CI,0.84–0.91), and 0.88 95% CI, (0.84–0.91), respectively. The two-step strategy performed significantly better than the O-RADS algorithms (P=.005 and P=.002). With all the algorithms, the observed malignancy rate was 1.9–2.2% among lesions categorized as almost certainly benign, twofold higher than the expected less than 1.0%. Lesions wrongly classified as almost certainly benign were borderline tumors (n=4) and metastases (n=3). CONCLUSION: In the hands of a novice operator, all algorithms performed well and were able to distinguish benign from malignant lesions. Although the two-step strategy performed slightly better than the O-RADSs, the difference did not appear to be clinically meaningful. The malignancy rate among lesions classified as almost certainly benign was unexpectedly high at 1.9–2.3%, approximately double the expected rate of less than 1.0%.

Radiofrequency Ablation of Leiomyomas: Correction

Establishment of Noninvasive Prediction Models for the Diagnosis of Uterine Leiomyoma Subtypes

OBJECTIVE: To establish prediction models for the diagnosis of the subtypes of uterine leiomyomas by machine learning using magnetic resonance imaging (MRI) data. METHODS: This is a prospective observational study. Ninety uterine leiomyoma samples were obtained from 51 patients who underwent surgery for uterine leiomyomas. Seventy-one samples (49 mediator complex subunit 12 [MED12] mutation–positive and 22 MED12 mutation–negative leiomyomas) were assigned to the primary data set to establish prediction models. Nineteen samples (13 MED12 mutation–positive and 6 MED12 mutation-negative leiomyomas) were assigned to the unknown testing data set to validate the prediction model utility. The tumor signal intensity was quantified by seven MRI sequences (T2-weighted imaging, apparent diffusion coefficient, magnetic resonance elastography, T1 mapping, magnetization transfer contrast, T2* blood oxygenation level dependent, and arterial spin labeling) that can estimate the collagen and water contents of uterine leiomyomas. After surgery, the MED12 mutations were genotyped. These results were used to establish prediction models based on machine learning by applying support vector classification and logistic regression for the diagnosis of uterine leiomyoma subtypes. The performance of the prediction models was evaluated by cross-validation within the primary data set and then finally evaluated by external validation using the unknown testing data set. RESULTS: The signal intensities of five MRI sequences (T2-weighted imaging, apparent diffusion coefficient, T1 mapping, magnetization transfer contrast, and T2* blood oxygenation level dependent) differed significantly between the subtypes. In cross-validation within the primary data set, both machine learning models (support vector classification and logistic regression) based on the five MRI sequences were highly predictive of the subtypes (area under the curve [AUC] 0.974 and 0.988, respectively). External validation with the unknown testing data set confirmed that both models were able to predict the subtypes for all samples (AUC 1.000, 100.0% accuracy). Our prediction models with T2-weighted imaging alone also showed high accuracy to discriminate the uterine leiomyoma subtypes. CONCLUSION: We established noninvasive prediction models for the diagnosis of the subtypes of uterine leiomyomas by machine learning using MRI data.

Leiomyoma Fistulization After Uterine Artery Embolization

BACKGROUND: Uterine artery embolization (UAE) has been used to treat symptomatic uterine leiomyomas since 1995. This case report describes a rare complication of UAE, with delayed recognition, ultimately requiring definitive hysterectomy. CASE: A 53-year-old women with symptomatic leiomyomas underwent imaging demonstrating an enlarged (16.9×11.3×11.5 cm) uterus with multiple leiomyomas. She underwent UAE and, over the subsequent 3 months, and had five emergency department visits for abdominal pain and dysuria. Pelvic magnetic resonance imaging (MRI) 4 months postprocedure showed nodular mural enhancement of the right anterior bladder dome, and cystoscopy demonstrated irregular tissue on the right dome of the bladder. The patient ultimately underwent total laparoscopic hysterectomy, bilateral salpingo-oophorectomy, partial cystectomy with reconstruction, and omental flap for bladder necrosis and leiomyoma fistulization. CONCLUSION: Bladder necrosis and leiomyoma fistulization are rare complications of UAE that can present with pelvic pain, hematuria, and recurrent bladder stones. Computed tomography and MRI can be useful tools in evaluating for complications, but clinicians should have a low threshold to use cystoscopy to directly visualize potential abnormalities identified on imaging. Patients with complex cases with suspected post-UAE complications warrant referral to tertiary care centers for a multidisciplinary approach.

New Paradigms in the Treatment of Cervical Cancer

Despite effective screening strategies and the development and implementation of prophylactic high-risk human papillomavirus vaccination, cervical cancer remains a significant public health burden. This burden is most pronounced in under-resourced countries without fully developed screening and vaccination programs, although the disease remains present worldwide, including in industrialized countries. To that end, the World Health Organization (WHO) has an active focus on the elimination of cervical cancer, with objective metrics to be achieved by countries by the year 2030. Although increased vaccination and screening will be needed to approach potential eradication of cervical cancer, as recognized by the WHO initiative, treatment will need to continue to not only be effective in the near term, but to improve outcomes as well. Accordingly, assessments to improve primary treatment options, including surgery for women with early-stage disease, modification of chemoradiation for those with locally advanced cervical cancer, and systemic therapy for those with recurrent or metastatic presentations, are ongoing. Accordingly, we highlight important areas of both recent and ongoing focus as they relate to improving cervical cancer outcomes.

Association of Hospital Surgical Volume With Survival in Early-Stage Cervical Cancer Treated With Radical Hysterectomy

OBJECTIVE: To evaluate the association of number of radical hysterectomies performed per year in each center with disease-free survival and overall survival. METHODS: We conducted an international, multicenter, retrospective study of patients previously included in the Surveillance in Cervical Cancer collaborative studies. Individuals with International Federation of Gynecology and Obstetrics (FIGO) 2009 stage IB1–IIA1 cervical cancer who underwent radical hysterectomy and had negative lymph nodes at final histology were included. Patients were treated at referral centers for gynecologic oncology according to updated national and international guidelines. Optimal cutoffs for surgical volume were identified using an unadjusted Cox proportional hazard model, with disease-free survival as the outcome and defined as the value that minimizes the P-value of the split in groups in terms of disease-free survival. Propensity score matching was used to create statistically similar cohorts at baseline. RESULTS: A total of 2,157 patients were initially included. The two most significant cutoffs for surgical volume were identified at seven and 17 surgical procedures, dividing the entire cohort into low-volume, middle-volume, and high-volume centers. After propensity score matching, 1,238 patients were analyzed—619 (50.0%) in the high-volume group, 523 (42.2%) in the middle-volume group, and 96 (7.8%) in the low-volume group. Patients who underwent surgery in higher-volume institutions had progressively better 5-year disease-free survival than those who underwent surgery in lower-volume centers (92.3% vs 88.9% vs 83.8%, P=.029). No difference was noted in 5-year overall survival (95.9% vs 97.2% vs 95.2%, P=.70). Cox multivariable regression analysis showed that FIGO stage greater than IB1, presence of lymphovascular space invasion, grade greater than 1, tumor diameter greater than 20 mm, minimally invasive surgical approach, nonsquamous cell carcinoma histology, and lower-volume centers represented independent risk factors for recurrence. CONCLUSION: Surgical volume of centers represented an independent prognostic factor affecting disease-free survival. Increasing number of radical hysterectomies performed in each center every year was associated with improved disease-free survival.

Are All Referrals to Colposcopy Clinics Appropriate?: Correction

Management of Endometrial Intraepithelial Neoplasia or Atypical Endometrial Hyperplasia

Summary Endometrial intraepithelial neoplasia (EIN) or atypical endometrial hyperplasia (AEH) often is a precursor lesion to adenocarcinoma of the endometrium. Hysterectomy is the definitive treatment for EIN–AEH. When a conservative (fertility-sparing) approach to the management of EIN–AEH is under consideration, it is important to attempt to exclude the presence of endometrial cancer to avoid potential undertreatment of an unknown malignancy in those who have been already diagnosed with EIN–AEH. Given the high risk of progression to cancer, those who do not have surgery require progestin therapy (oral, intrauterine, or combined) and close surveillance. Although data are conflicting and limited, studies have demonstrated that treatment with the levonorgestrel-releasing intrauterine device results in a higher regression rate when compared with treatment with oral progestins alone. Limited data suggest that cyclic progestational agents have lower regression rates when compared with continuous oral therapy. After initial conservative treatment for EIN–AEH, early detection of disease persistence, progression, or recurrence requires careful follow-up. Gynecologists and other clinicians should counsel patients that lifestyle modification resulting in weight loss and glycemic control can improve overall health and may decrease the risk of EIN–AEH and endometrial cancer.

Combined Bilateral Salpingo-oophorectomy and Cesarean Delivery in BRCA1/2 Alteration Carriers: A Case Series: Correction

Development and Potential Implementation of Endometrial Cancer Screening in a Poor-Prognosis Endemic Cancer Community [ID 2683642]: Correction

Tamoxifen Use and Risk of Uterine Diseases in Young Women With Breast Cancer

OBJECTIVE: Tamoxifen use has been associated with an increased risk of endometrial cancer in women with breast cancer, but data on premenopausal women in Asia remain limited. We investigated the association between tamoxifen treatment and risk of developing uterine diseases in women of premenopausal age with breast cancer. METHODS: We conducted a retrospective cohort study using a target trial emulation framework. Women aged 20–50 years who were diagnosed with estrogen receptor–positive breast cancer and had undergone mastectomy or lumpectomy from 2010 to 2019 were identified with Taiwan's National Health Insurance claims data linked to the cancer registry. Those with a history of hysterectomy, neoadjuvant therapy, and diagnosis of postmenopausal status and uterine diseases were excluded. Tamoxifen use was defined as receipt tamoxifen treatment only as adjuvant hormone treatment within 1 year after surgery. Inverse probability of treatment weighting controlled baseline confounding between the tamoxifen treatment and nontreatment groups. Observational analogs of the intention-to-treat and per-protocol effects were estimated with pooled logistic regression models. RESULTS: A total of 23,062 tamoxifen users and 3,000 nonusers were included. During the follow-up period, 3,889 users and 109 nonusers developed uterine diseases, including 106 and 5 cases of endometrial cancer, respectively. In the intention-to-treat analysis, the hazard ratio was 4.15 (95% CI, 2.65–6.50) for endometrial polyps, 5.42 (95% CI, 4.09–7.18) for endometrial hyperplasia, and 2.41 (95% CI, 0.86–6.72) for endometrial cancer. Corresponding estimates from the per-protocol analysis were 4.75 (95% CI, 2.55–8.86), 8.37 (95% CI, 5.24–13.35), and 4.20 (95% CI, 1.20–14.63), respectively. The risk of all uterine diseases increased with longer duration of tamoxifen use. CONCLUSION: Among women of premenopausal age with breast cancer in Taiwan, tamoxifen as adjuvant hormone therapy was associated with increased risk of uterine diseases, including endometrial cancer. These findings highlight the importance of monitoring uterine diseases among tamoxifen users in this age range.

Recommendations From the Women's Preventive Services Initiative on Breast Cancer Screening for Women at Average Risk and Patient Navigation Services for Breast and Cervical Cancer Screening

The Women's Preventive Services Initiative (WPSI) expanded its previous breast cancer screening recommendation—initiate annual or biennial mammography screening for women at average risk of breast cancer between the ages of 40 and 50 years—by including additional imaging and pathology evaluation as part of the screening process if needed. Consistent with the previous recommendation, screening should continue through at least age 74 years, and age alone should not be the basis for discontinuing screening. To increase utilization of screening recommendations, the WPSI also issued a new recommendation to provide patient navigation services for breast and cervical cancer screening. To update its 2016 breast cancer screening recommendation, the WPSI found no new evidence of benefits and harms of screening. However, additional studies reported that gaps in insurance coverage contributed to incomplete follow-up after an initial abnormal mammogram for many women. For its new patient navigation recommendation, the WPSI evaluated 42 randomized controlled trials of patient navigation services for breast and cervical cancer screening and follow-up that showed increased rates compared with usual care. Patient navigation services involve person-to-person contact and are individualized to the patient's specific needs. Services include but are not limited to person-centered assessment and planning, health care access and health system navigation, referrals to support services, and patient education. The new recommendations are intended to expand breast cancer screening follow-up and to improve access and equity for cancer screening. Beginning in 2026, under the Affordable Care Act, these services will be covered without copay or deductible charges for most eligible women.

Malignancy Assessment Using Gene Identification in Captured Cells Algorithm for the Prediction of Malignancy in Women With a Pelvic Mass

OBJECTIVE: To evaluate the detection of malignancy in women with a pelvic mass by using multiplexed gene expression analysis of cells captured from peripheral blood. METHODS: This was an IRB-approved, prospective clinical study. Eligible patients had a pelvic mass and were scheduled for surgery or biopsy. Rare cells were captured from peripheral blood obtained preoperatively by using a microfluidic cell capture device. Isolated mRNA from the captured cells was analyzed for expression of 72 different gene transcripts. Serum levels for several commonly assayed biomarkers were measured. All patients had a tissue diagnosis. Univariate and multivariate logistic regression analyses for the prediction of malignancy using gene expression and serum biomarker levels were performed, and receiver operating characteristic curves were constructed and compared. RESULTS: A total of 183 evaluable patients were enrolled (average age 56 years, range 19–91 years). There were 104 benign tumors, 17 low malignant potential tumors, and 62 malignant tumors. Comparison of the area under the receiver operating characteristic curve for individual genes and various combinations of genes with or without serum biomarkers to differentiate between benign conditions (excluding low malignant potential tumors) and malignant tumors showed that a multivariate model combining the expression levels of eight genes and four serum biomarkers achieved the highest area under the curve (AUC) (95.1%, 95% CI 92.0–98.2%). The MAGIC (Malignancy Assessment using Gene Identification in Captured Cells) algorithm significantly outperformed all individual genes (AUC 50.2–65.2%; all P <.001) and a multivariate model combining 14 different genes (AUC 88.0%, 95% CI 82.9–93.0%; P =.005). Further, the MAGIC algorithm achieved an AUC of 89.5% (95% CI 81.3–97.8%) for stage I–II and 98.9% (95% CI 96.7–100%) for stage III–IV patients with epithelial ovarian cancer. CONCLUSION: Multiplexed gene expression evaluation of cells captured from blood, with or without serum biomarker levels, accurately detects malignancy in women with a pelvic mass. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02781272. FUNDING SOURCE: This study was funded by ANGLE Europe Limited (Surrey Research Park, Guildford, Surrey, United Kingdom).

Adjuvant Human Papillomavirus Vaccine to Reduce Recurrent Cervical Dysplasia in Unvaccinated Women

OBJECTIVE: To perform a systematic review and meta-analysis evaluating the efficacy of adjuvant human papillomavirus (HPV) vaccination in preventing recurrent cervical intraepithelial neoplasia (CIN) 2 or greater after surgical excision. DATA SOURCES: Electronic databases (Cochrane, PubMed, EMBASE, MEDLINE, Scopus, and ClinicalTrials.gov) were searched for studies comparing surgical excision alone to surgical excision with adjuvant HPV vaccination for CIN 2 or greater. Studies published from January 1990 to January 2019 were included. METHODS: A total of 5,901 studies were reviewed. The primary outcomes evaluated included: recurrence of CIN 2 or greater, CIN 1 or greater, and HPV 16,18 associated CIN within 6–48 months. We used Covidence software to assist with screening, and meta-analysis was performed using Review Manager. TABULATION, INTEGRATION, AND RESULTS: Six studies met inclusion criteria and were included in the final analysis. In total 2,984 women were included; 1,360 (45.6%) received adjuvant HPV vaccination after surgical excision, and 1,624 (54.4%) received either placebo or surgical management alone for CIN 2 or greater. Recurrence of CIN 2 or greater occurred within 6–48 months in 115 women (3.9%) overall; however, recurrence was significantly lower for vaccinated women: 26 of 1,360 women (1.9%) vs 89 of 1,624 unvaccinated women (5.9%) (relative risk [RR] 0.36 95% CI 0.23–0.55). The risk of CIN 1 or greater was also significantly lower with adjuvant HPV vaccination, occurring in 86 of 1,360 vaccinated women (6.3%) vs 157 of 1,624 unvaccinated women (9.7%) (RR 0.67 95% CI 0.52–0.85). Thirty-five women developed recurrent CIN 2 or greater lesions specific to HPV 16,18; nine received adjuvant vaccination (0.9%) vs 26 who were unvaccinated (2.0%) (RR 0.41 95% CI 0.20–0.85). CONCLUSION: Adjuvant HPV vaccination in the setting of surgical excision for CIN 2 or greater is associated with a reduced risk of recurrent cervical dysplasia overall and a reduction in the risk of recurrent lesions caused by the most oncogenic strains (HPV 16,18). Human papillomavirus vaccination should therefore be considered for adjuvant treatment in patients undergoing surgical excision for CIN 2 or greater. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42019123786.

Diagnosis and Management of Adenocarcinoma in Situ

This publication represents an extensive literature review with the goal of providing guidelines for the evaluation and management of cervical adenocarcinoma in situ (AIS). The authors drafted the guidelines on behalf of the Society of Gynecologic Oncology, and the guidelines have been reviewed and endorsed by the ASCCP. These guidelines harmonize with the ASCCP Risk-Based Management Consensus Guidelines and provide more specific guidance beyond that provided by the ASCCP guidelines. Examples of updates include recommendations to optimize the diagnostic excisional specimen, AIS management in the setting of positive compared with negative margins on the excisional specimen, surveillance and definitive management after fertility-sparing treatment, and management of AIS in pregnancy. The increasing incidence of AIS, its association with human papillomavirus–18 infection, challenges in diagnosis owing to frequent origin within the endocervical canal, and the possibility of skip lesions all make AIS a unique diagnosis whose management needs to be differentiated from the management of the more prevalent squamous cell dysplasia.

Relative Risk of Cervical Neoplasms Among Copper and Levonorgestrel-Releasing Intrauterine System Users

OBJECTIVE: To evaluate the relative risk of cervical neoplasms among copper intrauterine device (Cu IUD) and levonorgestrel-releasing intrauterine system (LNG-IUS) users. METHODS: We performed a retrospective cohort analysis of 10,674 patients who received IUDs at Columbia University Medical Center. Our data were transformed to a common data model and are part of the Observational Health Data Sciences and Informatics network. The cohort patients and outcomes were identified by a combination of procedure codes, condition codes, and medication exposures in billing and claims data. We adjusted for confounding with propensity score stratification and propensity score 1:1 matching. RESULTS: Before propensity score adjustment, the Cu IUD cohort included 8,274 patients and the LNG-IUS cohort included 2,400 patients. The median age for both cohorts was 29 years at IUD placement. More than 95% of the LNG-IUS cohort used a device with 52 mg LNG. Before propensity score adjustment, we identified 114 cervical neoplasm outcomes. Seventy-seven (0.9%) cervical neoplasms were in the Cu IUD cohort and 37 (1.5%) were in the LNG-IUS cohort. The propensity score matching analysis identified 7,114 Cu IUD and 2,174 LNG-IUS users, with covariate balance achieved over 16,827 covariates. The diagnosis of high-grade cervical neoplasia was 0.7% in the Cu IUD cohort and 1.8% in the LNG-IUS cohort (2.4 [95% CI 1.5–4.0] cases/1,000 person-years and 5.2 [95% CI 3.7–7.1] cases/1,000 person-years, respectively). The relative risk of high-grade cervical neoplasms among Cu IUD users was 0.38 (95% CI 0.16–0.78, P<.02) compared with LNG-IUS users. By inspection, the Kaplan-Meier curves for each cohort diverged over time. CONCLUSION: Copper IUD users have a lower risk of high-grade cervical neoplasms compared with LNG-IUS users. The relative risk of cervical neoplasms of LNG-IUS users compared with the general population is unknown.

Combined Bilateral Salpingo-oophorectomy and Cesarean Delivery in BRCA1/2 Alteration Carriers

BACKGROUND: The cumulative lifetime risk of ovarian cancer is 16–68% and 11–30% in female BRCA1 and BRCA2 gene alteration carriers, respectively. Risk-reducing bilateral salpingo-oophorectomy (RRSO) is the only proven way to reduce ovarian cancer mortality. We report a series of patients who underwent risk-reducing surgery at the time of planned obstetric-indicated cesarean delivery. CASES: This is a case series of four women carrying a pathogenic germline BRCA1 or BRCA2 gene alteration who underwent RRSO at the time of cesarean delivery between March 1, 2018, and March 31, 2022. All women were referred during pregnancy to the University College London Hospitals Familial Cancer Clinic for consideration of RRSO at the time of obstetric-indicated cesarean delivery. Women were considered eligible for RRSO if they had a proven pathogenic germline alteration, would have completed childbearing after the cesarean delivery, and were older than age 35 or 40 years with BRCA1 or BRCA2 alterations, respectively. Operating time, blood loss, transfusion requirements, length of hospital stay, complications, and ability to breastfeed were assessed and, where possible, compared with the institutional means for similar patients who underwent cesarean delivery only, to determine whether RRSO was associated with increased morbidity. Women were contacted 11–59 months postprocedure to assess satisfaction. The mean blood loss was 687 mL (range 400–1,000 mL), mean operating time was 68 minutes, mean length of hospital stay was 3 days, and mean change in hemoglobin was −1 g/dL. No patient required a transfusion, had internal organ damage, returned to the operating room, or was readmitted. One of two women with intact breast tissue successfully breastfed, and the other chose to bottle feed. The mean contemporaneous institutional blood loss for cesarean delivery was not significantly different at 681 mL for singleton pregnancies and 872 mL for twin pregnancies. All four women reported a high level of satisfaction with the combined procedure. CONCLUSION: Our results show that RRSO can be performed at the time of cesarean delivery with high patient satisfaction. This approach can be offered to appropriately counseled individuals, with the benefit of avoiding the need for two separate procedures, with potentially reduced patient morbidity and health care costs.

Disparities in Timeliness of Endometrial Cancer Care

OBJECTIVE: We use the person-centered Pathway to Treatment framework to assess the scope of evidence on disparities in endometrial cancer stage at diagnosis. This report is intended to facilitate interventions, research, and advocacy that reduce disparities. DATA SOURCES: We completed a structured search of electronic databases: PubMed, EMBASE, Scopus, ClinicalTrials.gov, and Cochrane Central Register of Controlled Trials databases. Included studies were published between January 2000 and 2023 and addressed marginalized population(s) in the United States with the ability to develop endometrial cancer and addressed variable(s) outlined in the Pathway to Treatment. METHODS OF STUDY SELECTION: Our database search strategy was designed for sensitivity to identify studies on disparate prolongation of the Pathway to Treatment for endometrial cancer, tallying 2,171. Inclusion criteria were broad, yet only 24 studies addressed this issue. All articles were independently screened by two reviewers. TABULATION, INTEGRATION, AND RESULTS: Twenty-four studies were included: 10 on symptom appraisal, five on help seeking, five on diagnosis, and 10 on pretreatment intervals. Quality rankings were heterogeneous, between 3 and 9 (median 7.2) per the Newcastle–Ottawa Scale. We identified three qualitative, two participatory, and two intervention studies. Studies on help seeking predominantly investigate patient-driven delays. When disease factors were controlled for, delays of the pretreatment interval were independently associated with racism toward Black and Hispanic people, less education, lower socioeconomic status, and nonprivate insurance. CONCLUSIONS: Evidence gaps on disparities in timeliness of endometrial cancer care reveal emphasis of patient-driven help-seeking delays, reliance on health care–derived databases, underutilization of participatory methods, and a paucity of intervention studies. SYSTEMATIC REVIEW REGISTRATION: Given that PROSPERO was not accepting systematic scoping review protocols at the time this study began, this study protocol was shared a priori through Open Science Framework on January 13, 2021 (doi: 10.17605/OSF.IO/V2ZXY), and through peer review publication on April 13, 2021 (doi: https://doi.org/10.1186/s13643-021-01649-x).

Safety of Fezolinetant for Vasomotor Symptoms Associated With Menopause

OBJECTIVE: To evaluate the safety, tolerability, and effect of fezolinetant on endometrial health over 52 weeks. METHODS: We conducted a phase 3, randomized, double-blind, 52-week safety study (SKYLIGHT 4 [Study to Find Out How Safe Long-term Treatment With Fezolinetant is in Women With Hot Flashes Going Through Menopause]) of placebo, fezolinetant 30 mg, and fezolinetant 45 mg once daily (1:1:1). Participants were postmenopausal and seeking treatment for vasomotor symptoms associated with menopause. Primary endpoints were treatment-emergent adverse events, percentage of participants with endometrial hyperplasia, and percentage with endometrial malignancy. Endometrial hyperplasia or malignancy was evaluated according to U.S. Food and Drug Administration guidance (point estimate of 1% or less with an upper bound of one-sided 95% CI of 4% or less). Secondary endpoints included change in bone mineral density (BMD) and trabecular bone score. A sample size of 1,740 was calculated to enable observation of one or more events (≈80% probability for events with background rate of less than 1%). RESULTS: A total of 1,830 participants were randomized and took one or more medication dose (July 2019–January 2022). Treatment-emergent adverse events occurred in 64.1% (391/610) of the placebo group, 67.9% (415/611) of the fezolinetant 30-mg group, and 63.9% (389/609) of the fezolinetant 45-mg group. Treatment-emergent adverse events leading to discontinuation were similar across groups (placebo, 26/610 [4.3%]; fezolinetant 30 mg, 34/611 [5.6%]; fezolinetant 45 mg, 28/609 [4.6%]). Endometrial safety was assessed in 599 participants. In the fezolinetant 45-mg group, 1 of 203 participants had endometrial hyperplasia (0.5%; upper limit of one-sided 95% CI 2.3%); there were no cases in the placebo (0/186) or fezolinetant 30 mg (0/210) group. Endometrial malignancy occurred in 1 of 210 in the fezolinetant 30-mg group (0.5%; 95% CI 2.2%) with no cases in the other groups. Liver enzyme elevations more than three times the upper limit of normal occurred in 6 of 583 placebo, 8 of 590 fezolinetant 30 mg, and 12 of 589 fezolinetant 45 mg participants; no Hy's law cases were reported (ie, no severe drug-induced liver injury with alanine aminotransferase or aspartate aminotransferase more than three times the upper limit of normal and total bilirubin more than two times the upper limit of normal, with no elevation of alkaline phosphatase and no other reason to explain the combination). Changes in BMD and trabecular bone score were similar across groups. CONCLUSION: Results from SKYLIGHT 4 confirm the 52-week safety and tolerability of fezolinetant and support its continued development. FUNDING SOURCE: Astellas Pharma Inc. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT04003389.

Endometrial Cancer Detection During the Coronavirus Disease 2019 (COVID-19) Pandemic

During the first 12 weeks of the coronavirus disease 2019 (COVID-19) pandemic, endometrial cancer diagnoses declined 35% and patient calls for abnormal bleeding declined 33% compared with 2019 levels.

Effect of Prior 9-Valent Human Papillomavirus Vaccination on Subsequent Lower Genital Tract Dysplasia After Cervical Excisional Surgery

OBJECTIVE: To assess the efficacy of prior 9-valent human papillomavirus (9vHPV) vaccination on risk of subsequent cervical, vaginal, and vulvar disease after a cervical excisional procedure for cervical squamous intraepithelial lesion (SIL) in a retrospective clinical trial analysis. METHODS: Women aged 16–26 years were randomized to three-dose regimens of 9vHPV vaccine, quadrivalent HPV (4vHPV) vaccine, or placebo in three double-blind efficacy trials: a study of 9vHPV vaccine compared with 4vHPV vaccine (ClinicalTrials.gov, NCT00543543) and two historic placebo-controlled 4vHPV vaccine studies (ClinicalTrials.gov, NCT00092521 and NCT00092534). Incidence of subsequent condyloma, cervical, vulvar, or vaginal SIL was compared between 9vHPV vaccine and controls in women who underwent cervical excisional surgery after vaccination and had 6 months or more of follow-up after surgery. For HPV31/33/45/52/58–related endpoints, the control group was 4vHPV vaccine (from 9vHPV vaccine trial); for HPV6/11/16/18 analysis, the control group was historic placebo (from 4vHPV vaccine trials). RESULTS: This analysis included 295 9vHPV vaccine, 722 4vHPV vaccine, and 493 historic placebo recipients who underwent cervical surgery after a median of 1.7 years (range 0.1–4.4 years) after dose 1. Subsequent to surgery, HPV6/11/16/18–related SIL incidence was reduced by 95.4% (95% CI, 74.7–99.8%) with prior 9vHPV vaccine relative to historic placebo (1.3 vs 29.0/1,000 person-years, respectively); HPV31/33/45/52/58–related SIL incidence was reduced by 86.3% (95% CI, 47.5–97.8%) with 9vHPV vaccine compared with 4vHPV vaccine (2.7 vs 19.4/1,000 person-years, respectively). The incidence of high-grade SIL was numerically lower in the 9vHPV vaccine group relative to control, but this was not statistically significant (HPV6/11/16/18 related 69.6% reduction [95% CI, −133.5% to 98.7%]; HPV31/33/45/52/58 related 82.7% [95% CI, −29.2% to 99.2%]). CONCLUSION: Among female trial participants who underwent cervical excisional surgery, prior vaccination with 9vHPV vaccine (ie, 0.1–4.4 years before surgery) reduced the incidence of subsequent cervical and lower genital tract dysplasia. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT00543543, NCT00092521, NCT00092534.

Oncologic Outcomes of Laparoscopic Radical Hysterectomy Incorporating Modified Tumor-Free Techniques

OBJECTIVE: It remains unclear whether modifying laparoscopic radical hysterectomy to adopt tumor-free principles can improve oncologic outcomes in patients with early-stage cervical cancer. METHODS: We performed a single-center retrospective cohort study of 276 patients with early-stage cervical cancer who were treated between January 2017 and January 2023, including 151 patients who underwent laparoscopic radical hysterectomy that incorporated modified tumor-free techniques (MTF group) and 125 patients who underwent conventional laparoscopic radical hysterectomy with a uterine manipulator and unprotected intracorporeal colpotomy (non-MTF group). Oncologic outcomes and perioperative results were analyzed using inverse probability treatment weighting (IPTW). RESULTS: Patients in the MTF group had shorter length of hospital stay than those in the non-MTF group. However, there were no significant differences in operative time, decrease in hemoglobin, or complications. After a median follow-up of 36.0 months (range 15.3–62.0 months) for the MTF group and 66.8 months (range 3.0–82.5 months) for the non-MTF group, recurrence was observed in two (1.3%) and 16 (12.8%) of the patients, respectively. The 2-year disease-free survival (DFS) rates in the MTF group and non-MTF group were 99.3% and 91.9%, respectively. In the primary analysis limited to 2-year survival, the adjusted multivariate analysis showed that use of modified tumor-free techniques was an independent predictor of longer DFS (hazard ratio 0.10 95% CI, 0.01–0.77, P=.027). After IPTW, patients in the MTF group had a more favorable DFS than those in the non-MTF group (log-rank P=.031). CONCLUSION: Laparoscopic radical hysterectomy that incorporates modified tumor-free techniques is a feasible treatment for patients with early-stage cervical cancer. Oncologic outcomes of individuals who underwent this procedure were more favorable than those of conventional laparoscopic radical hysterectomy.

Pregnancy Outcomes After Transvaginal Radiofrequency Ablation of Leiomyomas

OBJECTIVE: To evaluate pregnancy outcomes after transvaginal radiofrequency ablation of leiomyomas. METHODS: We conducted a retrospective review of the medical records of 226 pregnant patients after transvaginal radiofrequency ablation of leiomyomas from January 1, 2017, to February 28, 2022. RESULTS: Patients' mean age was 37.4 years. The preoperative median leiomyoma volume before transvaginal radiofrequency ablation was 52.4 mL, and the median volume reduction at 6 and 12 months was 49.4% and 69.8%, respectively. The median interval time from transvaginal radiofrequency ablation to pregnancy was 9.3 months (interquartile range 5.6–15.1 months). Pregnancy was spontaneous in 78 patients (34.5%) and by assisted reproductive technologies in 148 (65.5%). Miscarriage occurred in 36 patients (15.9%), premature delivery (before 37 weeks of gestation) in 4.1%, and preeclampsia in 4.3%. There was one instance of placenta accreta in a patient with a history of open myomectomy. There were no instances of uterine rupture, placental abruption, or fetal growth restriction. The cesarean delivery rate was 26.4%; the remaining patients had normal spontaneous vaginal deliveries. Patients with a volume of leiomyoma more than 58.6 mL had a longer interval time from transvaginal radiofrequency ablation to pregnancy (P<.05). An increased miscarriage rate was observed when the interval time to pregnancy was shorter than 5.7 months (P<.05). CONCLUSION: Pregnancy outcomes after transvaginal radiofrequency ablation of leiomyomas were similar to those of a general population with no instances of uterine rupture, placental abruption, or fetal growth restriction.

Long-Term Risk of Reintervention After Surgical Leiomyoma Treatment in an Integrated Health Care System

OBJECTIVE: To compare long-term risk of reintervention across four uterus-preserving surgical treatments for leiomyomas and to assess effect modification by sociodemographic factors in a prospective cohort study in an integrated health care delivery system. METHODS: We studied a cohort of 10,324 patients aged 18–50 (19.9% Asian, 21.2% Black, 21.3% Hispanic, 32.5% White, 5.2% additional races and ethnicities) who had a first uterus-preserving procedure (abdominal, laparoscopic, or vaginal myomectomy [referred to as myomectomy]; hysteroscopic myomectomy; endometrial ablation; uterine artery embolization) after leiomyoma diagnosis in the 2009–2021 electronic health records of Kaiser Permanente Northern California. We followed up patients until reintervention (second uterus-preserving procedure or hysterectomy) or censoring. We used a Kaplan–Meier estimator to calculate the cumulative incidence of reintervention and Cox regression models to estimate hazard ratios and 95% CIs comparing rates of reintervention across procedures, adjusting for age, parity, race and ethnicity, body mass index (BMI), Neighborhood Deprivation Index, and year. We also assessed effect modification by demographic characteristics. RESULTS: Median follow-up was 3.8 years (interquartile range 1.8–7.4 years). Index procedures were 18.0% (1,857) hysteroscopic myomectomies, 16.2% (1,669) uterine artery embolizations, 21.4% (2,211) endometrial ablations, and 44.4% (4,587) myomectomies. Accounting for censoring, the 7-year reintervention risk was 20.6% for myomectomy, 26.0% for uterine artery embolization, 35.5% for endometrial ablation, and 37.0% for hysteroscopic myomectomy; 63.2% of reinterventions were hysterectomies. Within each procedure type, reintervention rates did not vary by BMI, race and ethnicity, or Neighborhood Deprivation Index. However, rates of reintervention after uterine artery embolization, endometrial ablation, and hysteroscopic myomectomy decreased with age, and reintervention rates for hysteroscopic myomectomy were higher for parous than nulliparous patients. CONCLUSION: Long-term reintervention risks for uterine artery embolization, endometrial ablation, and hysteroscopic myomectomy are greater than for myomectomy, with potential variation by patient age and parity but not BMI, race and ethnicity, or Neighborhood Deprivation Index.

Comparative Modeling of Recent and Projected Trends in the Incidence and Mortality of Uterine Cancer

OBJECTIVE: To aid in cancer control and prevention activities by developing, calibrating, and validating three distinct natural history simulation models of uterine cancer, a growing public health concern. METHODS: To perform comparative analyses, we developed two state-transition microsimulation models and a multistage clonal expansion model of uterine cancer. The models simulate uterine cancer incidence and mortality. All three models were calibrated to common data on the incidence of uterine cancer from the Surveillance, Epidemiology, and End Results (SEER) 18 database. Each model accounts for changing trends in hysterectomy and obesity over time and simulates incidence and mortality for endometrioid and nonendometrioid tumors and uterine sarcoma. After calibration, we projected the incidence and mortality of uterine cancer to 2050. RESULTS: The three uterine cancer models were well calibrated to population data and produced comparable results for projecting the burden of disease through 2050. Among non-Hispanic White women aged 40 years or older, the models project that by 2050 the incidence of uterine cancer will rise to 76.1–81.8 per 100,000 woman-years, up from 2018 SEER incidence of 60.0 per 100,000 woman-years. Among non-Hispanic Black women, new cases will rise to 90.3–107.2 per 100,000 woman-years, up from 2018 SEER incidence of 61.3 per 100,000 woman-years. Within these populations, incidence-based mortality will increase to 11.3–12.3 deaths per 100,000 woman-years for non-Hispanic White women and to 28.2–35.7 deaths per 100,000 woman-years for non-Hispanic Black women. CONCLUSION: Three distinct mathematical simulation models of uterine cancer have been calibrated to observed population-based incidence and mortality. All three models project substantial and continued increases in the incidence and mortality of uterine cancer.

Imiquimod for Cervical and Vaginal Intraepithelial Neoplasia

OBJECTIVE: To evaluate the treatment efficacy and the risk of adverse events of imiquimod for cervical intraepithelial neoplasia (CIN) and vaginal intraepithelial neoplasia (VAIN), compared with placebo or no intervention. DATA SOURCES: We searched Cochrane, PubMed, ISRCTN registry, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform up to November 23, 2022. METHODS OF STUDY SELECTION: We included randomized controlled trials and prospective nonrandomized studies with control arms that investigated the efficacy of imiquimod for histologically confirmed CIN or VAIN. The primary outcomes were histologic regression of the disease (primary efficacy outcome) and treatment discontinuation due to side effects (primary safety outcome). We estimated pooled odds ratios (ORs) of imiquimod, compared with placebo or no intervention. We also conducted a meta-analysis of the proportions of patients with adverse events in the imiquimod arms. TABULATION, INTEGRATION, AND RESULTS: Four studies contributed to the pooled OR for the primary efficacy outcome. An additional four studies were available for meta-analyses of proportions in the imiquimod arm. Imiquimod was associated with increased probability of regression (pooled OR 4.05, 95% CI 2.08–7.89). Pooled OR for CIN in the three studies was 4.27 (95% CI 2.11–8.66); results of one study were available for VAIN (OR, 2.67, 95% CI 0.36–19.71). Pooled probability for primary safety outcome in the imiquimod arm was 0.07 (95% CI 0.03–0.14). The pooled probabilities (95% CI) of secondary outcomes were 0.51 (0.20–0.81) for fever, 0.53 (0.31–0.73) for arthralgia or myalgia, 0.31 (0.18–0.47) for abdominal pain, 0.28 (0.09–0.61) for abnormal vaginal discharge or genital bleeding, 0.48 (0.16–0.82) for vulvovaginal pain, and 0.02 (0.01–0.06) for vaginal ulceration. CONCLUSION: Imiquimod was found to be effective for CIN, whereas data on VAIN were limited. Although local and systemic complications are common, treatment discontinuation is infrequent. Thus, imiquimod is potentially an alternative therapy to surgery for CIN. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42022377982.

A Risk-Adjusted Model for Ovarian Cancer Care and Disparities in Access to High-Performing Hospitals

OBJECTIVE: To validate the observed/expected ratio for adherence to ovarian cancer treatment guidelines as a risk-adjusted measure of hospital quality care, and to identify patient characteristics associated with disparities in access to high-performing hospitals. METHODS: This was a retrospective population-based study of stage I–IV invasive epithelial ovarian cancer reported to the California Cancer Registry between 1996 and 2014. A fit logistic regression model, which was risk-adjusted for patient and disease characteristics, was used to calculate the observed/expected ratio for each hospital, stratified by hospital annual case volume. A Cox proportional hazards model was used for survival analyses, and a multivariable logistic regression model was used to identify independent predictors of access to high-performing hospitals. RESULTS: The study population included 30,051 patients who were treated at 426 hospitals: low observed/expected ratio (n=304) 23.5% of cases; intermediate observed/expected ratio (n=92) 57.8% of cases; and high observed/expected ratio (n=30) 18.7% of cases. Hospitals with high observed/expected ratios were significantly more likely to deliver guideline-adherent care (53.3%), compared with hospitals with intermediate (37.8%) and low (27.5%) observed/expected ratios (P<.001). Median disease-specific survival time ranged from 73.0 months for hospitals with high observed/expected ratios to 48.1 months for hospitals with low observed/expected ratios (P<.001). Treatment at a hospital with a high observed/expected ratio was an independent predictor of superior survival compared with hospitals with intermediate (hazard ratio [HR] 1.06, 95% CI 1.01–1.11, P<.05) and low (HR 1.10, 95% CI 1.04–1.16, P<.001) observed/expected ratios. Being of Hispanic ethnicity (odds ratio [OR] 0.85, 95% CI 0.78–0.93, P<.001, compared with white), having Medicare insurance (OR 0.74, 95% CI 0.68–0.81 P<.001, compared with managed care), having a Charlson Comorbidity Index score of 2 or greater (OR 0.91, 95% CI 0.83–0.99, P<.05), and being of lower socioeconomic status (lowest quintile OR 0.41, 95% CI 0.36–0.46, P<.001, compared with highest quintile) were independent negative predictors of access to a hospital with a high observed/expected ratio. CONCLUSION: Ovarian cancer care at a hospital with a high observed/expected ratio is an independent predictor of improved survival. Barriers to high-performing hospitals disproportionately affect patients according to sociodemographic characteristics. Triage of patients with suspected ovarian cancer according to a performance-based observed/expected ratio hospital classification is a potential mechanism for expanded access to expert care.

Hereditary Cancer Risk Using a Genetic Chatbot Before Routine Care Visits

OBJECTIVE: To examine user uptake and experience with a clinical chatbot that automates hereditary cancer risk triage by collecting personal and family cancer history in routine women's health care settings. METHODS: We conducted a multicenter, retrospective observational study of patients who used a web-based chatbot before routine care appointments to assess their risk for hereditary breast and ovarian cancer, Lynch syndrome, and adenomatous polyposis syndromes. Outcome measures included uptake and completion of the risk-assessment and educational section of the chatbot interaction and identification of hereditary cancer risk as evaluated against National Comprehensive Cancer Network criteria. RESULTS: Of the 95,166 patients invited, 61,070 (64.2%) engaged with the clinical chatbot. The vast majority completed the cancer risk assessment (89.4%), and most completed the genetic testing education section (71.4%), indicating high acceptability among those who opted to engage. The mean duration of use was 15.4 minutes (SD 2 hours, 56.2 minutes) when gaps of inactivity longer than 5 minutes were excluded. A personal history of cancer was reported by 19.1% (10,849/56,656) and a family history of cancer was reported by 66.7% (36,469/54,652) of patients who provided the relevant information. One in four patients (14,850/54,547) screened with the chatbot before routine care appointments met National Comprehensive Cancer Network criteria for genetic testing. Among those who were tested, 5.6% (73/1,313) had a disease-causing pathogenic variant. CONCLUSION: A chatbot digital health tool can help identify patients at high risk for hereditary cancer syndromes before routine care appointments. This scalable intervention can effectively provide cancer risk assessment, engage patients with educational information, and facilitate a path toward preventive genetic testing. FUNDING SOURCE: Implementation of the chatbot in clinics was funded by industry support from commercial genetic testing laboratories Ambry, Invitae, and Progenity.

Updates and New Options in Advanced Epithelial Ovarian Cancer Treatment

The medical and surgical treatment strategies for women with epithelial ovarian cancer continue to evolve. In the past several years, there has been significant progress backed by landmark clinical trials. Although primary epithelial ovarian cancer is still treated with a combination of surgery and systemic therapy, more complex surgical procedures and novel therapeutics have emerged as standard of care. Cytotoxic chemotherapy and maximal surgical effort remain mainstays, but targeted therapies are becoming more widespread and new data have called into question the role of surgery for women with recurrent disease. Poly ADP-ribose polymerase inhibitors have improved progression-free survival outcomes in both the frontline and recurrent settings, and their use has become increasingly widespread. The recent creation of treatment categories based on genetic changes reinforces the recommendation that all women with epithelial ovarian cancer have germline genetic testing, and new biomarker-driven drug approvals indicate that women may benefit from somatic molecular testing as well. To continue to identify novel strategies, however, enrollment on clinical trials remains of the utmost importance. With the evolving data on surgical approaches, targeted therapies such as antiangiogenics and poly ADP-ribose polymerase inhibitors, and the new therapeutic agents and combinations in development, we hope that advanced epithelial ovarian cancer will eventually transition from an almost universally fatal disease to one that can increasingly be cured.

Human Papillomavirus Testing in the Last Cervical Screening Round at Age 60–64 Years

OBJECTIVE: To compare the real-life screening outcomes after cytology was replaced by human papillomavirus (HPV) testing for women aged 60–64 years. METHODS: Using the Danish national pathology register, we compared screening outcomes during two consecutive calendar periods, one where women were screened with cytology and one where most women were screened with HPV testing. Our primary outcomes were the proportions of women with positive test results, high-grade cervical intraepithelial neoplasia (CIN 2 or worse), and cervical cancer. RESULTS: Women screened during the HPV testing period were more likely to have a positive screening test result than were women screened during the cytology period (relative proportion 2.80, 95% CI 2.65–2.96). The detection of CIN 2 or worse was also increased (relative proportion 1.54, 95% CI 1.31–1.80), whereas there was no increase in screen-detected cervical cancer diagnoses (relative proportion 1.27, 95% CI 0.76–2.12). Within the first 4 years after a negative screening test result, including 168,477 woman-years at risk after a negative screen result in the HPV period and 451,421 woman-years after a negative screen result in the cytology period, the risk of a cervical cancer diagnosis was approximately 4 per 100,000 woman-years and was similar for both screening tests (relative risk 0.99, 95% CI 0.41–2.35). CONCLUSION: Human papillomavirus testing led to more positive screening test results and diagnoses of high-grade CIN lesions. Few women were diagnosed with cervical cancer after a negative screening test result.

Efficacy and Long-term Outcomes of Repeated Large Loop Excision of the Transformation Zone of the Cervix

OBJECTIVE: To evaluate the efficacy and long-term outcome of repeat large loop excision of the transformation zone in women with residual or recurrent cervical intraepithelial neoplasia. METHODS: PALGA (the Dutch Pathology Registry), a database of deidentified cervical cytologic and histologic data, was used to examine women with cervical dysplasia who underwent two or more large loop excision of the transformation zone procedures between January 2005 and June 2015. We obtained cervical cytology and histology results. The main outcome was efficacy of repeated large loop excision of the transformation zone procedure in women with residual or recurrent cervical intraepithelial neoplasia. We also examined subsequent excisional procedures and hysterectomy. RESULTS: We identified 499 women who had undergone two or more large loop excision of the transformation zone procedures. After their second procedure, 60.7% of women had a normal first cervical cytologic sample. The mean duration of follow-up was 68 months (0–163 months). Additional cervical excisional procedures were performed in 33.7% of women. Overall, 1.2% of women developed cervical cancer during follow-up. Moreover, 19.0% of women eventually underwent hysterectomy. CONCLUSION: One third of the women who undergo two large loop excision of the transformation zone procedures require an additional excisional procedure or hysterectomy. Almost one fifth of these women eventually undergo hysterectomy.

Out-of-Pocket Costs for Colposcopy Among Commercially Insured Women From 2006 to 2019

Out-of-pocket costs for women who undergo colposcopy are common, significant, and have increased over time.

Executive Summary of the Ovarian Cancer Evidence Review Conference

The Centers for Disease Control and Prevention awarded funding to the American College of Obstetricians and Gynecologists to develop educational materials for clinicians on gynecologic cancers. The American College of Obstetricians and Gynecologists convened a panel of experts in evidence review from the Society for Academic Specialists in General Obstetrics and Gynecology and content experts from the Society of Gynecologic Oncology to review relevant literature, best practices, and existing practice guidelines as a first step toward developing evidence-based educational materials for women's health care clinicians about ovarian cancer. Panel members conducted structured literature reviews, which were then reviewed by other panel members and discussed at a virtual meeting of stakeholder professional and patient advocacy organizations in February 2022. This article is the executive summary of the relevant literature and existing recommendations to guide clinicians in the prevention, early diagnosis, and special considerations of ovarian cancer. Substantive knowledge gaps are noted and summarized to provide guidance for future research.

Racial Differences in the Association of Endometriosis and Uterine Leiomyomas With the Risk of Ovarian Cancer

OBJECTIVE: To evaluate associations between endometriosis and uterine leiomyomas with ovarian cancer risk by race and the effect of hysterectomy on these associations. METHODS: We used data from four case–control studies and two case–control studies nested within prospective cohorts in the OCWAA (Ovarian Cancer in Women of African Ancestry) consortium. The study population included 3,124 Black participants and 5,458 White participants, of whom 1,008 Black participants and 2,237 White participants had ovarian cancer. Logistic regression was used to calculate odds ratios (ORs) and 95% CIs for the associations of endometriosis and leiomyomas with ovarian cancer risk, by race, stratified by histotype and hysterectomy. RESULTS: The prevalences of endometriosis and leiomyomas were 6.4% and 43.2% among Black participants and 7.0% and 21.5% among White participants, respectively. Endometriosis was associated with an increased risk of endometrioid and clear-cell ovarian cancer in both racial groups (eg, OR for endometrioid tumors for Black and White participants 7.06 [95% CI 3.86–12.91] and 2.17 [95% CI 1.36–3.45], respectively, P hetereogeneity=.003). The association between endometriosis and ovarian cancer risk in White participants was stronger in those without hysterectomy, but no difference was observed in Black participants (all P interaction≥.05). Leiomyomas were associated with an elevated risk of ovarian cancer only in those without hysterectomy in both Black (OR 1.34, 95% CI 1.11–1.62) and White (OR 1.22, 95% CI 1.05–1.41) participants (all P interaction≥.05). CONCLUSIONS: Black and White participants with endometriosis had a higher risk of ovarian cancer, and hysterectomy modified this association among White participants. Leiomyomas were associated with an increased risk of ovarian cancer in both racial groups, with hysterectomy modifying the risk in both groups. Understanding how racial differences in access to care and treatment options (eg, hysterectomy) may help guide future risk reduction strategies.

Association of Radical Hysterectomy Surgical Volume and Survival for Early-Stage Cervical Cancer: Correction

Low-Dose Elagolix for the Treatment of Heavy Menstrual Bleeding in Patients With Uterine Leiomyomas

OBJECTIVE: To evaluate the safety and efficacy of elagolix 150 mg once-daily monotherapy in patients with heavy menstrual bleeding associated with uterine leiomyomas. METHODS: A phase 4, randomized, double-blind, placebo-controlled, 6-month treatment study was conducted in premenopausal patients aged 18–51 years with heavy menstrual bleeding (defined as menstrual blood loss greater than 80 mL during one menstrual cycle) associated with uterine leiomyomas. Patients were randomized 2:1 to receive elagolix 150 mg once daily or placebo. The primary endpoint was reduction in menstrual blood loss volume to less than 80 mL at the final month and at least a 50% reduction in menstrual blood loss volume from baseline to the final month. RESULTS: Of 82 randomized patients, 54 received elagolix 150 mg and 28 received placebo. With elagolix, 49.4% (95% CI 35.1–63.8%) of patients met the primary endpoint, compared with 23.3% (95% CI 7.2–39.5%) of patients who received placebo (P=.035). Statistically significant differences between elagolix and placebo in mean reduction of menstrual blood loss from baseline were seen as early as month 1 (P<.05 for months 1–3 and 5). Significantly more patients receiving elagolix experienced suppression of bleeding compared with placebo (P=.036). Greater improvements were observed in the elagolix group (vs placebo) in the proportion of patients with amenorrhea, in hemoglobin concentrations, and in health-related quality of life. No serious or severe adverse events were reported for elagolix, compared with 7.1% of participants in the placebo group having serious adverse events (coronavirus disease 2019 [COVID-19] n=1, enlarged uvula n=1). Three patients (5.6%) discontinued elagolix due to adverse events. CONCLUSION: Elagolix 150 mg once-daily monotherapy significantly improved heavy menstrual bleeding associated with uterine leiomyomas compared with placebo in premenopausal patients. Treatment with elagolix 150 mg once daily was generally well-tolerated in this study, with no new safety signals. FUNDING SOURCE: AbbVie Inc. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT03886220.

Temporal Patterns and Adoption of Germline and Somatic BRCA Testing in Ovarian Cancer

OBJECTIVE: To describe the testing rate, patient characteristics, temporal trends, timing, and results of germline and somatic BRCA testing in patients with ovarian cancer using real-world data. METHODS: We included a cross-sectional subset of adult patients diagnosed with ovarian cancer between January 1, 2011, and November 30, 2018, who received frontline treatment and were followed for at least 1 year in a real-world database. The primary outcome was receipt of BRCA testing, classified by biosample source as germline (blood or saliva) or somatic (tissue). Lines of therapy (frontline, second line, third line) were derived based on dates of surgery and chemotherapy. Descriptive statistics were analyzed. RESULTS: Among 2,557 patients, 72.2% (n=1,846) had at least one documented BRCA test. Among tested patients, 62.5% (n=1,154) had only germline testing, 10.6% (n=197) had only somatic testing, and 19.9% (n=368) had both. Most patients had testing before (9.7%, n=276) or during (48.6%, n=1,521) frontline therapy, with 17.6% (n=273) tested during second-line and 12.7% (n=129) tested during third-line therapy. Patients who received BRCA testing, compared with patients without testing, were younger (mean age 63 years vs 66 years, P<.001) and were more likely to be treated at an academic practice (10.4% vs 7.0%, P=.01), with differences by Eastern Cooperative Oncology Group performance score (P<.001), stage of disease (P<.001), histology (P<.001), geography (P<.001), and type of frontline therapy (P<.001), but no differences based on race or ethnicity. The proportion of patients who received BRCA testing within 1 year of diagnosis increased from 24.6% of patients in 2011 to 75.6% of patients in 2018. CONCLUSION: In a large cohort of patients with ovarian cancer, significant practice disparities existed in testing for actionable BRCA mutations. Despite increased testing over time, many patients did not receive testing, suggesting missed opportunities to identify patients appropriate for targeted therapy and genetic counseling.

Enrollment of Individuals From Racial and Ethnic Minority Groups in Gynecologic Cancer Precision Oncology Trials

OBJECTIVE: To characterize whether enrollment patterns in precision oncology clinical trials for gynecologic cancers reflect the racial and ethnic diversity of patients with gynecologic cancers in the United States. METHODS: ClinicalTrials.gov was queried to perform this cross-sectional review. We included precision oncology trials—defined as trials using molecular profiling of a tumor or the patient genome to identify targetable alterations to guide treatment—of ovarian, uterine, cervical, and vulvar cancers in the United States. National Cancer Institute Surveillance, Epidemiology, and End Results and United States Census Bureau data were used to estimate cancer burden and the expected number of trial participants by race and ethnicity for each gynecologic cancer. The ratio of actual-to-expected participants was calculated. A ratio greater than 1 signified overenrollment. A random effects meta-analysis was performed to assess the relative weights of individual trials. RESULTS: We identified 493 trials, 61 of which met inclusion criteria. There were 2,573 patients enrolled in ovarian cancer trials, 1,197 in uterine cancer trials and 162 in cervical cancer trials. Non-Hispanic White women were overrepresented overall (enrollment ratio 1.26, 95% CI 1.20–1.32) and across all cancer types on subgroup analysis. Asian women, non-Hispanic Black women, and Hispanic women were underrepresented overall (enrollment ratios 0.63, 95% CI 0.41–0.86; 0.51, 95% CI 0.36–0.66 and 0.30, 95% CI 0.23–0.36, respectively). In subgroup analyses, Asian women and non-Hispanic Black women were underrepresented in ovarian and uterine cancer trials and Hispanic women were underrepresented across all cancer types. CONCLUSION: Non-Hispanic Black women, Asian women, and Hispanic women with gynecologic cancers are underrepresented in precision oncology trials. Few U.S.-based precision oncology trials exist for uterine and cervical cancers, which have a high burden of morbidity and mortality among racial and ethnic minority groups. Failure to equitably enroll patients who belong to racial and ethnic minority groups may perpetuate existing disparities in gynecologic cancer outcomes.

Symptoms of Women With High-Risk Early-Stage Ovarian Cancer

The Changing Landscape of Gynecologic Cancer Mortality in the United States

Uterine corpus cancer mortality is now similar to that for ovarian cancer, and the disproportionate burden among Black women is widening.

Symptoms of Women With High-Risk Early-Stage Ovarian Cancer

OBJECTIVE: To assess the presentation, characteristics, and prognostic significance of symptoms in patients with high-risk early-stage epithelial ovarian cancer. METHODS: A retrospective chart review was performed on all patients enrolled in a phase III clinical trial (GOG 157). All patients had surgically staged, high-risk early-stage epithelial ovarian cancer (stage IA–IB and grade 3, any clear cell, stage IC or II). Chi-square and Kaplan-Meier estimates and Cox proportional hazards models were used for statistical analyses. RESULTS: Of 419 patients evaluated for symptoms, 301 (72%) presented with one or more symptoms, and 118 (28%) were asymptomatic but had a mass found on examination. Forty percent had only one symptom, and 32% had more than one symptom. Among those with at least one symptom, the most common were abdominal and pelvic pain (31%), and increased girth or fullness (26%). Overall, 23% of patients with tumors 10 cm or smaller, 27% of patients with tumors larger than 10 cm to 15 cm, and 46% of patients with tumors larger than 15 cm had multiple symptoms (P<.001). There was no significant difference in presentation of symptoms based on age, stage, or histologic subtype. Symptoms at diagnosis were not associated with recurrence or survival. CONCLUSION: More than 70% of patients with high-risk early-stage, epithelial ovarian cancer present with one or more symptoms, with the most common being abdominal or pelvic pain. The proportion of women with symptoms and the number of symptoms increase with enlarging tumor size.

Radical Trachelectomy for the Treatment of Early-Stage Cervical Cancer

OBJECTIVE: To assess surgical, oncologic, and pregnancy outcomes in patients undergoing radical vaginal, abdominal, or laparoscopic trachelectomy for the treatment of early-stage cervical cancer, using a methodic review of published literature. DATA SOURCES: PubMed, EMBASE, and Cochrane Library sources, including ClinicalTrials.gov, were searched from 1990–2019 with terms “cervical cancer” and “(vaginal, abdominal, open, minimally invasive, or laparoscopic) radical trachelectomy.” Grey literature and unpublished data were omitted. METHODS OF STUDY SELECTION: After removal of duplicates from a combined EndNote library of results, 490 articles were reviewed using Covidence software. Two reviewers screened titles and abstracts, and then screened full texts. Selection criteria included articles that reported radical trachelectomy with lymph node assessment as primary therapy for cervical carcinoma, with stated follow-up intervals and recurrences. TABULATION, INTEGRATION, AND RESULTS: Variables of interest were manually extracted into an electronic database. A total 47 articles that reported on 2,566 women met inclusion criteria. Most tumors were of squamous histology (68.5%), stage IB1 (74.8%), 2 cm or less (69.2%), and without lymphovascular invasion (68.8%). Of planned trachelectomies, 9% were converted intraoperatively to hysterectomy. Separated by route of trachelectomy, 58.1%, 37.2%, and 4.7% were performed using radical vaginal, abdominal, and laparoscopic approaches, respectively. With median follow-up of 48 months (range 2–202 months) across studies, median recurrence rate was 3.3% (range 0–25%); median time to recurrence was 26 months (range 8–44 months). Median 5-year recurrence-free and overall survival were 94.6% (range 88–97.3%) and 97.4% (range 95–99%), respectively. The posttrachelectomy pregnancy rate was 23.9%, with a live-birth rate of 75.1%. CONCLUSION: Radical trachelectomy for fertility-preserving treatment of cervical cancer is widely reported in the literature, though publications are mainly limited to case reports and case series. Reported follow-up periods infrequently meet standard oncologic parameters but show encouraging recurrence-free and overall survival rates and pregnancy outcomes. Higher-level evidence needed for meta-analysis is lacking. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42019132443.

ASCCP Risk-Based Colposcopy Recommendations Applied in Thai Women With Atypical Squamous Cells of Undetermined Significance or Low-Grade Squamous Intraepithelial Lesion Cytology

OBJECTIVE: To compare the proportion of cervical intraepithelial neoplasia (CIN) 2 or worse pathology among different risk strata according to the ASCCP when applied in women who had atypical squamous cells of undetermined significance (ASC-US) or low-grade squamous intraepithelial lesion (LSIL) cervical cytology; to assess performance of colposcopy; and to assess the independent predictors for detected CIN 2 or worse pathology. METHODS: This is a secondary analysis of a previous prospective study, which included Thai women with ASC-US or LSIL cytology who underwent high-risk human papillomavirus (HPV) testing and subsequent colposcopy with directed biopsy. Patients were classified as lowest-risk, intermediate-risk, or highest-risk based on cervical cytology, high-risk HPV testing, and colposcopic impression. The proportion of CIN 2 or worse pathology and associated prognostic factors were analyzed. RESULTS: Of 697 women, 103 (14.8%), 573 (82.2%) and 21 (3%) were classified into lowest-risk, intermediate-risk, and highest-risk groups, respectively. The proportion of CIN 2 or worse pathology was 1%, 11.2%, and 61.9% in those same groups, respectively (P<.001). Colposcopy to detect CIN 2 or worse pathology had a sensitivity, specificity, positive predictive value, and negative predictive value of 98.7%, 18%, 13.2%, and 99.1%, respectively. Independent predictors for detecting CIN 2 or worse pathology were positive high-risk HPV, HPV 16/18 positivity, and high-grade colposcopic impression. CONCLUSION: This study supports a no biopsy with follow-up strategy in the lowest-risk group, inconsistent with ASCCP recommendations, but is in alignment with a strategy of multiple targeted biopsies in the intermediate-risk and highest-risk groups.

In Reply

Relative Risk of Cervical Neoplasms Among Copper and Levonorgestrel-Releasing Intrauterine System Users

Topical Imiquimod for the Treatment of High-Grade Squamous Intraepithelial Lesions of the Cervix

OBJECTIVE: To evaluate the histologic response rate of high-grade squamous intraepithelial lesions (HSIL) of the cervix after topical application of 5% imiquimod cream. METHODS: In this phase II trial, women with cervical HSIL (cervical intraepithelial neoplasia [CIN] 2–3) were randomly assigned to 250 mg of 5% imiquimod cream applied to the cervix weekly for 12 weeks, followed by loop electrosurgical excision procedure (LEEP) without preceding treatment. The sample size was calculated based on the HSIL regression rates previously reported by Grimm et al. The primary outcome was rate of histologic regression (to CIN 1 or less) in LEEP specimens. Prespecified secondary endpoints included surgical margin status and adverse events. Outcomes were stratified by human papillomavirus type and lesion grade (CIN 2 or CIN 3). Results were reported according to per protocol (PP) and intention-to-treat (ITT) analyses. RESULTS: Ninety women were enrolled: 49 in the experimental group and 41 in the control group. In the PP population, histologic regression was observed in 23 of 38 participants (61%) in the experimental group compared with 9 of 40 (23%) in the control group (P=.001). Surgical margins were negative for HSIL in 36 of 38 participants (95%) in the experimental group and 28 of 40 (70%) in the control group (P=.004). In the ITT population, rates of histologic regression also were significantly higher in the experimental group. Rates of adverse events in the experimental group were 74% (28/38) in the PP population and 78% (35/45) in the ITT population. Adverse events were mild, with abdominal pain being the most common. Three patients in the experimental group had grade 2 adverse events, including vaginal ulcer, vaginal pruritus with local edema, and moderate pelvic pain. CONCLUSION: Weekly topical treatment with imiquimod is effective in promoting regression of cervical HSIL. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT03233412.

Recurrence of High-Grade Vulvar Intraepithelial Neoplasia After Treatment With Excision Compared With Imiquimod

OBJECTIVE: To evaluate long-term recurrence rates and time to first recurrence for human papillomavirus (HPV)–associated high-grade vulvar intraepithelial neoplasia (VIN) by initial treatment. METHODS: This was a retrospective cohort study of patients treated with excision, imiquimod, or laser for HPV-associated VIN grade 2–3 at a high-risk colposcopy center. We collected demographic, clinical, and longitudinal pathology data. Given the small number (n=15), the cohort of patients treated with laser were excluded from analyses. We performed χ 2 and Wilcoxon rank-sum tests to compare the rates of recurrence and median time to first recurrence by treatment modality. Univariate and multivariate analyses were conducted to compare predictors of recurrence and time to recurrence. Multivariate models were adjusted for side effects or barriers to imiquimod use, lesion focality, and initial histology based on significant findings in the univariate models. RESULTS: Three hundred fifteen patients met the criteria for inclusion, 231 treated with excision and 84 with imiquimod. Median follow-up time from initial diagnosis was 36 months. Recurrence rates and median time to recurrence with imiquimod (40.5% and 7.4 months) and excision (34.6% and 11.3 months, P =.34, P =.38) did not differ significantly. In univariate analysis, positive margins (odds ratio [OR] 4.68, 95% CI, 2.53–8.62), multifocal disease (OR 2.27, 95% CI, 1.19–4.33), and presence of carcinoma in situ on initial diagnosis (OR 6.21, 95% CI, 1.45–26.6) were predictors of recurrence after excision. Only the presence of side effects or barriers to imiquimod use (OR 2.46, 95% CI, 1.01–6.02) was significant in the univariate model for recurrence after imiquimod. No significant difference remained for the odds of recurrence after treatment with imiquimod compared with excision in the multivariate model (OR 1.28, 95% CI, 0.77–2.14); there was similarly no significant difference in the multivariate model of time to recurrence (hazard ratio 1.41, 95% CI, 0.86–2.30). CONCLUSION: In appropriately selected patients, imiquimod appears to have outcomes similar to those of excision for the prevention of recurrent HPV-associated VIN.

Fluorescein Mapping in Vulvar Paget Disease

BACKGROUND: Vulvar Paget disease often requires extensive and, in some cases, multiple resections to treat. A fluorescein-mapping procedure followed by a staged vulvectomy may be an effective technique to tailor resection and identify clinically occult lesions. TECHNIQUE: We describe a two-step procedure; first, intravenous fluorescein sodium is injected, and the vulva is illuminated with a Wood's lamp. Representative biopsies are obtained and correlated on final pathology with the extent of disease to develop a final plan for excision. Second, using fluorescein to identify the confirmed areas of disease, the appropriate excisional procedure is performed once mapping biopsy pathology is known. EXPERIENCE: We describe our experience with eight patients with vulvar Paget disease undergoing fluorescein mapping biopsies and staged vulvectomy. Using intravenous fluorescein sodium, all patients were found to have Paget disease beyond the visible margins of their gross lesions. No patients experienced a recurrence of Paget disease within a median follow-up time of 32 months, comparable with other directed methods of surgical resection. CONCLUSION: We report a technique for the injection of fluorescein sodium for the visualization of vulvar Paget disease capable of providing accurate surgical margins and identification of occult satellite lesions with a high degree of safety and a favorable cost profile. This staged approach to vulvectomy could offer improved accuracy of resection for vulvar Paget disease with few drawbacks.

Differential Diagnosis of a Unique Vulvar Mass in an Adolescent

BACKGROUND: Vulvar masses in adolescents have a broad differential diagnosis, yet few reports exist detailing masses of mammary origin. CASE: A nulliparous, healthy 16-year-old adolescent presented with a longstanding, ulcerated, 17-cm vulvar mass of unknown origin and pronounced inguinal lymphadenopathy. The patient underwent a left radical partial vulvectomy, with pathology revealing terminal duct lobular units consistent with polymastia. CONCLUSION: Differential diagnosis of a vulvar mass in an adolescent should include polymastia.

Utility and Outcomes of Ovarian Tissue Cryopreservation and Transplantation for Gynecologic Cancers

OBJECTIVE: To evaluate the utility, success, and safety of ovarian tissue cryopreservation and autologous cryopreserved ovarian tissue transplantation for fertility preservation in patients with gynecologic cancers. DATA SOURCES: A comprehensive search was performed of the MEDLINE, EMBASE, ClinicalTrials.gov, and Cochrane Library databases to identify relevant studies on the utility and outcomes of ovarian tissue cryopreservation and autologous cryopreserved ovarian tissue transplantation for gynecologic cancers from inception until January 23, 2024. METHODS OF STUDY SELECTION: Two reviewers independently performed the study selection, data extraction, and risk-of-bias assessment, and the results were then reviewed together. Twenty-three studies were included in the current systematic review. TABULATION, INTEGRATION, AND RESULTS: The resultant data were meta-analyzed to produce a pooled-effect estimate of the utility of ovarian tissue cryopreservation and autologous transplantation in gynecologic cancers as a proportion of all indications. We found that 7.5% and 9.6% of women undergoing ovarian tissue cryopreservation and autologous transplantation, respectively, had gynecologic cancers. In comparison, hematologic malignancies and breast cancer accounted for approximately 66.0% of all indications for these procedures. The return rate for autologous cryopreserved ovarian tissue transplantation in gynecologic cancers (6.0%) was not statistically different from those for other indications. Among women with gynecologic cancer who underwent ovarian stimulation, 27.3% had at least one child, and the ovarian endocrine function was restored in 78.1% of the women after autologous transplantation. The median graft longevity was 32 months, and no graft-site recurrence was reported after autologous transplantation in women with gynecologic cancer. CONCLUSION: Our results suggest that ovarian tissue cryopreservation and autologous transplantation are feasible options for preserving ovarian function in women with gynecologic cancers, although ovarian tissue cryopreservation is underutilized, and further studies are needed to determine the longer-term outcomes of autologous transplantation. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42024498522.

Fertility-Sparing Surgery for Stage I Epithelial Ovarian Cancer

OBJECTIVE: To describe population-level utilization of fertility-sparing surgery and outcome of reproductive-aged patients with early epithelial ovarian cancer who underwent fertility-sparing surgery in the United States. METHODS: This retrospective study queried the National Cancer Institute's Surveillance, Epidemiology, and End Result Program. The study included 3,027 patients younger than age 50 years with stage I epithelial ovarian cancer receiving primary surgical therapy from 2007 to 2020. Fertility-sparing surgery was defined as preservation of one ovary and the uterus for unilateral lesion and preservation of the uterus for bilateral lesions. Temporal trend of fertility-sparing surgery was assessed with linear segmented regression with log-transformation. Overall survival associated with fertility-sparing surgery was assessed with Cox proportional hazard regression model. RESULTS: A total of 534 patients (17.6%) underwent fertility-sparing surgery. At the cohort level, the utilization of fertility-sparing surgery was 13.4% in 2007 and 21.8% in 2020 (P for trend=.009). Non-Hispanic White individuals (2.8-fold), those with high-grade serous histology (2.2-fold), and individuals with stage IC disease (2.3-fold) had a more than twofold increase in fertility-sparing surgery utilization during the study period (all P for trend<.05). After controlling for the measured clinicopathologic characteristics, patients who received fertility-sparing surgery had overall survival comparable with that of patients who had nonsparing surgery (5-year rates 93.6% vs 92.1%, adjusted hazard ratio 0.87, 95% CI, 0.57–1.35). This survival association was consistent in high-grade serous (5-year rates 92.9% vs 92.4%), low-grade serous (100% vs 92.2%), clear cell (97.5% vs 86.1%), mucinous (92.1% vs 86.6%), low-grade endometrioid (95.7% vs 97.7%), and mixed (93.3% vs 83.7%) histology (all P>.05). In high-grade endometrioid tumor, fertility-sparing surgery was associated with decreased overall survival (5-year rates 71.9% vs 93.8%, adjusted hazard ratio 2.90, 95% CI, 1.09–7.67). Among bilateral ovarian lesions, fertility-sparing surgery was not associated with overall survival (5-year rates 95.8% vs 92.5%, P=.364). Among 41,914 patients who had epithelial ovarian cancer with any age and stage, those younger than age 50 years with stage I disease increased from 8.6% to 10.9% during the study period (P for trend=.002). CONCLUSION: Nearly one in five reproductive-aged patients with stage I epithelial ovarian cancer underwent fertility-sparing surgery in recent years in the United States. More than 90% of reproductive-aged patients with stage I epithelial ovarian cancer who underwent fertility-sparing surgery were alive at the 5-year timepoint, except for those with high-grade endometrioid tumors.

Minimally Invasive Compared With Open Surgery in High-Risk Endometrial Cancer

OBJECTIVE: To compare outcomes between minimally invasive surgery and open surgery in patients with high-risk endometrial cancer. DATA SOURCES: A cohort study of all patients who underwent surgery for high-risk endometrial cancer between 1999 and 2016 at Mayo Clinic (Rochester, Minnesota) and a literature search of MEDLINE, EMBASE, ClinicalTrials.gov, Cochrane Central Register of Controlled Trials, and Scopus of all published studies until December 2020. METHODS OF STUDY SELECTION: The systematic review identified 2,332 patients (14 studies, all retrospective except a subanalysis of a randomized comparison) and the cohort study identified 542 additional patients. Articles were included if reporting original data on overall survival and disease-free survival among patients with high-risk endometrial cancer, defined as International Federation of Gynecology and Obstetrics grade 3 endometrioid, serous, clear cell, mixed histology, or uterine carcinosarcoma. Studies that did not report at least one of the main outcomes, those in which one surgical technique (robotic or laparoscopic surgery) was missing in the comparison analysis with open surgery, and case reports were excluded. Additional data were extracted from a retrospective cohort of patients from Mayo. A random-effect model was used for meta-analysis. TABULATION, INTEGRATION, AND RESULTS: This systematic review and meta-analysis was registered in PROSPERO. Literature search and data extraction were performed independently by two reviewers, as well as quality assessment using GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology, and the Newcastle-Ottawa Scale. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed. Meta-analysis showed that disease-free survival and overall survival in patients with high-risk endometrial cancer who underwent minimally invasive surgery were not statistically different from those of patients who underwent open abdominal surgery (relative risk [RR] 0.93, 95% CI 0.82–1.05, I2 20%, P=.23; and RR 0.92, 95% CI 0.77–1.11, I2 31%, P=.12, respectively). Subgroup analysis by stage (early vs advanced) did not identify a difference between surgical approaches. CONCLUSION: Minimally invasive surgery and open surgery had similar disease-free survival and overall survival in patients with high-risk endometrial cancer. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42021275535.

Trends in Location of Death for Individuals With Ovarian Cancer in the United States

Using the publicly available Centers for Disease Control and Prevention’s WONDER (Wide-ranging Online Data for Epidemiologic Research) database from 2003 to 2019, we evaluated associations between decedent characteristics and location of death for patients with ovarian malignancy. We found that Black, Native American, Asian American, and Hispanic patients were more likely to die in hospitals than White patients, despite an overall reduction in hospital deaths and an overall increase in hospice facility deaths. Additionally, patients with lesser educational attainment were more likely to die in nursing facilities and less likely to die in hospice facilities. Although there may be some contribution from cultural preferences, these findings may represent disparities in access to palliative care affecting people with cancer from racial and ethnic minoritized groups.

Complete Compared With Partial Salpingectomy for Postpartum Sterilization

In this narrative review, we describe evidence regarding the associated risks, benefits, and cost effectiveness of postpartum complete salpingectomy compared with partial salpingectomy. Permanent contraception can be performed via several methods, but complete salpingectomy is becoming more common secondary to its coincident benefit of ovarian cancer risk reduction. Small prospective studies and larger retrospective cohort studies have demonstrated the feasibility and safety of complete salpingectomy in the postpartum period. Additionally, multiple cost-effectiveness analyses have demonstrated the cost effectiveness of this method secondary to ovarian cancer reduction over the life span. Although future larger cohort studies will allow for more precise estimates of the effect of complete salpingectomy on ovarian cancer risk and incidence of rare complications, current data suggest that complete salpingectomy should be offered to patients as a method of permanent contraception in the postpartum period.

Early Ovarian Cancer Detection in the Age of Fallopian Tube Precursors

OBJECTIVE: To determine biomarkers other than CA 125 that could be used in identifying early-stage ovarian cancer. DATA SOURCES: Ovid MEDLINE ALL, EMBASE, Web of Science Core Collection, ScienceDirect, Clinicaltrials.gov, and CAB Direct were searched for English-language studies between January 2008 and April 2023 for the concepts of high-grade serous ovarian cancer, testing, and prevention or early diagnosis. METHODS OF STUDY SELECTION: The 5,523 related articles were uploaded to Covidence. Screening by two independent reviewers of the article abstracts led to the identification of 245 peer-reviewed primary research articles for full-text review. Full-text review by those reviewers led to the identification of 131 peer-reviewed primary research articles used for this review. TABULATION, INTEGRATION, AND RESULTS Of 131 studies, only 55 reported sensitivity, specificity, or area under the curve (AUC), with 36 of the studies reporting at least one biomarker with a specificity of 80% or greater specificity or 0.9 or greater AUC. CONCLUSION: These findings suggest that although many types of biomarkers are being tested in ovarian cancer, most have similar or worse detection rates compared with CA 125 and have the same limitations of poor detection rates in early-stage disease. However, 27.5% of articles (36/131) reported biomarkers with better sensitivity and an AUC greater than 0.9 compared with CA 125 alone and deserve further exploration.

Variables Associated With Resolution and Persistence of Ovarian Cysts

OBJECTIVE: To estimate surveillance intervals of incident ovarian cysts, and describe variables associated with cyst resolution times. METHODS: The UK-OCST (University of Kentucky Ovarian Cancer Screening Trial) was a prospective cohort that enrolled 47,762 individuals over 30 years, including 2,638 individuals with incident cysts. Cyst diameter and structure and patient age, body mass index, use of hormone therapy (HT), family history of ovarian cancer, and menopausal status were examined as variables associated with cyst resolution using t tests, χ 2 test, Kaplan Meier, and Cox multiple regression. RESULTS: Of 2,638 individuals with incident cysts, 1,667 experienced resolution (63.2%) within 1.2 years, and 971 experienced persistence (36.8%). Within 1 year, unilocular and septated cysts had similar resolution rates (35.4% and 36.7%, respectively, P >.05), but time to resolution was shorter for unilocular cysts compared with septated cysts (mean 1.89 years vs 2.58 years, respectively, P <.001). Both unilocular and septated cysts smaller than 3 cm resolved faster than cysts larger than 6 cm ( P <.001). Variables associated with percent resolution included being of younger age, premenopausal status (but not for synchronous bilateral cysts), and those reporting a family history of ovarian cancer ( P <.05). Variables associated with a faster cyst resolution rate included being older than age 70 years and not using hormone therapy. Body mass index and family history were not associated with cyst resolution time. CONCLUSION: Different surveillance times may be appropriate depending on cyst structure and size and patient age and HT use. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT04473833.

Disparities in Fertility-Sparing Treatment and Use of Assisted Reproductive Technology After a Diagnosis of Cervical, Ovarian, or Endometrial Cancer

OBJECTIVE: To assess the presence of sociodemographic and clinical disparities in fertility-sparing treatment and assisted reproductive technology (ART) use among patients with a history of cervical, endometrial, or ovarian cancer. METHODS: We conducted a population-based cohort study of patients aged 18–45 years who were diagnosed with cervical cancer (stage IA, IB), endometrial cancer (grade 1, stage IA, IB), or ovarian cancer (stage IA, IC) between January 1, 2000, and December 31, 2015, using linked data from the CCR (California Cancer Registry), the California Office of Statewide Health Planning and Development, and the Society for Assisted Reproductive Technology. The primary outcome was receipt of fertility-sparing treatment , defined as surgical or medical treatment to preserve the uterus and at least one ovary. The secondary outcome was fertility preservation , defined as ART use after cancer diagnosis. Multivariable logistic regression analysis was used to estimate odds ratios and 95% CIs for the association between fertility-sparing treatment and exposures of interest: age at diagnosis, race and ethnicity, health insurance, socioeconomic status, rurality, and parity. RESULTS: We identified 7,736 patients who were diagnosed with cervical, endometrial, or ovarian cancer with eligible histology. There were 850 (18.8%) fertility-sparing procedures among 4,521 cases of cervical cancer, 108 (7.2%) among 1,504 cases of endometrial cancer, and 741 (43.3%) among 1,711 cases of ovarian cancer. Analyses demonstrated nonuniform patterns of sociodemographic disparities by cancer type for fertility-sparing treatment, and ART. Fertility-sparing treatment was more likely among young patients, overall, and of those in racial and ethnic minority groups among survivors of cervical and ovarian cancer. Use of ART was low (n=52) and was associated with a non-Hispanic White race and ethnicity designation, being of younger age (18–35 years), and having private insurance. CONCLUSION: This study demonstrates that clinical and sociodemographic disparities exist in the receipt of fertility-sparing treatment and ART use among patients with a history of cervical, endometrial, or ovarian cancer.

Predicting Endometrial Hyperplasia and Endometrial Cancer on Recurrent Abnormal Uterine Bleeding

OBJECTIVE: To develop predictive models for endometrial hyperplasia and endometrial cancer in patients with recurrent abnormal uterine bleeding (AUB). METHODS: This retrospective cohort study analyzed patients with recurrent AUB who had previous endometrial sampling that showed benign results between January 2013 and December 2021. A model was constructed from the significant factors associated with endometrial hyperplasia and endometrial cancer using multivariate logistic regression. Risk scores were calculated from the log odds of each significant predictive factor and were subsequently subcategorized into risk groups. The overall performance and internal validation of the model were assessed with the area under the receiver operating characteristic curve (AUC) and bootstrap methods. RESULTS: Of the total 456 patients with recurrent AUB, endometrial hyperplasia and endometrial cancer were detected in 8.3% and 2.2% of cases, respectively. The average interval between the first and second endometrial samplings was 25.1 months. Factors significantly associated with endometrial hyperplasia and endometrial cancer included age older than 45 years (odds ratio [OR] 2.86, 95% CI, 1.31–7.03), nulliparity (OR 3.50, 95% CI, 1.76–6.85), a history of endometrial polyp (OR 3.69, 95% CI, 1.93–7.05), and an interval of less than 12 months between sampling (OR 2.36, 95% CI, 1.25–4.42). Predictive factors were scored and categorized into three groups: 0–3, 5–8, and 9–11 points. The corresponding risks for endometrial hyperplasia and endometrial cancer in these groups were 4.7%, 15.5%, and 57.1%, respectively. The AUC was 73.1%, with a mean absolute error of 0.01. CONCLUSION: Endometrial hyperplasia and endometrial cancer occur at low incidence among one-fifth of patients with AUB who experience recurrent bleeding. Older age, nulliparity, a history of endometrial polyps, and an interval of less than 12 months between samplings are predictive factors for endometrial hyperplasia and endometrial cancer in this cohort.

Utilization and Surgical Outcomes of Sentinel Lymph Node Biopsy for Endometrial Intraepithelial Neoplasia

OBJECTIVE: To describe the rate and surgical outcomes of sentinel lymph node (SLN) biopsy in patients with endometrial intraepithelial neoplasia (EIN). METHODS: We conducted a cohort study that used the prospective American College of Surgeons National Surgical Quality Improvement Program database. Women with EIN on postoperative pathology who underwent minimally invasive hysterectomy from 2012 to 2020 were included. The cohort was dichotomized based on the performance of SLN biopsy. Patients' characteristics, perioperative morbidity, and mortality were compared between patients who underwent SLN biopsy and those who did not. Postoperative complications were defined using the Clavien-Dindo classification system. RESULTS: Overall, 4,447 patients were included; of those, 586 (13.2%) underwent SLN biopsy. The proportion of SLN biopsy has increased steadily from 0.6% in 2012 to 26.1% in 2020 (P<.001), with a rate of 16% increase per year. In a multivariable regression that included age, body mass index (BMI), and year of surgery, a more recent year of surgery was independently associated with an increased adjusted odds ratio of undergoing SLN biopsy (1.51, 95% CI, 1.43–1.59). The mean total operative time was longer in the SLN biopsy group (139.50±50.34 minutes vs 131.64±55.95 minutes, P=.001). The rate of any complication was 5.9% compared with 6.7%, the rate of major complications was 2.3% compared with 2.4%, and the rate of minor complications was 4.1% compared with 4.9% for no SLN biopsy and SLN biopsy, respectively. In a single complications analysis, the rate of venous thromboembolism was higher in the SLN biopsy group (four [0.7%] vs four [0.1%], P=.013). In a multivariable regression analysis adjusted for age, BMI, American Society of Anesthesiologists classification, uterus weight, and preoperative hematocrit, the performance of SLN biopsy was not associated with any complications, major complications, or minor complications. CONCLUSION: The performance of SLN biopsy in EIN is increasing. Sentinel lymph node biopsy for EIN is associated with an increased risk of venous thromboembolism and a negligible increased surgical time.

Survival Association of Intrauterine Manipulator Use During Minimally Invasive Hysterectomy for Endometrial Cancer

OBJECTIVE: To evaluate the association between intrauterine manipulator use and survival outcomes in patients undergoing minimally invasive hysterectomy for endometrial cancer because the oncologic effects of intrauterine manipulator use remain controversial. DATA SOURCES: A comprehensive systematic review of the literature published up to December 31, 2024, was conducted with the PubMed, Scopus, Web of Science, and Cochrane Library databases. METHODS OF STUDY SELECTION: Two independent investigators screened comparative studies, including prospective or retrospective studies and randomized controlled trials, examining oncologic outcomes in patients with endometrial cancer who underwent minimally invasive hysterectomy with or without an intrauterine manipulator. Studies with insufficient outcome data, including those involving patients who underwent open abdominal hysterectomy and those published in languages other than English, were excluded. TABULATION, INTEGRATION, AND RESULTS: Data extraction and synthesis were performed in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines. Random-effects analysis was used for data pooling. The primary outcomes were disease-free survival and overall survival. Confounding factors affecting prognosis and risk of bias were also evaluated. Between 2013 and 2024, 12 eligible studies, including 10 retrospective studies and two randomized controlled trials, enrolled 6,029 patients who underwent minimally invasive hysterectomy with an intrauterine manipulator and 4,776 patients without one. In the unadjusted pooled analysis, disease-free survival was lower in patients who underwent surgery with an intrauterine manipulator than in those without (nine studies, hazard ratio 1.18, 95% CI, 1.01–1.38, P =.04). Albeit statistically nonsignificant, the hazard ratio for all-cause mortality comparing intrauterine manipulator use with nonuse was 1.27 (six studies, 95% CI, 0.99–1.62, P =.06). Only a limited number of studies (4 of 12 studies, 33.3%) examined survival outcomes after adjustment for factors such as adjuvant treatment and tumor histology. Most studies (7 of 12, 58.3%) had a moderate risk of bias, and five (41.6%) had a serious risk of bias. CONCLUSION: This meta-analysis suggests that intrauterine manipulator use during minimally invasive hysterectomy may be associated with decreased disease-free survival in patients with endometrial cancer; however, the association with overall survival is marginal and did not reach statistical significance. Considering that most studies included in this meta-analysis were retrospective, did not adjust for prognostic factors such as postoperative treatment, and were of low to moderate quality, the associations found in this study warrant further investigation in future prospective trials. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42023428140.

Endometrial Cancer in a Transgender Man with Prolonged Exogenous Testosterone Use

BACKGROUND: Hormone therapy (HT) in transgender males requires monitoring. For amenorrheic transmasculine individuals on HT, episodes of abnormal vaginal bleeding should be assessed promptly. CASE: A 33-year-old transgender man on exogenous testosterone therapy for medical gender transition was found to have stage IV endometrioid endometrial adenocarcinoma. Surgical resection was performed for symptom control, and the patient was treated with palliative chemotherapy. The tumor was androgen receptor–negative, and, after a multidisciplinary discussion of the risks and benefits of continuing exogenous testosterone, testosterone therapy was restarted postoperatively. CONCLUSION: Long-term androgen use may have unknown implications for the development of malignancy, and treating reproductive organ cancer in transgender males may be complicated by the desire to continue androgen therapy.

Ultrasonography-Based Measurements of Endometrial Thickness in Patients With p53 Abnormal Endometrial Carcinomas

OBJECTIVE: To evaluate prediagnostic endometrial thickness measured by transvaginal ultrasonography (TVUS) in a cohort of patients with endometrial cancer stratified by p53 status to assess accuracy of endometrial thickness as a screening tool in this patient population. METHODS: We conducted a retrospective cohort study of patients diagnosed with endometrial cancer who underwent prediagnostic TVUS between 2004 and 2017. Using a tissue microarray, we categorized cases as p53 abnormal (p53abn) or p53 wild type (p53wt) according to the presence or absence of p53 aberrant immunohistochemistry staining. Cases were stratified according to established screening thresholds of 4-mm or less endometrial thickness used to evaluate postmenopausal bleeding. Clinical data were manually abstracted. All patients included underwent surgical staging, including hysterectomy. Student t , χ 2 , and Fisher exact tests were performed to assess for variables associated with p53abn endometrial carcinoma. Multivariate logistic regression was performed to assess variables associated with cases of endometrial cancer, with false-negative TVUS screening results defined as an endometrial thickness of 4 mm or less. RESULTS: Of the 133 patients identified, 60 (45.1%) were classified as p53abn and 73 (54.9%) as p53wt. The median age of the cohort was 66 years (interquartile range 58–74 years), and median body mass index (BMI) was 31.3 (interquartile range 26.8–37.3). Median endometrial thickness was 16 mm (interquartile range 9–22 mm), and 48 patients (36.1%) had submucosal or intramural leiomyomas identified on TVUS. Patients diagnosed with p53abn endometrial cancers were more likely to have thinner endometrial measurements compared with p53wt cases (10 mm [interquartile range 5–18.5 mm] vs 18 mm [interquartile range 13–23 mm], P <.001). At a threshold of 4 mm or less, patients with p53abn endometrial cancer were more likely to screen negative compared with patients with p53wt endometrial cancer (25% vs 4.1%, P <.001). In multivariate analysis, a threshold of 4 mm or less for endometrial thickness, lower BMI (odds ratio [OR] 0.906, 95% CI, 0.833–0.986, P =.023), and p53 status (OR 9.415, 95% CI, 2.441–36.309, P =.001) remained significant predictors of false-negative screening results. CONCLUSION: Endometrial thickness assessed by TVUS does not appear to be a reliable screening method in patients diagnosed with p53abn endometrial cancers. The use of endometrial thickness as a screening test for endometrial cancer may miss a significant portion of p53abn cases because of false-negative results. In the presence of postmenopausal bleeding, endometrial tissue sampling should be strongly considered.

Molecular Characterization and Clinical Implications of Endometrial Cancer

The classification of endometrial cancer (EC) has diverged from traditional histologic features based on microscopic appearance to objective molecular characterization. Molecular characterization of EC is pivotal to inform prognosis and to guide therapeutic recommendations. First described by the Cancer Genome Atlas, molecular profiling was later revised by the Proactive Molecular Risk Classifier for Endometrial Cancer and TransPORTEC algorithms to create clinically applicable and relatively easy-to-implement molecular classification systems. Since 2020, the World Health Organization recommended molecular classification of EC into four distinct prognostic subtypes: ECs with polymerase ε (POLE) pathogenic mutations assessed by gene sequencing, mismatch repair deficiency determined by immunohistochemistry or microsatellite instability assay, and p53 abnormalities determined by immunohistochemistry or next-generation sequencing. The final molecular subtype without any of these defining features is called “no specific molecular profile” (NSMP). This is further stratified by estrogen receptor (ER) immunohistochemistry status. Patients with cancers identified as POLE pathogenic mutations have the best prognosis with almost no recurrence or death events, followed by those with strong ER-positive NSMP cancers. Mismatch repair deficiency ECs have intermediate prognosis, whereas p53 abnormalities and ER-negative NSMP have the worst prognosis. Other molecular and pathologic biomarkers of interest include tumor mutational burden, human epidermal growth factor receptor 2, L1 cell adhesion molecule, β-catenin (CTNNB1), and lymph vascular space invasion, which may have prognostic and predictive implications. The current guidelines will continue to evolve; however, at minimum, it is recommended that all patients undergo testing for mismatch repair, p53, and ER, and POLE testing may be prioritized in select circumstances. Molecular classification provides the critical framework to deliver effective, personalized, high-quality care and informs clinical trial design. Molecular assessment ensures consistent diagnosis and provides prognostic information and predictive data to guide appropriate management.

Incidence and Timing of Venous Thromboembolism in Patients With Advanced Endometrial Cancer

Patients with advanced endometrial cancer (EC) are at risk for venous thromboembolism (VTE), though risk by treatment phase remains unclear. This single-institution retrospective study evaluated 84 patients receiving neoadjuvant chemotherapy (NACT, n=34) or adjuvant chemotherapy (n=50) for stage III–IV EC. Overall VTE incidence was 27.4% (95% CI, 18.8–38.0%). Among patients receiving NACT, VTE occurred in 14.3% during NACT and in 16.7% during ongoing chemotherapy. Postoperative and adjuvant treatment rates were less than 10.0%. Khorana score was a poor predictor of VTE, with 52.0% of intermediate-risk patients developing VTE. These findings highlight the need for improved VTE risk-reduction strategies, including larger studies to evaluate optimization of risk stratification and VTE prophylaxis during systemic therapy for advanced EC.

Evaluation of Efficacy and Adverse Events After Second Immunotherapy Exposure in Endometrial and Cervical Carcinoma

Immunotherapy has changed the treatment paradigm for gynecologic malignancies. The RUBY (NCT03981796) and NRG-GY018 (NCT03914612) studies have shown significant improvements in survival for immunotherapy in combination with chemotherapy in advanced and recurrent endometrial cancer, and immunotherapy likely will become the first-line standard-of-care therapy. However, the efficacy of repeated exposure to immunotherapy for gynecologic cancers is unknown. In this retrospective series, 11 patients with endometrial cancer and four patients with cervical cancer were identified who received subsequent immunotherapy after first immunotherapy. With subsequent immunotherapy, three patients (20.0%) had complete response, three (20.0%) had partial response, three (20.0%) had stable disease, and six (40.0%) had disease progression; progression-free survival was similar to first-line immunotherapy. These data provide proof of concept for subsequent treatment with immunotherapy in gynecologic cancers, specifically endometrial cancer.

Risk of Cancer Progression of Non–Atypical Endometrial Hyperplasia

Endometrial Cancer and Reproductive Justice

Endometrial cancer (EC) is the most common gynecologic cancer in the United States. Black individuals with EC have had a more than 90% higher 5-year mortality risk than White people while being subject to lower quality care across the entire disease process. In this commentary, I offer the perspective that EC is part of the reproductive justice movement, as a representation of threat to reproductive health independent of childbearing. With this work, I want to place EC squarely among the discursive arguments that reproductive justice makes in the interconnectedness of fertility, reproductive health, parenthood, and, ultimately, life.

Endometrial Cancer Surgery With or Without Concomitant Stress Urinary Incontinence Surgery

OBJECTIVE: To compare quality of life (QOL) among patients with endometrial intraepithelial neoplasia or early-stage endometrial cancer and stress urinary incontinence (SUI) who chose to have concomitant surgery with cancer surgery alone. METHODS: A multicenter, prospective cohort study was conducted across eight U.S. sites. Potentially eligible patients were screened for SUI symptoms. Those who screened positive were offered referral to urogynecology and incontinence treatment, including concomitant surgery. Participants were categorized into two groups: 1) concomitant cancer and SUI surgery or 2) cancer surgery alone. The primary outcome was cancer-related QOL as measured by the FACT-En (Functional Assessment of Cancer Therapy–Endometrial) (range 0–100; higher score indicates better QOL). The FACT-En and questionnaires assessing urinary symptom–specific severity and effects were assessed before surgery and 6 weeks, 6 months, and 12 months after surgery. Adjusted median regression accounting for clustering was used to examine the relationship between SUI treatment group and FACT-En scores. RESULTS: Of 1,322 (53.1%) patients, 702 screened positive for SUI with 532 analyzed; 110 (21%) chose concomitant cancer and SUI surgery, and 422 (79%) chose cancer surgery alone. FACT-En scores increased for both the concomitant SUI surgery and cancer surgery–only groups from the preoperative to the postoperative period. After adjustment for timepoint and preoperative covariates, the median change in FACT-En score (postoperative−preoperative) was 1.2 points higher (95% CI −1.3 to 3.6) for the concomitant SUI surgery group compared with the cancer surgery–only group across the postoperative period. Median time until surgery (22 days vs 16 days; P<.001), estimated blood loss (150 mL vs 72.5 mL; P<.001), and operative time (185.5 minutes vs 152 minutes; P<.001) were all greater for the concomitant cancer and SUI surgery group compared with the cancer-only group, respectively. CONCLUSION: Concomitant surgery did not result in improved QOL compared with cancer surgery alone for endometrial intraepithelial neoplasia and patients with early-stage endometrial cancer with SUI. However, FACT-En scores were improved in both groups.

Endometrial Hyperplasia

The objectives of this Clinical Expert Series on endometrial hyperplasia are to review the etiology and risk factors, histologic classification and subtypes, malignant progression risks, prevention options, and to outline both surgical and nonsurgical treatment options. Abnormal uterine and postmenopausal bleeding remain the hallmark of endometrial pathology, and up to 10–20% of postmenopausal bleeding will be either hyperplasia or cancer; thus, immediate evaluation of any abnormal bleeding with either tissue procurement for pathology or imaging should be undertaken. Although anyone with a uterus may develop atypical hyperplasia, also known as endometrial intraepithelial neoplasia (EIN), genetic predispositions (eg, Lynch syndrome), obesity, chronic anovulation, and polycystic ovarian syndrome all markedly increase these risks, whereas use of oral contraceptive pills or progesterone-containing intrauterine devices will decrease the risk. An EIN diagnosis carries a high risk of concomitant endometrial cancer or eventual progression to cancer in the absence of treatment. The definitive and curative treatment for EIN remains hysterectomy; however, the obesity epidemic, the potential desire for fertility-sparing treatments, the recognition of varying rates of malignant transformation, medical comorbidities, and an aging population all may factor into decisions to employ nonsurgical treatment modalities.

Increasing Utilization of Surgical Nodal Evaluation at Hysterectomy for Endometrial Hyperplasia

Utilization and Outcomes of Sentinel Lymph Node Biopsy for Early Endometrial Cancer

OBJECTIVE: To examine trends, characteristics, and oncologic outcomes of sentinel lymph node biopsy for early endometrial cancer. METHODS: This observational study queried the National Cancer Institute's Surveillance, Epidemiology, and End Results Program by examining 83,139 women with endometrial cancer who underwent primary hysterectomy with nodal evaluation for T1 disease from 2003 to 2018. Primary outcome measures were the temporal trends in utilization of sentinel lymph node biopsy and patient characteristics associated with sentinel lymph node biopsy use, assessed by multivariable binary logistic regression models. Secondary outcome measure was endometrial cancer–specific mortality associated with sentinel lymph node biopsy, assessed by propensity score inverse probability of treatment weighting. RESULTS: The utilization of sentinel lymph node biopsy increased from 0.2 to 29.7% from 2005 to 2018 ( P <.001). The uptake was higher for women with endometrioid (0.3–31.6% between 2005 and 2018) compared with nonendometrioid (0.6–21.0% between 2006 and 2018) histologic subtypes (both P <.001). In a multivariable analysis, more recent year surgery, endometrioid histology, well-differentiated tumors, T1a disease, and smaller tumor size were independently associated with sentinel lymph node biopsy use ( P <.05). Performance of sentinel lymph node biopsy was not associated with increased endometrial cancer–specific mortality compared with lymphadenectomy for endometrioid tumors (subdistribution hazard ratio [HR] 0.96, 95% CI 0.82–1.13) or nonendometrioid tumors (subdistribution HR 0.85, 95% CI 0.69–1.04). For low-risk endometrial cancer, the increase in sentinel lymph node biopsy resulted in a 15.3 percentage-point (1.4-fold) increase in surgical nodal evaluation by 2018 (expected vs observed rates, 37.8 vs 53.1%). CONCLUSION: The landscape of surgical nodal evaluation is shifting from lymphadenectomy to sentinel lymph node biopsy for early endometrial cancer in the United States, with no indication of a negative effect on cancer-specific survival.

Racial–Ethnic and Socioeconomic Disparities in Guideline-Adherent Treatment for Endometrial Cancer

OBJECTIVE: To evaluate the association of race–ethnicity and neighborhood socioeconomic status with adherence to National Comprehensive Cancer Network guidelines for endometrial carcinoma. METHODS: Data are from the SEER (Surveillance, Epidemiology, and End Results) cancer registry of women diagnosed with endometrial carcinoma for the years 2006–2015. The sample included 83,883 women after inclusion and exclusion criteria were applied. Descriptive statistics, bivariate analyses, univariate, and multivariate logistic regression models were performed to evaluate the association between race–ethnicity and neighborhood socioeconomic status with adherence to treatment guidelines. RESULTS: After controlling for demographic and clinical covariates, Black (odds ratio [OR] 0.89, P<.001), Latina (OR .92, P<.001), and American Indian or Alaska Native (OR 0.82, P=.034) women had lower odds of receiving adherent treatment and Asian (OR 1.14, P<.001) and Native Hawaiian or Pacific Islander (OR 1.19 P=.012) women had higher odds of receiving adherent treatment compared with White women. After controlling for covariates, there was a gradient by neighborhood socioeconomic status: women in the high–middle (OR 0.89, P<.001), middle (OR 0.84, P<.001), low–middle (OR 0.80, P<.001), and lowest (OR 0.73, P<.001) neighborhood socioeconomic status categories had lower odds of receiving adherent treatment than the those in the highest neighborhood socioeconomic status group. CONCLUSIONS: Findings from this study suggest there are racial–ethnic and neighborhood socioeconomic disparities in National Comprehensive Cancer Network treatment adherence for endometrial cancer. Standard treatment therapies should not differ based on sociodemographics. Interventions are needed to ensure that equitable cancer treatment practices are available for all individuals, regardless of racial–ethnic or socioeconomic background.