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1.
Artículo en Inglés | MEDLINE | ID: mdl-39152278

RESUMEN

PURPOSE: Cervical screening is used to detect and treat precancers to prevent invasive cancers. However, successful prevention also requires adequate follow-up and treatment of individuals with abnormal screening results. The aim was to investigate demographics, clinical characteristics, and follow-up status for individuals needing colposcopy after an abnormal screening result. METHODS: The STRIDES (Studying Risk to Improve DisparitiES) cohort comprises individuals undergoing cervical cancer screening and management at a Mississippi Health Department or University of Mississippi clinic. Follow-up status, demographics, and clinical data were assessed from electronic health records and, if necessary, patient navigation on individuals identified as needing a colposcopy after an abnormal screening. RESULTS: Of the 1,458 individuals requiring colposcopy, 43.0% had the procedure within 4 months, 16.4% had a delayed procedure, and 39.5% had no documented colposcopy follow-up, with significant predictors of follow-up identified as age and cytology diagnosis. Individuals 30 + were more likely to have follow up with a colposcopy compared to individuals < 30 years (49% and 38.7%, respectively; p < .001). Individuals with cytology diagnoses of LSIL (52.9%), ASC-H (51.4%), and HSIL (62.3%) had higher percentages of adherence to follow-up guidelines (p < .001). In total, we found that 78% of individuals had some type of follow-up, including a repeat screening visit. CONCLUSION: Despite high cervical cancer screening rates among Mississippians, a substantial proportion did not have adequate next-step intervention. However, it is encouraging that highest risk individuals were more likely to have a colposcopy. Regardless, continuing to understand the underlying causes for incomplete follow-up is crucial for timely secondary targeted interventions to reduce cervical cancer burden, promote awareness, and improve health outcomes.

2.
J Med Virol ; 96(3): e29475, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38415472

RESUMEN

To investigate age and type-specific prevalences of high-risk human papillomavirus (hrHPV) and cervical intraepithelial neoplasia (CIN) in hrHPV+ women referred to colposcopy. This is a retrospective, multicenter study. Participants were women referred to one of seven colposcopy clinics in China after testing positive for hrHPV. Patient characteristics, hrHPV genotyping, colposcopic impressions, and histological diagnoses were abstracted from electronic records. Main outcomes were age-related type-specific prevalences associated with hrHPV and CIN, and colposcopic accuracy. Among 4419 hrHPV+ women referred to colposcopy, HPV 16, 52, and 58 were the most common genotypes. HPV 16 prevalence was 39.96%, decreasing from 42.57% in the youngest group to 30.81% in the eldest group. CIN3+ prevalence was 15.00% and increased with age. As lesion severity increases, HPV16 prevalence increased while the prevalence of HPV 52 and 58 decreased. No age-based trend was identified with HPV16 prevalence among CIN2+, and HPV16-related CIN2+ was less common in women aged 60 and above (44.26%) compared to those younger than 60 years (59.61%). Colposcopy was 0.73 sensitive at detecting CIN2+ (95% confidence interval[CI]: 0.71, 0.75), with higher sensitivity (0.77) observed in HPV16+ women (95% CI: 0.74, 0.80) compared to HPV16- women (0.68, 95% CI: 0.64, 0.71). Distributions of hrHPV genotypes, CIN, and type-specific CIN in Chinese mainland hrHPV+ women referred to colposcopy were investigated for the first time. Distributions were found to be age-dependent and colposcopic performance appears related to HPV genotypes. These findings could be used to improve the management of women referred to colposcopy.


Asunto(s)
Infecciones por Papillomavirus , Displasia del Cuello del Útero , Neoplasias del Cuello Uterino , Femenino , Humanos , Embarazo , Colposcopía , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/epidemiología , Neoplasias del Cuello Uterino/patología , Estudios Retrospectivos , Infecciones por Papillomavirus/diagnóstico , Infecciones por Papillomavirus/epidemiología , Infecciones por Papillomavirus/complicaciones , Displasia del Cuello del Útero/epidemiología , Genotipo , Papillomavirus Humano 16/genética , Papillomaviridae/genética , Detección Precoz del Cáncer
3.
J Med Virol ; 96(10): e70016, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39415343

RESUMEN

The concordance rate between conization and colposcopy-directed biopsy (CDB) proven cervical high-grade squamous intraepithelial lesion (HSIL) were 64-85%. We aimed to identify the risk factors associated with pathological upgrading or downgrading after conization in patients with cervical HSIL and to provide risk-stratified management based on a machine learning predictive model. This retrospective study included patients who visited the Obstetrics and Gynecology Hospital of Fudan University from January 1 to December 31, 2019, were diagnosed with cervical HSIL by CDB, and subsequently underwent conization. A wide variety of data were collected from the medical records, including demographic data, laboratory findings, colposcopy descriptions, and pathological results. The patients were categorized into three groups according to their postconization pathological results: low-grade squamous intraepithelial lesion (LSIL) or below (downgrading group), HSIL (HSIL group), and cervical cancer (upgrading group). Univariate and multivariate analyses were performed to identify the independent risk factors for pathological changes in patients with cervical HSIL. Machine learning prediction models were established, evaluated, and subsequently verified using external testing data. In total, 1585 patients were included, of whom 65 (4.1%) were upgraded to cervical cancer after conization, 1147 (72.4%) remained having HSIL, and 373 (23.5%) were downgraded to LSIL or below. Multivariate analysis showed a 2% decrease in the incidence of pathological downgrade for each additional year of age and a 1% increase in lesion size. Patients with cytology > LSIL (odds ratio [OR] = 0.33; 95% confidence interval [CI], 0.21-0.52), human papillomavirus (HPV) infection (OR = 0.33; 95% CI, 0.14-0.81), HPV 33 infection (OR = 0.37; 95% CI, 0.18-0.78), coarse punctate vessels on colposcopy examination (OR = 0.14; 95% CI, 0.06-0.32), HSIL lesions in the endocervical canal (OR = 0.48; 95% CI, 0.30-0.76), and HSIL impression (OR = 0.02; 95% CI, 0.01-0.03) were less likely to experience pathological downgrading after conization than their counterparts. The independent risk factors for pathological upgrading to cervical cancer after conization included the following: age (OR = 1.08; 95% CI, 1.04-1.12), HPV 16 infection (OR = 4.07; 95% CI, 1.70-9.78), the presence of coarse punctate vessels during colposcopy examination (OR = 2.21; 95% CI, 1.08-4.50), atypical vessels (OR = 6.87; 95% CI, 2.81-16.83), and HSIL lesions in the endocervical canal (OR = 2.91; 95% CI, 1.46-5.77). Among the six machine learning prediction models, the back propagation (BP) neural network model demonstrated the highest and most uniform predictive performance in the downgrading, HSIL, and upgrading groups, with areas under the curve (AUCs) of 0.90, 0.84, and 0.69; sensitivities of 0.74, 0.84, and 0.42; specificities of 0.90, 0.71, and 0.95; and accuracies of 0.74, 0.84, and 0.95, respectively. In the external testing set, the BP neural network model showed a higher predictive performance than the logistic regression model, with an overall AUC of 0.91. Therefore, a web-based prediction tool was developed in this study. BP neural network prediction model has excellent predictive performance and can be used for the risk stratification of patients with CDB-diagnosed HSIL.


Asunto(s)
Aprendizaje Automático , Neoplasias del Cuello Uterino , Humanos , Femenino , Estudios Retrospectivos , Adulto , Persona de Mediana Edad , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/cirugía , Neoplasias del Cuello Uterino/virología , Neoplasias del Cuello Uterino/diagnóstico , Factores de Riesgo , Conización/métodos , Displasia del Cuello del Útero/patología , Displasia del Cuello del Útero/virología , Displasia del Cuello del Útero/cirugía , Lesiones Intraepiteliales Escamosas de Cuello Uterino/patología , Lesiones Intraepiteliales Escamosas de Cuello Uterino/cirugía , Colposcopía/métodos , Anciano , Biopsia , Adulto Joven , Cuello del Útero/patología , Cuello del Útero/virología , Cuello del Útero/cirugía , Infecciones por Papillomavirus/virología , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/patología , Lesiones Intraepiteliales Escamosas/patología , Lesiones Intraepiteliales Escamosas/virología , Lesiones Intraepiteliales Escamosas/cirugía
4.
BMC Cancer ; 24(1): 349, 2024 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-38504211

RESUMEN

BACKGROUND: Colposcopy plays an essential role in diagnosing cervical lesions and directing biopsy; however, there are few studies of the capabilities of colposcopists in medically underserved communities in China. This study aims to fill this gap by assessing colposcopists' competencies in medically underserved communities of China. METHODS: Colposcopists in medically underserved communities across China were considered eligible to participate. Assessments involved presenting participants with 20 cases, each consisting of several images and various indications. Participants were asked to determine transformation zone (TZ) type, colposcopic diagnoses and to decide whether biopsy was necessary. Participants are categorized according to the number of colposcopic examinations, i.e., above or below 50 per annum. RESULTS: There were 214 participants in this study. TZ determination accuracy was 0.47 (95% CI 0.45,0.49). Accuracy for colposcopic diagnosis was 0.53 (95% CI 0.51,0.55). Decision to perform biopsies was 0.73 accurate (95% CI 0.71,0.74). Participants had 0.61 (95% CI 0.59,0.64) sensitivity and a 0.80 (95% CI 0.79,0.82) specificity for detecting high-grade lesions. Colposcopists who performed more than 50 cases were more accurate than those performed fewer across all indicators, with a higher sensitivity (0.66 vs. 0.57, p = 0.001) for detecting high-grade lesions. CONCLUSIONS: In medically underserved communities of China, colposcopists appear to perform poorly at TZ identification, colposcopic diagnosis, and when deciding to biopsy. Colposcopists who undertake more than 50 colposcopies each year performed better than those who perform fewer. Therefore, colposcopic practice does improve through case exposure although there is an urgent need for further pre-professional and clinical training.


Asunto(s)
Colposcopía , Neoplasias del Cuello Uterino , Femenino , Embarazo , Humanos , Colposcopía/métodos , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/patología , Área sin Atención Médica , Biopsia/métodos , China
5.
BMC Cancer ; 24(1): 780, 2024 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-38943072

RESUMEN

OBJECTIVE: Exploring the predictive value of NLR, PLR, MLR, and SII for the severity of cervical cancer screening abnormalities in patients. METHODS: A retrospective analysis was conducted on the data of 324 patients suspected of cervical lesions due to abnormal TCT and/or HPV in our hospital from January 2023 to December 2023, who underwent colposcopy. The pathological results of colposcopic biopsy confirmed that there were 140 cases of chronic cervicitis, which classified as the group without cervical lesions. The cervical lesion group included 184 cases, including 91 cases of LSIL, 71 cases of HSIL, and 22 cases of cervical cancer. Compared the differences in preoperative peripheral blood NLR, PLR, MLR, and SII among different groups of patients, and evaluated their predictive value for the severity of cervical lesions using Receiver Operating Characteristic (ROC) curves. RESULTS: The levels of NLR, PLR, and SII in the group without cervical lesions were lower than those in the group with cervical lesions (p < 0.05), and there was no statistically significant difference in MLR (p > 0.05). The comparison of NLR among LSIL, HSIL, and cervical cancer groups showed statistically significant differences (p < 0.05), while PLR, MLR, and SII showed no statistically significant differences (p > 0.05). The AUC of peripheral blood NLR, PLR, and SII for predicting cervical lesions were 0.569, 0.582, and 0.572, respectively. The optimal cutoff values were 2.3,176.48, and 603.56. The sensitivity and specificity were 38.6% and 73.6%, 28.8% and 85.7%, 37.5% and 76.4%, respectively. At the same time, the joint testing of the three had the highest efficiency, with sensitivity of 69% and specificity of 45%. CONCLUSION: Although the peripheral blood NLR, PLR, and SII of the cervical lesions patients were higher than those without cervical lesions in cervical cancer screening abnormal patients, the predictive ROC curve discrimination was low. Therefore, it is not recommended to use preoperative peripheral blood inflammatory markers as markers for cervical cancer screening abnormal patient diversion.


Asunto(s)
Neoplasias del Cuello Uterino , Humanos , Femenino , Neoplasias del Cuello Uterino/sangre , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/patología , Estudios Retrospectivos , Adulto , Persona de Mediana Edad , Curva ROC , Valor Predictivo de las Pruebas , Displasia del Cuello del Útero/sangre , Displasia del Cuello del Útero/diagnóstico , Displasia del Cuello del Útero/patología , Detección Precoz del Cáncer/métodos , Colposcopía , Índice de Severidad de la Enfermedad , Biomarcadores de Tumor/sangre , Neutrófilos/patología , Inflamación/sangre
6.
BMC Cancer ; 24(1): 913, 2024 Jul 29.
Artículo en Inglés | MEDLINE | ID: mdl-39080593

RESUMEN

BACKGROUND: In China, the national cervical cancer screening protocol involves initial testing for high-risk human papillomavirus (hrHPV), followed by cytology for hrHPV-positive cases. This study evaluates the effectiveness of PAX1 methylation (PAX1m) analysis in identifying precancerous or cancerous lesions in cervical samples from Chinese women positive for non-16/18 hrHPV strains. METHODS: Between February 2022 and March 2023, 281 cervical samples from non-16/18 hrHPV-positive women underwent cytological examination and PAX1m analysis. The study assessed the statistical relationship between PAX1m levels and the presence of cervical lesions, comparing the diagnostic performance of PAX1m to conventional cytology. RESULTS: A significant association was found between PAX1 methylation levels and the risk of CIN2 + and CIN3 + lesions, with 47 instances of CIN2 + detected. Odds ratios (ORs) for moderate and high PAX1m levels were 8.86 (95% CI: 2.24-42.17) and 166.32 (95% CI: 47.09-784.97), respectively. The area under the ROC curve for PAX1m in identifying CIN2 + lesions was 0.948 (95% CI: 0.895-0.99). PAX1m demonstrated similar sensitivity and negative predictive value (NPV) to cytology but reduced the colposcopy referral rate from 47.7% with cytology alone to 25.6% with PAX1m, showing superior specificity and positive predictive value across age groups. CONCLUSIONS: PAX1 methylation is a strong indicator of CIN2 + and CIN3 + risk, offering diagnostic performance comparable to cytology with the added benefit of reduced unnecessary colposcopy referrals. These findings support the use of PAX1m analysis as a reliable tool for triaging non-16/18 hrHPV-positive women in outpatient settings.


Asunto(s)
Metilación de ADN , Detección Precoz del Cáncer , Factores de Transcripción Paired Box , Infecciones por Papillomavirus , Triaje , Displasia del Cuello del Útero , Neoplasias del Cuello Uterino , Humanos , Femenino , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/virología , Neoplasias del Cuello Uterino/genética , Persona de Mediana Edad , Detección Precoz del Cáncer/métodos , Adulto , Factores de Transcripción Paired Box/genética , Infecciones por Papillomavirus/virología , Infecciones por Papillomavirus/diagnóstico , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/genética , Triaje/métodos , Displasia del Cuello del Útero/diagnóstico , Displasia del Cuello del Útero/virología , Displasia del Cuello del Útero/genética , China/epidemiología , Anciano , Curva ROC , Biomarcadores de Tumor/genética , Frotis Vaginal
7.
BMC Cancer ; 24(1): 381, 2024 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-38528547

RESUMEN

BACKGROUND: Inaccurate colposcopy diagnosis may lead to inappropriate management and increase the incidence of cervical cancer. This study aimed to evaluate the diagnostic accuracy of colposcopy in the detection of histologic cervical intraepithelial neoplasia grade 2 or worse (CIN2+) in women with transformation zone type 3 (TZ3). METHODS: Records from 764 patients with TZ3 who underwent colposcopy-directed biopsy and/or endocervical curettage in Putuo Hospital China between February 2020 and March 2023 were retrospectively collected. Colposcopy was carried out based on 2011 International Federation of Cervical Pathology and Colposcopy (IFCPC) and Colposcopy nomenclature. The diagnostic performance of colposcopy for identifying CIN2 + was evaluated compared with biopsies. The Kappa and McNemar tests were used to perform statistical analyses. RESULTS: Among the study population, 11.0% had pathologic CIN2+. The relative sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of colposcopy for histologic CIN2 + were 51.2%, 96.5%, 64.2% and 94.1%, respectively. The senior colposcopists (80.6%) had a higher colposcopic accuracy to diagnose histologic CIN2 + than junior colposcopists (68.6%). In subgroup analyses, age group ≥ 60 years (70.3%) showed lowest diagnostic accuracy when compared with age groups of < 45 years (84.4%) and 45-59 years (74.9%). CONCLUSION: Our findings suggest an increased risk of diagnostic inaccuracy of colposcopy in identifying CIN2 + in those ≥ 60 years of age with TZ3, and the accuracy of colposcopy is required to be further improved.


Asunto(s)
Lesiones Intraepiteliales Escamosas , Displasia del Cuello del Útero , Neoplasias del Cuello Uterino , Humanos , Femenino , Embarazo , Persona de Mediana Edad , Colposcopía , Estudios Retrospectivos , Cuello del Útero/patología , Displasia del Cuello del Útero/diagnóstico , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/patología , Biopsia
8.
Virol J ; 21(1): 164, 2024 Jul 29.
Artículo en Inglés | MEDLINE | ID: mdl-39075510

RESUMEN

Cervical cancer is one of the most common malignant tumours. Human papillomavirus (HPV) infection is the main cause of this cancer so that it could be prevented by screening and early treatment. Developing reginal screen protocols of maximum public health efficacy requires in-depth understandings of local HPV distribution and consequential cancer risks. Therefore, test results of HPV genotyping, cytology testing (TCT) and colposcopy inspection with biopsy were collected in this retrospective research. Data included by this research involved 63,906 women received screen related tests from Shenzhen Baoan Shiyan People's Hospital and the subsidiary institutes between 2017.01 and 2023.05. 10,238 colposcopies were performed in this period collecting 8,716 samples and 814 high-grade CIN were discovered. Within the 763 high-grade CIN cases with both TCT and HPV testing results, 232 were tested cytologically normal but only 30 were negative in HPV test. Besides, the rates of high-grade CIN observed in coinfection were all lower than the estimated rates generated from related single infection. HPV 52, 58 and 16 were found to be the most common types in Baoan, Shenzhen. The result also suggested that HPV coinfections should not increase risk for cervical cancers.


Asunto(s)
Coinfección , Genotipo , Papillomaviridae , Infecciones por Papillomavirus , Neoplasias del Cuello Uterino , Humanos , Femenino , Infecciones por Papillomavirus/virología , Infecciones por Papillomavirus/epidemiología , Infecciones por Papillomavirus/complicaciones , Neoplasias del Cuello Uterino/virología , Neoplasias del Cuello Uterino/epidemiología , China/epidemiología , Coinfección/virología , Coinfección/epidemiología , Adulto , Estudios Retrospectivos , Papillomaviridae/genética , Papillomaviridae/aislamiento & purificación , Papillomaviridae/clasificación , Persona de Mediana Edad , Adulto Joven , Displasia del Cuello del Útero/virología , Displasia del Cuello del Útero/epidemiología , Colposcopía , Detección Precoz del Cáncer , Anciano
9.
Gynecol Oncol ; 190: 160-166, 2024 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-39197415

RESUMEN

OBJECTIVE: In 2012, updated ASCCP management guidelines for abnormal cervical cytology recommended observation rather than immediate referral to colposcopy for low-grade abnormalities in women ages 21-24. We evaluated the impact of these guidelines on changes in colposcopy procedure rates among young women. METHODS: We analyzed administrative and claims data from the largest statewide family planning program between July 2011 and June 2015. Using a difference-in-differences approach, we estimated changes in colposcopy procedure rates among women ages 21-24 years before and after the 2012 ASCCP management guidelines, relative to a comparison group of women ages 25-44. RESULTS: Our analysis included 333,977 women from 216 primary care provider sites. After publication of the 2012 ASCCP management guidelines, colposcopy rates significantly declined from 6.70% (95% CI 6.21-7.19) to 3.94% (95% CI 3.60-4.29) among women ages 21-24 and from 4.35% (95% CI 4.03-4.67) to 3.53% (3.25-3.80) among women over 24 years. These declines correspond to a 1.93 percentage point reduction (95% CI 1.62-2.25; p < 0.001) in colposcopy rate among women 21-24 vs. over 24 years, or a two-fold relative reduction. Among women ages 21-24, colposcopy receipt was associated with speaking primarily English vs. non-English (OR 1.46, 95% CI 1.35-1.57), having a cervical cytology test within the past year vs. not (OR 1.55, 95% CI 1.44-1.66), and receiving care from a public vs. private provider (OR 1.31, 95% CI 1.06-1.62). CONCLUSIONS: Colposcopy procedure rates among young women significantly declined following publication of the 2012 management guidelines, which has implications for reducing potential harms of overtreatment.

10.
Cancer Control ; 31: 10732748241244678, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38563112

RESUMEN

INTRODUCTION: Women living with HIV (WLHIV) have higher prevalence and persistence rates of high-risk human papillomavirus (hr-HPV) infection with a six-fold increased risk of cervical cancer. Thus, more frequent screening is recommended for WLHIV. OBJECTIVES: This retrospective descriptive cross-sectional study was conducted to investigate and compare the prevalence of hr-HPV infection and abnormal findings on mobile colposcopy in two cohorts of WLHIV following cervical screening in rural and urban settings in Ghana. METHODS: Through the mPharma 10 000 Women Initiative, WLHIV were screened via concurrent hr-HPV DNA testing (MA-6000; Sansure Biotech Inc., Hunan, China) and visual inspection (Enhanced Visual Assessment [EVA] mobile colposcope; MobileODT, Tel Aviv, Israel) by trained nurses. The women were screened while undergoing routine outpatient reviews at HIV clinics held at the Catholic Hospital, Battor (rural setting) and Tema General Hospital (urban setting), both in Ghana. RESULTS: Two-hundred and fifty-eight WLHIV were included in the analysis (rural, n = 132; urban, n = 126). The two groups were comparable in terms of age, time since HIV diagnosis, and duration of treatment for HIV. The hr-HPV prevalence rates were 53.7% (95% CI, 45.3-62.3) and 48.4% (95% CI, 39.7-57.1) among WLHIV screened in the rural vs urban settings (p-value = .388). Abnormal colposcopy findings were found in 8.5% (95% CI, 5.1-11.9) of the WLHIV, with no significant difference in detection rates between the two settings (p-value = .221). Three (13.6%) of 22 women who showed abnormal colposcopic findings underwent loop electrosurgical excision procedure (LEEP), leaving 19/22 women from both rural and urban areas with pending treatment/follow-up results, which demonstrates the difficulty faced in reaching early diagnosis and treatment, regardless of their area of residence. Histopathology following LEEP revealed CIN III in 2 WLHIV (urban setting, both hr-HPV negative) and CIN I in 1 woman in the rural setting (hr-HPV positive). CONCLUSIONS: There is a high prevalence of hr-HPV among WLHIV in both rural and urban settings in this study in Ghana. Concurrent HPV DNA testing with a visual inspection method (colposcopy/VIA) reduces loss to follow-up compared to performing HPV DNA testing as a standalone test and recalling hr-HPV positive women for follow up with a visual inspection method. Concurrent HPV DNA testing and a visual inspection method may also pick up precancerous cervical lesions that are hr-HPV negative and may be missed if HPV DNA testing is performed alone.


Asunto(s)
Infecciones por VIH , Infecciones por Papillomavirus , Lesiones Precancerosas , Displasia del Cuello del Útero , Neoplasias del Cuello Uterino , Embarazo , Femenino , Humanos , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/epidemiología , Neoplasias del Cuello Uterino/patología , Colposcopía , Detección Precoz del Cáncer/métodos , Estudios Transversales , Estudios Retrospectivos , Ghana , Papillomaviridae/genética , Displasia del Cuello del Útero/diagnóstico , Displasia del Cuello del Útero/epidemiología , Tamizaje Masivo/métodos , Lesiones Precancerosas/diagnóstico , Lesiones Precancerosas/epidemiología , Infecciones por VIH/diagnóstico , Infecciones por VIH/epidemiología
11.
BMC Infect Dis ; 24(1): 558, 2024 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-38834951

RESUMEN

In January 2020, a different cervical cancer screening program started in Germany. Women above the age of 35 are recommended to have a combined HPV and cytology swab every three years. Showing persistent high-risk human papillomavirus (hrHPV), cytologic negative cervical samples at baseline and after 12 months, patients are referred to colposcopy. Entailing considerable additional workload due to the required colposcopies, we analyzed the risk of high-grade cervical intraepithelial neoplasia (CIN 3) in cytologic negative and persistent hrHPV women according to their hrHPV genotypes.Methods In this single center retrospective study, patients with persistent hrHPV, cytology negative cervical samples from our certified Colposcopy Unit in 2020 and 2021 were analyzed. Patient demographics, hrHPV types, biopsy rates and histological reports were collected.Results During the study, 69 patients were enrolled. Most frequent hrHPV genotypes were: hrHPV other 72.5%; HPV 16, 20.3% and HPV 18, 7.2%. Colposcopy showed no or minor changes in 92.7% and major changes in 7.2%. CIN 3 was found in 7 patients (10.1%). Prevalence of CIN 3 by hrHPV genotypes was 27.3% for HPV16, 20.0% for HPV18 and 7.1% for HPVO. A statistically significant dependency between hrHPV and cervical intraepithelial neoplasia was demonstrated (p = 0.048).Conclusion Within this single center study of persistent hrHPV, cytologic negative samples, patients with HPV 16 were more likely to have high-grade disease compared to other hrHPV subtypes. Larger prospective randomized trials are needed to substantiate our results and obtain adjusted cervical cancer screening time intervals according to the hrHPV genotypes.


Asunto(s)
Colposcopía , Genotipo , Papillomaviridae , Infecciones por Papillomavirus , Displasia del Cuello del Útero , Neoplasias del Cuello Uterino , Humanos , Femenino , Estudios Retrospectivos , Infecciones por Papillomavirus/virología , Adulto , Persona de Mediana Edad , Neoplasias del Cuello Uterino/virología , Neoplasias del Cuello Uterino/patología , Displasia del Cuello del Útero/virología , Displasia del Cuello del Útero/patología , Displasia del Cuello del Útero/epidemiología , Papillomaviridae/genética , Papillomaviridae/aislamiento & purificación , Papillomaviridae/clasificación , Alemania/epidemiología , Anciano , Detección Precoz del Cáncer , Cuello del Útero/virología , Cuello del Útero/patología , Virus del Papiloma Humano
12.
BJOG ; 131(3): 309-318, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37408516

RESUMEN

OBJECTIVE: Human papillomavirus (HPV) integration is a crucial genetic step in cervical carcinogenesis. This study aimed to evaluate the performance of an HPV integration test for the triage of HPV-positive women. DESIGN: An observational cohort study. SETTING: A cervical cancer screening programme in China. POPULATION: 1393 HPV-positive women aged 25-65 years undergoing routine cervical cancer screening and HPV integration testing with 1-year follow-up. METHODS: The sensitivity, specificity, positive predictive value and negative predictive value between HPV integration and cytology were compared. MAIN OUTCOME MEASURES: Cervical intraepithelial neoplasia grade 3 or more severe (CIN3+). RESULTS: Among 1393 HPV-positive patients, 138 (9.9% [8.3-11.5%]) were HPV integration test positive compared with 537 who had abnormal cervical cytology (38.5% [36.0-41.1%]). Compared with cytology, HPV integration exhibited higher specificity (94.5% [93.3-95.8%] versus 63.8% [61.2-66.4%]) and equivalent sensitivity (70.5% [61.4-79.7%] versus 70.5% [61.4-79.7%]) for detection of CIN3+. HPV integration-negative women accounted for 90.1% (1255/1393) of the total population and had a low immediate CIN3+ risk (2.2%). At 1-year follow-up, the progression rate in the HPV integration-positive women was higher than in the HPV integration-negative women (12.0% versus 2.1%, odds ratio 5.6, 95% CI, 2.6-11.9). In 10 conservatively managed integration-negative CIN2 patients, all showed spontaneous regression and seven showed HPV clearance after 1-year follow-up. CONCLUSION: The HPV integration test may be a precise risk stratification tool for HPV-positive women and could avoid excessive use of invasive biopsies.


Asunto(s)
Infecciones por Papillomavirus , Displasia del Cuello del Útero , Neoplasias del Cuello Uterino , Humanos , Femenino , Embarazo , Neoplasias del Cuello Uterino/patología , ADN Viral , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/diagnóstico , Detección Precoz del Cáncer , Displasia del Cuello del Útero/diagnóstico , Estudios de Cohortes , Papillomaviridae/genética , Frotis Vaginal , Colposcopía
13.
Acta Obstet Gynecol Scand ; 103(9): 1745-1752, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38922851

RESUMEN

INTRODUCTION: Colposcopy is an important part of the diagnostic work-up of women with an abnormal cervical screening test as it is used to guide the collection of biopsies. Although quality assurance has been used in the evaluation of screening programs, not much is known about quality indicators for the diagnostics and treatment of screen-positive women. Therefore, the European Federation for Colposcopy developed quality indicators aiming to support colposcopy practice across Europe. We performed a survey of colposcopy cases to determine if the quality indicators are understandable, relevant, and reproducible. MATERIAL AND METHODS: We conducted a survey among all members of the European Federation for Colposcopy Quality and Standards Group from November 2022 to March 2023. Members were asked to collect information on a total of 17 quality indicators for 50 women who had been newly referred for colposcopy due to an abnormal screening test between January 1, 2020 to December 31, 2021. Results were reported descriptively. RESULTS: We included data on 609 cases from 12 members across Europe. The majority of the quality indicators were either achieved or within reach of the agreed standard, often due to few countries with outlying data. One quality indicator had very low performance, although stratified results indicated that two countries had different clinical management of the patient type thereby skewing the results. In addition, discrepancies between the number of cases included in each quality indicator raised concerns regarding potential misunderstanding of the quality indicator and its objective. CONCLUSIONS: Quality indicators on colposcopy must be understandable to those collecting data, highlighting the importance of validating quality indicators before data collection.


Asunto(s)
Colposcopía , Indicadores de Calidad de la Atención de Salud , Neoplasias del Cuello Uterino , Humanos , Colposcopía/normas , Colposcopía/estadística & datos numéricos , Femenino , Europa (Continente) , Reproducibilidad de los Resultados , Adulto , Neoplasias del Cuello Uterino/diagnóstico , Encuestas y Cuestionarios , Persona de Mediana Edad , Sociedades Médicas , Detección Precoz del Cáncer/normas
14.
BMC Womens Health ; 24(1): 189, 2024 Mar 21.
Artículo en Inglés | MEDLINE | ID: mdl-38515088

RESUMEN

OBJECTIVE: To determine whether knowledge of cytology affects the colposcopist's diagnostic accuracy in the identification of cervical intraepithelial neoplasia grade 2 and worse (≥ CIN2). METHOD: In this cross-over study, healthcare professionals interpreted colposcopy images from 80 patient cases with known histological diagnoses. For each case, 2 images taken with a colposcope were provided (native and after acetic acid application). Inclusion criteria consisted of women with a transformation zone type 1 or 2, who had both a cytological and histological diagnosis. Cases were distributed across two online surveys, one including and one omitting the cytology. A wash-out period of six weeks between surveys was implemented. Colposcopists were asked to give their diagnosis for each case as < CIN2 or ≥ CIN2 on both assessments. Statistical analysis was conducted to compare the two interpretations. RESULTS: Knowledge of cytology significantly improved the sensitivity when interpreting colposcopic images, from 51.1% [95%CI: 39.3 to 62.8] to 63.7% [95%CI: 52.1 to 73.9] and improved the specificity from 63.5% [95%CI: 52.3 to 73.5] to 76.6% [95%CI: 67.2 to 84.0]. Sensitivity was higher by 38.6% when a high-grade cytology (ASC-H, HSIL, AGC) was communicated compared to a low-grade cytology (inflammation, ASC-US, LSIL). Specificity was higher by 31% when a low-grade cytology was communicated compared to a high-grade. CONCLUSIONS: Our data suggests that knowledge of cytology increases sensitivity and specificity for diagnosis of ≥ CIN2 lesions at colposcopy. Association between cytology and histology may have contributed to the findings.


Asunto(s)
Infecciones por Papillomavirus , Displasia del Cuello del Útero , Neoplasias del Cuello Uterino , Femenino , Humanos , Colposcopía/métodos , Estudios Cruzados , Citodiagnóstico , Papillomaviridae , Infecciones por Papillomavirus/diagnóstico , Displasia del Cuello del Útero/diagnóstico , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/patología , Frotis Vaginal/métodos
15.
BMC Public Health ; 24(1): 952, 2024 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-38566137

RESUMEN

BACKGROUND: Urogenital schistosomiasis (UgS) remains a persistent health challenge among adolescents in Anambra State, Nigeria, despite ongoing control efforts. Mass praziquantel treatment programs, initiated in 2013, primarily target primary school-aged children (5-14 years old), leaving adolescents (10-19 years old) enrolled in secondary schools vulnerable to urogenital schistosomiaisis. Additionally, the extent of female genital schistosomiasis (FGS), a neglected gynaecological manifestation of UgS remains unclear. METHODOLOGY: To address these gaps, a cross-sectional study was conducted in Anaocha Local Government Area from February to May 2023. Four hundred and seventy consenting adolescents aged 10-19 years were enrolled. Urinalysis including urine filtration was employed to confirm haematuria and detect urogenital schistosomiasis (UGS) among the participants. For females with heavy infections (≥ 50 eggs/10 ml urine), a gynaecologist performed colposcopy examinations, complemented by acetic acid and Lugol's iodine staining to assess for female genital schistosomiasis (FGS) lesions or other related reproductive health conditions. Socio-demographic data, including information on potential risk factors, were systematically collected using the Kobo ToolBox software, following gender-sensitive data collection guidelines. Data were analysed using SPSS version 25, incorporating descriptive statistics, multinomial logistic regression, odds ratios, and significance testing. RESULTS: Among the 470 adolescents (52.8% females, 47.2% males) examined, an overall UgS prevalence of 14.5% was observed, with an average of 5.25 eggs per 10 ml of urine. Females had a slightly higher prevalence (16.1%), and 7.5% had heavy infections. Although gender differences in infection rates were not statistically significant, males had slightly higher odds of infection (OR: 1.332; 95% CI: 0.791-2.244; p-value: 0.280). Adolescents aged 10-14 had the highest prevalence, with significantly increased odds of infection (OR: 1.720; 95% CI: 1.012-2.923; p-value: 0.045). Colposcopy examinations of females with heavy infections revealed FGS lesions and co-infections with Trichomonas vaginalis. Haematuria, though prevalent (24.6%), was not the sole indicator, as those without it faced significantly higher odds of infection (OR: 2.924; 95% CI: 1.731-4.941; p-value: 0.000). Dysuria and genital itching/burning sensation were other UgS and FGS associated symptoms. Direct water contact was associated with higher infection odds (OR: 2.601; 95% CI: 1.007-6.716; p-value: 0.048). Various risk factors were associated with UgS. CONCLUSION: The study highlights the need for a comprehensive Urogenital Schistosomiasis (UGS) control strategy that includes secondary school adolescents, emphasizes risk factor management, promotes safe water practices, and raises awareness about UGS and Female Genital Schistosomiasis (FGS) among adolescents, thus improving control efforts and mitigating this health challenge in the region.


Asunto(s)
Esquistosomiasis Urinaria , Masculino , Niño , Humanos , Femenino , Adolescente , Preescolar , Adulto Joven , Adulto , Animales , Esquistosomiasis Urinaria/diagnóstico , Esquistosomiasis Urinaria/epidemiología , Estudios Transversales , Hematuria/epidemiología , Nigeria/epidemiología , Genitales Femeninos , Prevalencia , Agua , Schistosoma haematobium
16.
J Obstet Gynaecol Can ; 46(12): 102668, 2024 Sep 26.
Artículo en Inglés | MEDLINE | ID: mdl-39341496

RESUMEN

OBJECTIVES: Cervical cancer is on the rise in Canada. Addressing patient anxiety and improving patient understanding of colposcopy and results may improve adherence. This randomized controlled trial examined the impact of colposcopy results delivery by a Nurse Liaison versus the referring primary care provider (PCP) on patient anxiety, and secondary outcomes including patient satisfaction, knowledge of diagnosis, and 9-month adherence to follow-up. METHODS: Patients ≥18 years old presenting for initial appointment at the study colposcopy clinic were randomized 1:1 to an intervention group (Nurse Liaison) versus a control group (PCP). After receiving colposcopy results, participants completed online measures of anxiety (State-Trait Anxiety Inventory), health care satisfaction scales (Patient Satisfaction Questionnaire-18, Health Anxiety Inventory, Visit-Specific Satisfaction Questionnaire-9), self-reported colposcopy diagnosis, and demographics. Chart review at 9 months assessed adherence to recommended colposcopy follow-up. Groups were compared on continuous and categorical variables, controlling for diagnosis severity and trait anxiety. RESULTS: The intervention group had significantly lower state anxiety with State-Trait Anxiety Inventory-state mean scores of 37.3 versus 40.7 in controls (P = 0.03). Intervention group participants were more likely to correctly report their diagnosis (84% vs. 66.3%, P = 0.003). Questionnaire responders were more likely to be in the intervention group and had a higher proportion of cervical intraepithelial neoplasia 2+ pathology. There were no differences in demographics, patient satisfaction, or adherence to follow-up between groups. CONCLUSIONS: Direct delivery of colposcopy results by a trained Nurse Liaison was associated with decreased patient anxiety around colposcopy results, and increased patient knowledge regarding diagnosis. This model may be considered to improve patient-centred care.

17.
Cytopathology ; 35(1): 122-130, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37872834

RESUMEN

OBJECTIVE: To compare the sensitivity and specificity of DNA ploidy with cytology, human papillomavirus (HPV) testing and colposcopy in diagnosis of high-grade cervical intraepithelial neoplasia (CIN) and to assess the role of aneuploidy in cervical lesions with the worst prognosis. A prospective observational cohort study was conducted on 254 women with altered colpocytology. METHODS: Colposcopy, biopsy, DNA-ICM and HPV examinations were applied to cervical cytological and histological samples. Participants were evaluated every 6 months and divided into two groups: 'Harm' and 'No-harm'. Logistic regression and multivariate COX model were used to identify independent risk factors for diagnosis and prognosis of high-grade CIN, and ROC curve to assess the sensitivity and specificity of methods. RESULTS: Variables 'age greater than or equal to 30 years', 'lesion size greater than 20%', 'aneuploidy' and 'HPV 16' were associated with diagnosis of high-grade CIN and 'aneuploidy' and 'women living with HIV', with a worse prognosis. Agreement for colposcopy was good, with a sensitivity of 79.3% and specificity of 94.4%; DNA-ICM and cytology were moderate, with sensitivity of 74.6% and 72.3% and specificity of 85.3% and 76.1%, respectively. High-risk HPV and HPV 16 tests were weak, with sensitivity of 75.0% and 43.75% and specificity of 50.0% and 88.64%, respectively. CONCLUSIONS: In relation to high-grade CIN diagnosis, DNA-ICM presented similar sensitivity and specificity to cytology and high-risk HPV test when associated with HPV 16. Regarding prognosis, this research certifies that aneuploidy is considered a predictor of more severe cervical injury.


Asunto(s)
Infecciones por Papillomavirus , Displasia del Cuello del Útero , Neoplasias del Cuello Uterino , Embarazo , Femenino , Humanos , Estudios Prospectivos , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/patología , Infecciones por Papillomavirus/diagnóstico , Infecciones por Papillomavirus/genética , Infecciones por Papillomavirus/complicaciones , Papillomaviridae/genética , Displasia del Cuello del Útero/patología , Sensibilidad y Especificidad , Colposcopía , Aneuploidia , Papillomavirus Humano 16/genética , ADN , ADN Viral/genética , Frotis Vaginal/métodos
18.
Cytopathology ; 35(6): 757-760, 2024 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-38989556

RESUMEN

OBJECTIVE: We aimed to investigate differences between HPV-16 mono- and HPV-16/18 co-infections in terms of cervical dysplasia and invasive cancer. METHODS: This multicentre, retrospective study spanned from December 2017 to December 2020, involving women who visited gynaecological oncology clinics for colposcopy with either HPV-16 or HPV-16/18 positivity. A total of 736 patients, 670 in Group 1 (HPV-16 positivity) and 66 in Group 2 (HPV-16/18 positivity), were compared for the presence of CIN2+ lesions detected by colposcopic biopsy or endocervical curettage (ECC). Exclusions included hysterectomized patients, those with prior gynaecological cancers, and patients with HPV positivity other than types 16 and 18. RESULTS: Among the included patients, 42.4% had a diagnosis of CIN2+ lesions. The cytology results demonstrated abnormal findings in 45.3% in Group 1 and 42.2% in Group 2, with no significant difference between the groups. ECC revealed CIN2+ lesion in 49 (8.7%) patients in group 1, while only 1 (1.7%) patient had CIN2+ lesion in group 2. There was no difference between 2 groups in terms of ECC result (p = 0.052). In group 1, 289 (43.1%) patients had CIN2+ lesion, while 23 (34.8%) patients had CIN2+ lesions in group 2. There was no difference between group 1 and 2 in terms of diagnosis of CIN2+ lesions (p = 0.19). CONCLUSION: This multicentre retrospective study found no significant differences between HPV-16 mono- and HPV-16/18 co-infections regarding cervical pathologies. Larger studies are needed to validate and further explore these findings.


Asunto(s)
Coinfección , Papillomavirus Humano 16 , Papillomavirus Humano 18 , Infecciones por Papillomavirus , Displasia del Cuello del Útero , Neoplasias del Cuello Uterino , Humanos , Femenino , Papillomavirus Humano 16/aislamiento & purificación , Papillomavirus Humano 16/patogenicidad , Infecciones por Papillomavirus/patología , Infecciones por Papillomavirus/virología , Infecciones por Papillomavirus/diagnóstico , Infecciones por Papillomavirus/complicaciones , Papillomavirus Humano 18/aislamiento & purificación , Papillomavirus Humano 18/patogenicidad , Estudios Retrospectivos , Adulto , Coinfección/patología , Coinfección/virología , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/virología , Neoplasias del Cuello Uterino/diagnóstico , Persona de Mediana Edad , Displasia del Cuello del Útero/patología , Displasia del Cuello del Útero/virología , Displasia del Cuello del Útero/diagnóstico , Colposcopía , Cuello del Útero/patología , Cuello del Útero/virología
19.
Arch Gynecol Obstet ; 309(6): 2799-2809, 2024 06.
Artículo en Inglés | MEDLINE | ID: mdl-38461428

RESUMEN

BACKGROUND: Colposcopy has a key role to play in see-and-treat programs for premalignant cervical lesions. The aim of the study/was to observe cervical changes with a colposcope using the Swede scoring system in fertile age group women using various contraceptives: conventional methods (barrier methods, coitus interruptus), oral contraceptives (OCPs), copper-T and bilateral tubectomy. The aim of the study was to observe and evaluate the colposcopic findings using the Swede scoring system for the diagnosis of premalignant/malignant lesions in reproductive age group women using various contraceptives. METHODS: This was a prospective observational study, conducted among 200 women of reproductive age group using various contraceptives in a tertiary care institute in North India. PAP smear, direct visual examination, VIA (Visual Inspection with Acetic Acid) examination, colposcopic examination, and (biopsy if indicated) were done. The data were collected, and analysis was done using Microsoft Excel Office Software 2019 version 19.11 and epi info (CDC Atlanta) 7.23.1. Statistical analysis was done using percentages, mean, mode, median, standard deviation, Chi-square, Fisher's Test, and Anova Test. RESULTS: We found positive PAP (Papanicolaou test) smears in 61.50%, positive VIA examination in 9%, and positive findings in colposcopic examination in 28.50%, Swede score of 0-3 in 100% (0-91%, 1-2%, 2-6%, and 3-1%) and positive biopsy in 9% subjects. Malignant findings were observed in 1.00% of PAP smears. Colposcopic findings were CIN 1 (cervical intraepithelial neoplasia 1) in 8.5% and CIN 2 in 0.5% subjects. Swede score was zero in 91%, 1 in 2%, 2 in 6%, and 3 in 1% of subjects. HPE (histopathological examination) was chronic cervicitis in 8.50% and mild dysplasia/CIN 1 in 0.5%. No significant statistical associations between contraceptive choice and false-positive test results or disease prevalence was found in any group except Cu-T users p = 0.0184 (especially for CIN 2; p = 0.0109 and CIN 1 more in all groups than Cu-T users). Colposcopy had sensitivity 100%, specificity 91.46% (0/0 = 0%) PPV = 5.56%, NPV = 100%, Accuracy = 91.5% for detecting mild dysplasia/CIN-non-significant (p = 0.055). Our study had mainly low-grade lesions with 100% NPV. With increase in Swede Score, sensitivity increases but at the expense of specificity but it was statistically non-significant (p = 0.055). CONCLUSIONS: Our study may guide the rational use of colposcopy with Swede scoring for see-and-treat lesions, which is easy and with a low learning curve, as a tool for diagnosis but only in cases where indicated like unhealthy cervix because of the high rate of false-positive results. In low-grade lesions, it is highly useful to rule out the disease.


Asunto(s)
Colposcopía , Prueba de Papanicolaou , Displasia del Cuello del Útero , Neoplasias del Cuello Uterino , Humanos , Femenino , Adulto , Estudios Prospectivos , Displasia del Cuello del Útero/patología , Displasia del Cuello del Útero/diagnóstico , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/diagnóstico , Adulto Joven , India , Cuello del Útero/patología , Frotis Vaginal , Persona de Mediana Edad , Adolescente
20.
Arch Gynecol Obstet ; 2024 Oct 29.
Artículo en Inglés | MEDLINE | ID: mdl-39472340

RESUMEN

PURPOSE: Diagnostic challenges in colposcopy arise especially in women aged 50 or older, with postmenopausal status and transformation zone type 3 (TZ3). Endocervical curettage (ECC) is a valuable tool for diagnosing intracervical lesions. The aim of this retrospective analysis was to evaluate the use of ECC in colposcopy for detecting cervical intraepithelial lesions. METHODS: A retrospective study was carried out of colposcopies performed in the certified Dysplasia Unit at Erlangen University Hospital between July 2016 and June 2023. Pap and human papillomavirus (HPV) results were correlated with the histologic findings via ECC, obtained during examinations or surgery. The primary outcome was the rate of accuracy between the colposcopic and histologic findings with regard to cytology, age of patients, and type of transformation zone (TZ). RESULTS: A total of 429 colposcopies in 413 women with histologic samples obtained via ECC were included in the final analysis. In all, 355 women had TZ3. Among patients with TZ3, evidence of high-grade lesions and invasive carcinoma was also found in women with normal or low-grade abnormal cytology. For patients with normal colposcopic findings, cervical intraepithelial neoplasia (CIN) 2 and CIN 3/adenocarcinoma in situ (AIS) were found in 56 patients (16%), and invasive carcinoma was found in four patients (0.1%). CONCLUSION: This analysis suggests that ECC is a valuable tool in the diagnosis of cervical intraepithelial neoplasia, especially for patients who present with a normal colposcopy of the cervix and vagina but have either recurrent abnormal cytologic findings or high-grade abnormal cytology indicating CIN 2 + .

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