Mila P. Salcedo

Cervical Cancer Outcomes in Mozambique: Impact of an International Gynecologic Oncology Training Program

PURPOSE Cervical cancer is the most common cancer among women in Mozambique and is a major health burden. Surgery for cervical cancer is currently performed at only one hospital in the country, Maputo Central Hospital. Before 2020, there were no gynecologists in Mozambique trained to care for women with cervical cancer. In 2017, the International Gynecologic Cancer Society (IGCS) started a gynecologic oncology training program in Mozambique, and in 2020, the first three fellows graduated from this program. The main objective of this study was to report the outcomes of patients with cervical cancer who were treated surgically by the three newly trained Mozambican gynecologic oncologists. METHODS We performed a retrospective chart review of women diagnosed with cervical cancer who underwent surgical treatment by the Mozambican gynecologic oncologists between November 2020 and October 2022. The outcome of interest was survival at 2 years. RESULTS Thirty-three patients underwent radical hysterectomy with pelvic lymphadenectomy for cervical cancer treatment. The median age at diagnosis was 43 years. After surgery, 15 patients (45%) were dispositioned to surveillance and 18 (55%) were referred for adjuvant treatment with radiotherapy and/or chemotherapy. All patients had follow-up data available, with a median follow-up time of 19 months (range, 0.2 to 37.5). Only one patient died, and the overall survival is 95.7% (95% CI, 87.7% to 100%) at 12.7 months. CONCLUSION The IGCS program has provided training to physicians at Maputo Central Hospital, resulting in surgery for cervical cancer being available to patients in Mozambique. This is an important step in the global elimination of cervical cancer.

Multiscale Optical Imaging Fusion for Cervical Precancer Diagnosis: Integrating Widefield Colposcopy and High-Resolution Endomicroscopy

Early detection and treatment of cervical precancers can prevent disease progression. However, in low-resource communities with a high incidence of cervical cancer, high equipment costs and a shortage of specialists hinder preventative strategies. This manuscript presents a low-cost multiscale in vivo optical imaging system coupled with a computer-aided diagnostic system that could enable accurate, real-time diagnosis of high-grade cervical precancers. The system combines portable colposcopy and high-resolution endomicroscopy (HRME) to acquire spatially registered widefield and microscopy videos. A multiscale imaging fusion network (MSFN) was developed to identify cervical intraepithelial neoplasia grade 2 or more severe (CIN 2+). The MSFN automatically identifies and segments the ectocervix and lesions from colposcopy images, extracts nuclear morphology features from HRME videos, and integrates the colposcopy and HRME information. With a threshold value set to achieve sensitivity equal to clinical impression (0.98 [p = 1.0]), the MSFN achieved a significantly higher specificity than clinical impression (0.75 vs. 0.43, p = 0.000006). Our findings show that multiscale optical imaging of the cervix allows the highly sensitive and specific detection of high-grade precancers. The multiscale imaging system and MSFN could facilitate the accurate, real-time diagnosis of cervical precancers in low-resource settings.

The International Gynecologic Cancer Society Preinvasive Certificate Program: building a skilled workforce for the detection and treatment of cervical pre-cancer

The Capulana study: a prospective evaluation of cervical cancer screening using human papillomavirus testing in Mozambique

Cervical cancer is the leading cause of cancer and related deaths among women in Mozambique. There is limited access to screening and few trained personnel to manage women with abnormal results. Our objective was to implement cervical cancer screening with human papillomavirus (HPV) testing, with navigation of women with abnormal results to appropriate diagnostic and treatment services. We prospectively enrolled women aged 30-49 years living in Maputo, Mozambique, from April 2018 to September 2019. All participants underwent a pelvic examination by a nurse, and a cervical sample was collected and tested for HPV using the careHPV test (Qiagen, Gaithersburg, Maryland, USA). HPV positive women were referred for cryotherapy or, if ineligible for cryotherapy, a loop electrosurgical excision procedure. Women with findings concerning for cancer were referred to the gynecologic oncology service. Participants (n=898) had a median age of 38 years and 20.3% were women living with the human immunodeficiency virus. HPV positivity was 23.7% (95% confidence interval 21.0% to 26.6%); women living with human immunodeficiency virus were twice as likely to test positive for HPV as human immunodeficiency virus negative women (39.2% vs 19.9%, p<0.001). Most HPV positive women (194 of 213, 91.1%) completed all steps of their diagnostic work-up and treatment. Treatment included cryotherapy (n=158, 77.5%), loop electrosurgical excision procedure (n=30, 14.7%), or referral to a gynecologist or gynecologic oncologist (n=5, 2.5%). Of eight invasive cervical cancers, 5 (2.8%) were diagnosed in women living with human immunodeficiency virus and 3 (0.4%) in human immunodeficiency virus negative women (p=0.01). Cervical cancer screening with HPV testing, including appropriate follow-up and treatment, was feasible in our study cohort in Mozambique. Women living with human immunodeficiency virus appear to be at a significantly higher risk for HPV infection and the development of invasive cervical cancer than human immunodeficiency virus negative women.

Cervical cancer screening abnormalities in immunosuppressed renal transplant women: case–control study in Southern Brazil

To evaluate the prevalence of cervical pre-malignancies in the cervical cytology of female renal transplant recipients (RTR) and compare to immunocompetent patients. A prospective case-control study of 165 RTR (cases) and 372 immunocompetent women (controls) was carried out from May 2015 to August 2016. The participants completed a questionnaire with demographic characteristics, habits, reproductive history, and information about the renal transplant. Cervical cytology samples were collected at their visit for cervical cancer screening. Relevant medical history was obtained from medical records and previous cervical cytology results were retrieved: from the time of kidney transplantation to the beginning of this study for RTR and all collected throughout life for controls. The mean age was similar between groups (42.6 ± 11.4 vs. 41.8.2 ± 11.1 years, p = 0.447). Considering cervical cytology collected since the kidney transplant, RTR had three times higher rates of abnormal cervical cytology test (24.8% of RTR vs. 6.3% for controls), and the abnormalities were more frequent (p  0.05). When the altered results were broken down, a higher frequency of LSIL could be seen in RTR (3.6% vs 0.0%, p = 0.008). RTR had significantly higher rates of cervical cytology abnormalities comparing to the control group and most of it was composed of LSIL.

Addressing high cervical cancer rates in the Rio Grande Valley along the Texas–Mexico border: a community-based initiative focused on education, patient navigation, and medical provider training/telementoring

Aims: Cervical cancer incidence and mortality rates are approximately 55% higher in the Rio Grande Valley (RGV) along the Texas–Mexico border compared with the average rates in the US. Our aim was to improve cervical cancer prevention efforts in the RGV through a comprehensive multilevel intervention initiative focused on community education, patient navigation, and training of local providers. Methods: We initiated a program in the RGV which consisted of (1) community education, (2) patient navigation, and (3) a training/mentoring program for local medical providers including hands-on training courses coupled with telementoring using Project ECHO® (Extension for Community Health Outcomes). We assessed the number of women undergoing cervical cancer screening, diagnosis, and treatment at three participating clinics caring for underserved women in the region. Results: From November 2014 to October 2018, 14,846 women underwent cervical cancer screening. A total of 2030 (13.7%) women underwent colposcopy for abnormal results (179% increase over baseline) and 453 women underwent loop electrosurgical excision procedures (LEEPs) for treatment of cervical dysplasia. Invasive cancer was diagnosed in 39 women who were navigated to a gynecologic oncologist for treatment. Seven local medical providers were trained to perform colposcopy and/or LEEP. Project ECHO telementoring videoconferences were held every 2 weeks for a total 101 sessions with an average of 22 participants per session and a total of 180 patient cases presented and discussed. Conclusions: Our program led to a large number of women undergoing diagnosis and treatment of cervical dysplasia in the RGV. If sustained, we anticipate these efforts will decrease cervical cancer rates in the region. The program is currently being expanded to additional underserved areas of Texas and globally to low- and middle-income countries.

A Cross-Sectional Study of the Prevalence of Anal Dysplasia among Women with High-Grade Cervical, Vaginal, and Vulvar Dysplasia or Cancer: The PANDA Study

Background: High-risk human papillomavirus (HR-HPV) infection is a risk factor for anal cancer, yet no anal cancer screening guidelines exist for women with lower genital tract HPV-related disease. We sought to describe the prevalence of anal HR-HPV or cytologic abnormalities in such women. Methods: This cross-sectional study was performed between October 2018 and December 2021. Inclusion criteria were ≥21 years of age and a prior diagnosis of high-grade dysplasia/cancer of the cervix, vagina, or vulva. Participants underwent anal cytology and anal/cervicovaginal HR-HPV testing. Women with abnormal anal cytology were referred for high-resolution anoscopy (HRA). Results: 324 evaluable women were enrolled. Primary diagnosis was high-grade dysplasia/cancer of the cervix (77%), vagina (9%), and vulva (14%). Anal HR-HPV was detected in 92 patients (28%) and included HPV-16 in 24 (26%), HPV-18 in 6 (7%), and other HR-HPV types in 72 (78%) patients. Anal cytology was abnormal in 70 patients (23%) and included atypical squamous cells of undetermined significance (80%), low-grade squamous intraepithelial lesion (9%), high-grade intraepithelial lesion (HSIL; 1%), and atypical squamous cells-cannot rule out HSIL (10%). Of these patients, 55 (79%) underwent HRA. Anal biopsies were performed in 14 patients: 2 patients had anal intraepithelial neoplasia (AIN) 2/3, 1 patient had AIN 1, and 11 patients had negative biopsies. Both patients with AIN 2/3 had a history of cervical dysplasia. Conclusions: Our results suggest an elevated risk of anal HR-HPV infection and cytologic abnormalities in women with lower genital tract dysplasia/cancer. Impact: These results add to the growing body of evidence suggesting the need for evaluation of screening methods for anal dysplasia/cancer in this patient population to inform evidence-based screening recommendations.

Accuracy of Smartphone Images of the Cervix After Acetic Acid Application for Diagnosing Cervical Intraepithelial Neoplasia Grade 2 or Greater in Women With Positive Cervical Screening: A Systematic Review and Meta-Analysis

PURPOSE Smartphones are used in cervical screening for visual inspection after acetic acid or Lugol's iodine (VIA/VILI) application to capture and share images to improve the sensitivity and interobserver variability of VIA/VILI. We undertook a systematic review and meta-analysis assessing the diagnostic accuracy of smartphone images of the cervix at the time of VIA/VILI (termed S-VIA) in the detection of precancerous lesions in women undergoing cervical screening. METHODS This systematic review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies from January 1, 2010, to June 30, 2020, were assessed. MEDLINE/PubMed, Embase, CINAHL, Cochrane, and LILACS were searched. Cohort and cross-sectional studies were considered. S-VIA was compared with the reference standard of histopathology. We excluded studies where additional technology was added to the smartphone including artificial intelligence, enhanced visual assessment, and other algorithms to automatically diagnose precancerous lesions. The primary outcome was the accuracy of S-VIA for the diagnosis of cervical intraepithelial neoplasia grade 2 or greater (CIN 2+). Data were extracted, and we plotted the sensitivity, specificity, negative predictive value, and positive predictive value of S-VIA using forest plots. This study was prospectively registered with The International Prospective Register of Systematic Reviews:CRD42020204024. RESULTS Six thousand three studies were screened, 71 full texts assessed, and eight studies met criteria for inclusion, with six included in the final meta-analysis. The sensitivity of S-VIA for the diagnosis of CIN 2+ was 74.56% (95% CI, 70.16 to 78.95; I2 61.30%), specificity was 61.75% (95% CI, 56.35 to 67.15; I2 95.00%), negative predictive value was 93.71% (95% CI, 92.81 to 94.61; I2 0%), and positive predictive value was 26.97% (95% CI, 24.13 to 29.81; I2 61.3%). CONCLUSION Our results suggest that S-VIA has accuracy in the detection of CIN 2+ and may provide additional support to health care providers delivering care in low-resource settings.

Hands-On Training Courses for Cervical Cancer Screening, Diagnosis, and Treatment Procedures in Low- and Middle-Income Countries

In 2018, there were approximately 570,000 new cases of cervical cancer worldwide. More than 85% of cases occurred in low- and middle-income countries (LMICs), primarily because of poor access to screening and a limited number of medical providers trained to diagnose and treat cervical precancerous lesions. Our objective was to provide locally arranged, hands-on training courses for medical providers in LMICs to learn to perform cervical cancer screening, diagnosis, and treatment procedures. The courses included didactic lectures and hands-on training stations using low-cost simulation models developed by bioengineers and students at Rice University in Houston, TX, United States, and the Malawi Polytechnic in Blantyre, Malawi. The hands-on training stations included visual inspection with acetic acid (VIA), colposcopy, cervical biopsy, endocervical curettage, loop electrosurgical excision procedure (LEEP), and thermal ablation. Provider pre- and postcourse confidence levels in performing the procedures were evaluated. From February 2017 to January 2020, we arranged 15 hands-on training courses in seven cities across six countries (El Salvador, Mozambique, Trinidad and Tobago, Lesotho, Malawi, and Nepal). Overall, there were 506 participants. The average number of participants per course was 38 (range 19-92). The participants included doctors, nurses, and midwives. The course duration varied from 1 to 3 days. Increased confidence in performing VIA, colposcopy and cervical biopsy, ablation, and LEEP was reported by 69%, 71%, 61%, and 76% of participants, respectively. Our findings suggest that locally arranged, hands-on cervical cancer prevention training courses in LMICs can improve provider confidence in performing cervical cancer screening, diagnosis, and treatment procedures. These courses are part of a larger strategy to build local capacity for delivering and improving cervical cancer prevention services in LMICs.

The Mulher Study: cervical cancer screening with primary HPV testing in Mozambique

To evaluate cervical cancer screening with primary human papillomavirus (HPV) testing in Mozambique, a country with one of the highest burdens of cervical cancer globally. Women aged 30-49 years were prospectively enrolled and offered primary HPV testing using either self-collected or provider-collected specimens. Patients who tested positive for HPV underwent visual assessment for treatment using visual inspection with acetic acid to determine eligibility for thermal ablation. If ineligible, they were referred for excision with a loop electrosurgical excision procedure, for cold knife conization, or for cervical biopsy if malignancy was suspected. Between January 2020 and January 2023, 9014 patients underwent cervical cancer screening. Median age was 37 years (range 30-49) and 4122 women (45.7%) were patients living with HIV. Most (n=8792, 97.5%) chose self-collection. The HPV positivity rate was 31.1% overall and 39.5% among patients living with HIV. Of the 2805 HPV-positive patients, 2588 (92.3%) returned for all steps of their diagnostic work-up and treatment, including ablation (n=2383, 92.1%), loop electrosurgical excision procedure (n=169, 6.5%), and cold knife conization (n=5, 0.2%). Thirty-one patients (1.2%) were diagnosed with cancer and referred to gynecologic oncology. It is feasible to perform cervical cancer screening with primary HPV testing and follow-up in low-resource settings. Participants preferred self-collection, and the majority of screen-positive patients completed all steps of their diagnostic work-up and treatment. Our findings provide important information for further implementation and scale-up of cervical cancer screening and treatment services as part of the WHO global strategy for the elimination of cervical cancer.

Expanding Cervical Cancer Screening in Mozambique: Challenges Associated With Diagnosing and Treating Cervical Cancer

PURPOSE Mozambique has one of the highest burdens of cervical cancer globally. Treatment options are few as most women present with advanced disease, and there are limited trained health professionals and health care resources. The objective of this study was to describe the outcomes of women diagnosed with invasive cancer as part of the Mozambican women undergoing cervical cancer screening with human papillomavirus (HPV) testing in conjunction with family planning services (MULHER) study. MATERIALS AND METHODS Women age 30-49 years were prospectively enrolled in the MULHER study and offered screening with primary HPV testing followed by treatment of screen-positive women with thermal ablation or excision as appropriate. Women with cervical examination findings suspicious for cancer were referred to one of the three gynecologic oncologists in the country. RESULTS Between January 2020 and January 2023, 9,014 women underwent cervical cancer screening and 30 women were diagnosed with cervical cancer. In this cohort, four patients (13.3%) had early-stage disease, 18 (60.0%) had locally advanced disease, one (3.3%) had distant metastatic disease, and seven (23.3%) did not have staging information available. Five patients (16.6%) died without receiving oncologic treatment, and seven patients (23.3%) are still awaiting treatment. Of the remaining 18 patients, three (17.6%) underwent surgery and four (23.5%) received radiotherapy. Eleven (36.7%) patients received only chemotherapy. CONCLUSION As cervical screening programs are implemented in low-resource settings, there will likely be an increase in the number of women diagnosed with invasive cervical cancer. Our results in Mozambique demonstrate the need to increase access to advanced surgery, radiation, and palliative care services.

Conservative Treatment of Stage IA1 Cervical Carcinoma Without Lymphovascular Space Invasion: A 20-year Retrospective Study in Brazil

Abstract Purpose: To evaluate recurrence rates and risk factors among women with stage IA1 cervical cancer without lymph vascular space invasion managed conservatively. Methods: retrospective review of women with stage IA1 squamous cervical cancer who underwent cold knife cone or loop electrosurgical excision procedure, between 1994 and 2015, at a gynecologic oncology center in Southern Brazil. Age at diagnosis, pre-conization findings, conization method, margin status, residual disease, recurrence and survival rates were collected and analyzed. Results: 26 women diagnosed with stage IA1 squamous cervical cancer without lymphovascular space invasion underwent conservative management and had at least 12 months follow-up. The mean follow-up was 44.6 months. The mean age at diagnosis was 40.9 years. Median first intercourse occurred at age 16 years, 11.5% were nulliparous and 30.8% were current or past tobacco smokers. There was one Human immunodeficiency virus positive patient diagnosed with cervical intraepithelial neoplasia grade 2 at 30 months after surgery. However, there were no patients diagnosed with recurrent invasive cervical cancer and there were no deaths due to cervical cancer or other causes in the cohort. Conclusion: Excellent outcomes were noted in women with stage IA1 cervical cancer without lymphovascular space invasion and with negative margins who were managed conservatively, even in a developing country.

A randomized clinical trial to assess the effectiveness of thermal ablation versus loop electrosurgical excision procedure for cervical cancer risk reduction in women living with HIV in Mozambique.

Cervical cancer remains a leading cause of death in low- and middle-income countries. Women living with human immunodeficiency virus (HIV) carry a 6-fold higher risk of cervical cancer than the general population. The effectiveness of thermal ablation versus loop electrosurgical excision procedure (LEEP) in women living with HIV is uncertain, prompting this study. To compare the effectiveness of thermal ablation versus LEEP for the management of abnormal cervical cancer screening results in women living with HIV. Thermal ablation is non-inferior to LEEP for treatment of cervical intra-epithelial neoplasia (CIN) 2/3 and high-risk human papillomavirus (hrHPV) infection in women living with HIV. This is a prospective randomized clinical trial. Participants undergo screening with primary hrHPV testing. Those with positive hrHPV results undergo visual inspection with acetic acid and a review of genotyping results to determine eligibility for treatment. Those who are hrHPV-positive and positive by visual assessment with acetic acid, or human papillomavirus16/18 positive regardless of visual assessment with acetic acid result, are randomized to thermal ablation or LEEP. Participants undergo follow-up at 4 to 8 weeks, 6 months, and 12 months post-procedure. Participants include 25 to 49-year-old women living with HIV in Mozambique. Exclusion criteria include pregnancy, previous total hysterectomy, history of cervical cancer or prior treatment for CIN, or any condition that would preclude adherence to the study protocol. Persistent or recurrent CIN 2/3 (or worse diagnosis) and hrHPV infection at 12 months after initial treatment. To meet our primary objectives and to achieve a power of 0.8 (α = 0.025), we will need to randomize 126 participants with CIN 2/3, 63 to thermal ablation, and 63 to LEEP. We estimate that this will require screening a total of 4844 women living with HIV. We anticipate that study accrual will be completed in 3 years (2027), with an additional 18 months to complete all follow-up visits and data analysis. We anticipate presenting results in 2029. ClinicalTrials.gov #NCT06326294.

Scaling cervical cancer screening in Mozambique: analysis of loop electrosurgical excision procedure (LEEP) specimens

As cervical cancer screening programs are implemented and expanded, an increasing number of women require loop electrosurgical excision procedure (LEEP) for treatment of pre-invasive cervical disease. Our objective was to describe the pathological results of LEEP specimens performed as part of the MULHER study and identify factors associated with positive LEEP margins. The MULHER study enrolled 9014 women who underwent HPV testing followed by visual assessment for treatment (VAT) using visual inspection with acetic acid (VIA) and thermal ablation for those with positive results. Participants with lesions ineligible for ablation underwent LEEP. Pathology reports were reviewed for specimen size/volume, number of fragments, pathological diagnosis and margin status. Multivariable regression analysis was performed to identify variables associated with positive LEEP margins. 169 participants underwent LEEP. The median age was 38 years (range 30-49). 65.1% were women living with HIV. Pathological diagnosis was available for 154 patients and included cancer (n=6, 3.9%); cervical intraepithelial neoplasia (CIN) 2/3 (n=75, 48.7%); CIN 1 (n=67, 43.5%); and normal/benign findings (n=6,3.9%). 31.8% of LEEP specimens were removed in more than one fragment. The mean specimen volume was 2.9 cm Our results showed a high number of LEEP specimens with positive margins. Additional evaluation is needed to better understand the characteristics of precancerous cervical lesions in this high-risk population. As cervical cancer screening programs are scaled in Mozambique and other lower-resource countries, there is a need to train providers to perform high-quality LEEP and for accurate and timely pathological interpretation.

Efficacy of topical treatments for high-risk human papillomavirus in preventing CIN II+ lesions: a systematic review

This study aimed to systematically review the literature regarding topical therapies for reducing the risk of cervical intra-epithelial neoplasia (CIN) grade 2 or higher (CIN II+) lesions among women with high-risk human papillomavirus (HPV) infection and histologically confirmed CIN I or either no cervical lesions. We conducted a systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and registered the protocol in PROSPERO (CRD42024629608). We searched Ovid MEDLINE, Ovid EMBASE, Cochrane Central, and ClinicalTrials.gov from inception through December 16, 2024 for randomized controlled trials evaluating any cervical topical treatment in women with high-risk HPV and, at most, CIN I. The primary outcome was progression to histologically confirmed CIN II+. Secondary outcomes were treatment-related adverse events. Of 305 records, 19 full-text articles were reviewed. Finally, 16 trials were assessed. None met all our eligibility criteria, with some trials being excluded for multiple reasons. Twelve were excluded due to an inadequate study population (included women with CIN II+, lacked histologic confirmation of lesion grade, or lacked confirmatory high-risk HPV testing), 4 used inappropriate interventions, and 2 did not include a placebo or watchful waiting comparator. Although many studies reported HPV clearance or cytologic regression, none were powered or designed to assess progression to CIN II+. The current evidence from randomized trials is insufficient to determine whether topical cervical therapies reduce the risk of progression to CIN II+ in women with high-risk HPV infection. Future trials should prioritize histologic outcomes and adhere to current management protocols to establish the clinical utility of such therapies.