Overall survival in patients with FIGO stage IVA cervical cancer.

OBJECTIVE: FIGO stage IVA cervical cancer is a unique diagnosis that conveys a poor prognosis. Despite the use of PET/CT for staging, concurrent chemotherapy, and image-guided brachytherapy, overall survival (OS) in these patients is low. Treatment requires aggressive use of radiotherapy and chemotherapy. We report results of a prospective observational cohort study for patients with de novo stage IVA cervical cancer treated at a single institution. METHODS: Patients with a new diagnosis of stage IVA cervical cancer treated at an academic institution between 1997 and 2020 were prospectively monitored. Staging was retroactively assigned using the 2018 FIGO staging system. All patients had a PET/CT prior to treatment and were treated with definitive intent radiotherapy with or without chemotherapy. The primary outcome of interest was OS. Secondary outcomes were local control, progression-free survival (PFS), and disease-specific survival (DSS). RESULTS: 32 patients with de novo stage IVA cervical cancer were treated with definitive intent radiotherapy. Median follow-up time was 4.27 years (1.31-10.35). 22/32 (69%) of patients received brachytherapy as a part of their definitive treatment, and 28/32 (88%) received chemotherapy concurrently with radiotherapy. 14/32 (44%) of patients had no evidence of disease at last follow-up. The 5-year local control, PFS, DFS, and OS estimates were 79%, 49%, 53%, and 48%, respectively. On multivariate analysis, complete metabolic response was associated with a statistically significant improvement in PFS (HR = 0.256, 95% CI = 0.078-0.836, p = 0.024) and OS (HR = 0.273, 95% CI 0.081-0.919). CONCLUSIONS: These data demonstrate a robust OS in patients with stage IVA cervical cancer when treated with definitive chemoradiotherapy.

FIGO 2018 staging criteria for cervical cancer: Impact on stage migration and survival.

OBJECTIVE: To compare FIGO 2009 and FIGO 2018 cervical cancer staging criteria with a focus on stage migration and treatment outcomes. METHODS: This study is based on a database cohort of 1282 patients newly diagnosed with cervical cancer from 1997 to 2019. All underwent standard clinical examination and whole-body FDG-PET. Tumor stage was recorded using the FIGO 2009 system, which excluded surgical pathologic, FDG-PET and other advanced imaging findings, and then re-classified to the FIGO 2018 system, including surgical pathologic and imaging findings. Patient management was based on clinical, surgical, and imaging findings. Stage migration and prognosis were evaluated. RESULTS: The distribution per the 2009 staging system was stage I in 593 (46%), stage II in 342 (27%), stage III in 263 (21%), and stage IV in 84 (7%) and the 2018 staging system was stage I in 354 (28%), stage II in 156 (12%), stage III in 601 (47%), and stage IV in 171 (13%). No patients were down-staged. Stage migration occurred in 53% (676/1282) and was attributable to detection of occult lymph node metastasis in 520 (41%), occult distant metastasis in 90 (7%), and tumor size and extent in 66 (5%). The 5-year progression-free survivals (PFS) by FIGO 2009 versus FIGO 2018 were as follows: stage I, 80% vs. 87% (p = 0.02); stage II, 59% vs. 71% (p = 0.002); stage III, 35% vs. 55% (p < 0.001), and stage IV, 20% vs. 16% (p = 0.41). CONCLUSION: Inclusion of surgical pathologic and imaging findings resulted in upward stage migration in the majority, mostly related to nodal and distant metastasis. While FIGO 2018 improves survival discriminatory ability for stages I and IV patients, survival remains heterogeneous among stage III substages.

Epidemiological evidence that common HPV types may be common because of their ability to evade immune surveillance: Results from the Women's Interagency HIV study.

Infection by human papillomavirus (HPV) type 16, the most oncogenic HPV type, was found to be the least affected by HIV-status and CD4 count of any of the approximately 13 oncogenic HPV types. This relative independence from host immune status has been interpreted as evidence that HPV16 may have an innate ability to avoid the effects of immunosurveillance. However, the impact of immune status on other individual HPV types has not been carefully assessed. We studied type-specific HPV infection in a cohort of 2,470 HIV-positive (HIV[+]) and 895 HIV-negative (HIV[-]) women. Semi-annually collected cervicovaginal lavages were tested for >40 HPV types. HPV type-specific prevalence ratios (PRs), incidence and clearance hazard ratios (HRs), were calculated by contrasting HPV types detected in HIV[+] women with CD4 < 200 to HIV[-] women. HPV71 and HPV16 prevalence had the weakest associations with HIV-status/CD4 count of any HPV, according to PRs. No correlations between PRs and HPV phylogeny or oncogenicity were observed. Instead, higher HPV type-specific prevalence in HIV[-] women correlated with lower PRs (ρ = -0.59; p = 0.0001). An alternative (quadratic model) statistical approach (PHIV+ = a*PHIV- + b*PHIV- 2 ; R2 = 0.894) found similar associations (p = 0.0005). In summary, the most prevalent HPV types in HIV[-] women were the types most independent from host immune status. These results suggest that common HPV types in HIV[-] women may have a greater ability to avoid immune surveillance than other types, which may help explain why they are common.

Longitudinal assessment of abnormal Papanicolaou test rates among women with HIV.

OBJECTIVE: To describe longitudinal changes in the prevalence of abnormal Papanicolau testing among women living with HIV. DESIGN: Prospective cohort study with sequential enrollment subcohorts. METHODS: Four waves of enrollment occurred in the Women's Interagency HIV Study, the US women's HIV cohort (1994-1995, 2001-2002, 2011-2012, 2013-2015). Pap testing was done at intake, with colposcopy prescribed for any abnormality. Rates of abnormal Pap test results (atypical squamous cells of uncertain significance or worse) and cervical intraepithelial neoplasia grade 2 (CIN2) or worse were calculated. Logistic regression models assessed changes in prevalence across cohorts after controlling for severity of HIV disease and other risk factors for abnormal Pap tests. RESULTS: The unadjusted prevalence of any Pap abnormality was 679/1769 (38%) in the original cohort, 195/684 (29%) in the 2001-2002 cohort, 46/231 (20%) in the 2011-2012 cohort, and 71/449 (16%) in the 2013-2015 cohort. In multivariable analysis, compared with risk in the 1994-1995 cohort, the adjusted risk in the 2001-2002 cohort was 0.79 (95% CI 0.59-1.05), in the 2011-2012 cohort was 0.67 (95% CI 0.43-1.04), and in the 2013-2015 cohort was 0.41 (95% CI 0.27-0.62) with P for trend less than 0.0001. CONCLUSION: Rates of abnormal cytology among women with HIV have fallen during the past two decades.

Factors influencing residents' interest in gynecologic oncology fellowship.

OBJECTIVES: To identify the role of mentorship and other factors associated with obstetrics and gynecology (OB/GYN) resident interest in pursuing a fellowship in gynecologic oncology. METHODS: A survey link was emailed to U.S. OB/GYN residency program coordinators to disperse to current residents. The 80-item survey asked about plans to pursue fellowship and influencing factors. Participants were stratified based on decision to pursue a fellowship in gynecologic oncology. Student's t-test and Mann-Whitney tests were applied. RESULTS: Among 236 surveyed residents, 32 (13.6%) were planning to pursue a fellowship in gynecologic oncology. There were no demographic differences favoring the choice of gynecologic oncology; however, trainees at academic programs were more likely to aspire to the subspecialty (p = 0.01). Residents interested in gynecologic oncology had marginally more mentors than others (p = 0.06), were more likely to have a gynecologic oncology mentor (p < 0.01), and were more likely to have cited mentorship as a reason for their career aspirations (p = 0.01). These residents were also less likely to report obvious burnout among faculty and fellows in their department (p < 0.01 and p = 0.01, respectively). CONCLUSIONS: Strong mentor relationships and the display of job satisfaction and work-life balance influence OB/GYN residents' interest in gynecologic oncology fellowships. Programs should consider formal mentorship programs for residents, with priority on matching by subspecialty. The value of fellow and faculty efforts in mentorship should be recognized, and appropriate time should be protected for these relationships, along with efforts to support fellows and faculty at risk for burnout.

Risk of cervical and vaginal dysplasia after surgery for vulvar intraepithelial neoplasia or cancer: A 6 year follow-up study.

OBJECTIVES: To estimate the frequency of abnormal surveillance cytology leading to high-grade dysplasia after surgical management for high-grade vulvar intraepithelial neoplasia (VIN) and vulvar cancer and to determine whether prior hysterectomy reduces this risk. METHODS: Women who underwent surgery for high-grade VIN or vulvar cancer between 2006 and 2014 were identified retrospectively. Patients who underwent prior hysterectomy for any indication were included. Univariate and multivariate logistic regression analyses were used to identify clinical correlates of abnormal cytology after surgical treatment for VIN and vulvar cancer. RESULTS: During a median follow-up for 72 months, 302 women underwent surveillance with cytologic screening after vulvar surgery including 99 (33%) women with prior hysterectomy. 75 (25%) women had abnormal cytology results. Of those, 47 (63%) were low-grade and 28 (37%) were high-grade, including 2 (3%) cases of invasive cancer. The rates of high-grade vaginal intraepithelial neoplasia (VAIN), cervical intraepithelial neoplasia (CIN), or cancer were not significantly different despite prior hysterectomy (9% VAIN 2+, 7% CIN 2+). Multivariate analysis showed that correlates of high-grade cytology following treatment for VIN or vulvar cancer included non-white race [odds radio (OR) 3.6, 95% confidence interval (CI) 1.7-7.8], prior abnormal cytology (OR 3.5, 95% CI 1.6-7.6), and immunodeficiency (OR 3.4, 95% CI 1.3-8.8). Prior hysterectomy did not significantly decrease risk of high-grade cytology (OR 0.87, 95% CI 0.5-1.6). CONCLUSIONS: Women treated surgically for VIN/vulvar cancer have an 8% risk of at least high-grade dysplasia from surveillance screening and prior hysterectomy does not mitigate the risk. Extrapolating from current guidelines, we recommend surveillance cytology screening at least 6-12 months after treatment.

Continuous epidural infusion in gynecologic oncology patients undergoing exploratory laparotomy: The new standard for decreased postoperative pain and opioid use.

OBJECTIVE: To compare the incidence of postoperative complications and opioid pain medication usage in gynecologic oncology patients who did and did not receive an epidural prior to undergoing exploratory laparotomy. METHODS: Retrospective cohort study of all patients undergoing exploratory laparotomy with the gynecologic oncology division at Washington University in St Louis between January 2012 and October 2015. Data on demographics, pathology, postoperative pain and opioid use, and incidence of postoperative complications were collected. RESULTS: Five hundred and sixty-one patients underwent laparotomy, 305 with an epidural and 256 without. Patients with an epidural used significantly less hydromorphone in the post-anesthesia care unit (PACU) (p = 0.003) and on postoperative day (POD)#1 (p = 0.05), less total opioids on POD#0 (p < 0.01), and more non-opioid pain medication on POD#1-3 (p < 0.01). Patients with an epidural had lower pain scores in the PACU (p = 0.01), on POD#0 (p < 0.01), POD#1 (p < 0.01), and POD#3 (p = 0.03). Patients with epidurals had shorter hospital length of stay (p < 0.01), no difference in hospital readmission or incidence of venous thromboembolism up to 90 days postoperatively, longer duration of Foley catheter (20.4 vs 10.3 h, p = 0.02) with no difference in postoperative urinary tract infection, higher incidence of postoperative hypotension (63% vs 36.3%, p < 0.01), and lower incidence of wound complications (5% vs 14.1%, p < 0.01). CONCLUSIONS: Perioperative epidurals used in patients undergoing major abdominal surgery correlate with decreased postoperative opioid use, increased use of non-opioid pain medications, and improved pain relief postoperatively with acceptable postoperative risks and should be standard of care for these patients.

Intensity Modulated Radiation Therapy and Image-Guided Adapted Brachytherapy for Cervix Cancer.

PURPOSE: This study reported long-term outcomes of patients with cervical cancer who were treated with intensity modulated radiation therapy and 3-dimensional (3D) image-guided adapted brachytherapy (IMRT/3D-IGABT) compared with those treated with 2-dimensional (2D) external irradiation and 2D brachytherapy (2D EBRT/BT). METHODS AND MATERIALS: This study included patients with newly diagnosed cervical cancer and pretreatment fluorodeoxyglucose positron emission tomography scans who were treated with curative-intent irradiation from 1997 to 2013. The treatment policy changed from using 2D EBRT/BT to IMRT/3D-IGABT in 2005. Patterns of recurrence, cancer-specific survival (CSS), and overall survival (OS) were evaluated. Late gastrointestinal and genitourinary toxicity were scored with National Cancer Institute Common Terminology Criteria for Adverse Events. RESULTS: The median follow-up for patients alive at the time of last follow-up in the 2D EBRT/BT group (n = 300) was 15.3 years (range, 10.8-20.5 years). In the IMRT/3D-IGABT group (n = 300), it was 7 years (range, 5-12.4 years). According to the International Federation of Gynecology and Obstetrics, 33% of tumors were stage IB1 to IB2, 41% were stage IIA to IIB, and 26% were stage IIIA to IVA. The results after 5 years for patients treated with 2D EBRT/BT showed that freedom from relapse (FFR) was 57%, CSS was 62%, and OS was 57%. For the IMRT/3D-IGABT group, the 5-year results showed that FFR was 65% (P = .04), CSS was 69% (P = .01), and OS was 61% (P = .04). When stratified by lymph node status according to positron emission tomography scan results, disease control was most improved with IMRT/3D-IGABT versus 2D EBRT/BT in patients with positive pelvic lymph nodes only (P = .02). Cumulatively, 88 of 600 patients (15%) had grade ≥3 late bowel/bladder toxicity. The 2D EBRT/BT group had 55 patients (18%), and the IMRT/3D-IGABT group had 33 patients (11%; P = .02). CONCLUSIONS: IMRT/3D-IGABT was associated with improved survival and decreased gastrointestinal and genitourinary toxicity in patients with cervical cancer compared with those who received 2D EBRT/BT.

Natural History of Cervical Intraepithelial Neoplasia-2 in HIV-Positive Women of Reproductive Age.

OBJECTIVE: To evaluate the natural history of treated and untreated cervical intraepithelial neoplasia-2 (CIN2) among HIV-positive women. METHODS: Participants were women enrolled in the Women's Interagency HIV Study between 1994 and 2013. One hundred four HIV-positive women diagnosed with CIN2 before age 46 were selected, contributing 2076 visits over a median of 10 years (interquartile range 5-16). The outcome of interest was biopsy-confirmed CIN2 progression, defined as CIN3 or invasive cervical cancer. CIN2 treatment was abstracted from medical records. RESULTS: Most women were African American (53%), current smokers (53%), and had a median age of 33 years at CIN2 diagnosis. Among the 104 HIV-positive women, 62 (59.6%) did not receive CIN2 treatment. Twelve HIV-positive women (11.5%) showed CIN2 progression to CIN3; none were diagnosed with cervical cancer. There was no difference in the median time to progression between CIN2-treated and CIN2-untreated HIV-positive women (2.9 vs. 2.7 years, P = 0.41). CIN2 treatment was not associated with CIN2 progression in multivariate analysis (adjusted hazard ratio 1.82; 95% confidence interval: 0.54 to 7.11), adjusting for combination antiretroviral therapy and CD4 T-cell count. In HIV-positive women, each increase of 100 CD4 T cells was associated with a 33% decrease in CIN2 progression (adjusted hazard ratio 0.67; 95% confidence interval: 0.47 to 0.88), adjusting for CIN2 treatment and combination antiretroviral therapy. CONCLUSIONS: CIN2 progression is uncommon in this population, regardless of CIN2 treatment. Additional studies are needed to identify factors to differentiate women at highest risk of CIN2 progression.

Correlates of Bacterial Vaginosis Over Long-Term Follow-Up: Impact of HIV Infection.

Correlates of bacterial vaginosis (BV) are poorly understood, especially in HIV infection. In a cohort study, HIV-seropositive and comparison seronegative women were assessed every 6 months during 1994-2015. BV was considered present when three of four Amsel criteria were met. Behavioral characteristics were assessed using structured interviews. Multivariable logistic regression used generalized estimating equation models to determine factors associated with BV. Cumulative incidence of BV over time was assessed using the log-rank test. Among 3,730 women (964 HIV seronegative and 2,766 HIV seropositive) contributing 70,970 visits, BV was diagnosed at 2,586 (14.0%) visits by HIV-seronegative women and 6,224 (11.9%) visits by HIV-seropositive women (p < .0001). The cumulative incidence of BV was 530/964 (55.0%) in HIV-seronegative women and 1,287/2,766 (46.5%) in seropositive women (p < .0001). In adjusted analyses, factors associated with BV were younger age, ethnicity, lower income, less education, recruitment site, recruitment in the 2001-2002 cohort, heavier drinking, current smoking, depression, and sex with a male partner; both hormonal contraception and menopause were negatively associated with BV. Of 533 women with prevalent BV, 228 (42.8%) recurred within a year, while persistent BV was found in 12.8% of participants; neither proportion differed by HIV serostatus. Time trends in the proportion of women with BV at any single visit were not identified. BV is common among women with and at risk for HIV, but HIV infection does not predispose to BV, which is associated instead with behavioral and cultural factors.

See-and-Treat Loop Electrosurgical Excision Procedure for High-Grade Cervical Cytology: Are We Overtreating?

OBJECTIVES: To report the overtreatment rate for see-and-treat versus 3-step conventional strategy (cervical cytology, colposcopic biopsies, then LEEP) for patients with high-grade squamous intraepithelial lesion (HSIL) cytology. Our second aim was to identify risk factors for overtreatment. METHODS: We included 178 women with HSIL cytology from our university-based colposcopy clinic who underwent LEEP between 2007 and 2014. Overtreatment was defined as cervical intraepithelial neoplasia (CIN) 1 or less on LEEP specimen. Differences between treatment groups were compared using chi-square test, 2-sample t test, or Mann-Whitney rank-sum test as appropriate. RESULTS: CIN2+ was found in 69 (80%) of women in the see-and-treat group and 69 (75%) of the conventional management group (P = 0.093), with overtreatment in 17 (20%) and 23 (25%, P = 0.403), respectively. Women who underwent see-and-treat (n = 86) were older (mean age, 36 vs 31 years; P = 0.007), and a greater proportion completed childbearing (30% vs 13%, P = 0.024). There were no differences in top hat excision; however, a higher proportion of the see-and-treat group had CIN2+ in endocervical samples (54% vs 27%, P = 0.047). Overtreatment, regardless of management strategy, was associated with age at time of LEEP, where older women were more likely to be overtreated (median age, 37 vs 32 years, respectively; OR, 1.04; 95% CI, 1.01-1.08; P = 0.011). CONCLUSIONS: A see-and-treat strategy minimizes risk of loss to follow-up with a similar overtreatment rate compared with conventional management. With CIN2+ in some three-fourths of women with HSIL, a see-and-treat should be favored especially when adherence to follow-up is questionable.

Functional attributes of mucosal immunity in cervical intraepithelial neoplasia and effects of HIV infection.

The role of mucosal immunity in human papillomavirus (HPV)-related cervical diseases is poorly understood. To characterize the local immune microenvironment in cervical intraepithelial neoplasia (CIN) 2/3 and determine the effects of HIV infection, we compared samples from three groups: normal cervix, CIN 2/3 from immunocompetent women (HIV- CIN 2/3), and CIN 2/3 from HIV seropositive women (HIV+ CIN 2/3). CIN 2/3 lesions contained increased numbers of immune cells from both the acquired and innate arms of the immune response in stroma [CD4+ and CD8+ T cells, macrophages, mast cells, B cells, neutrophils, and natural killer (NK) cells] and dysplastic epithelium (CD4+ T cells, macrophages, and NK cells). Immune cells in CIN 2/3 expressed activation markers, as measured by interleukin-2 receptor (IL-2R) and transcription factor T bet. Interferon-gamma production was significantly up-regulated in CIN lesions and was expressed by CD4+ and CD8+ T cells and NK cells, indicating the activation of immune cells. Abundant presence of transforming growth factor-beta+ CD25+ cells in the infiltrates associated with CIN lesions, and of immature CD1a+ dendritic cells expressing IL-10 and transforming growth factor-beta, indicate that CIN is associated with an influx of immune cells that produce a mixture of proinflammatory and regulatory cytokines. In HIV+ CIN, immune cell densities (CD4+ T cells, macrophages, neutrophils, and NK cells) and expression of interferon-gamma were significantly decreased compared with HIV- CIN. Regulatory cytokines were also down-regulated in this group. Therefore, both pro- and anti-inflammatory responses present in CIN 2/3 lesions are suppressed in HIV-seropositive women.

Effect of hormonal contraceptive use on plasma HIV-1-RNA levels among HIV-infected women.

We compared the HIV-1-RNA and CD4 lymphocyte counts from users and non-users of hormonal contraception cross-sectionally upon entry into the Women's Interagency HIV Study, and again longitudinally. There did not appear to be an association between hormonal contraception use and HIV-1-RNA levels in our study. There was a small increase in CD4 cell counts among hormonal users of doubtful clinical significance.

Serum immunoglobulin G response to human papillomavirus type 16 virus-like particles in human immunodeficiency virus (HIV)-positive and risk-matched HIV-negative women.

Baseline serum samples from 2815 human immunodeficiency virus (HIV)-positive and 963 HIV-negative women enrolled in 2 cohort studies were tested for immunoglobulin G antibodies to human papillomavirus type 16 (HPV-16) capsids. HPV-16 seropositivity was associated with lifetime number of sex partners (P<.001) among both HIV-positive and HIV-negative women. Approximately 50%-60% of HPV-16 DNA-positive women were HPV-16 positive. HPV-16 seropositivity was associated with HIV infection; however, after adjustment for baseline cervical HPV infection and disease, the association disappeared. Thus, the high seroprevalence of HPV-16 among HIV-positive women may be explained by a high prevalence of HPV of all types. Approximately 50% of HIV-positive women had serological evidence of prior HPV-16 infection, but only approximately 5% had an HPV-16 cervical infection at baseline. Despite the higher prevalence of HPV infection in this group, most HIV-positive women are able to control HPV-16 replication at the cervix, and reactivation, if it occurs, is not very common.