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1.
Surg Clin North Am ; 104(3): 517-527, 2024 Jun.
Article En | MEDLINE | ID: mdl-38677817

Anal intraepithelial neoplasia (AIN) are precancerous lesions and are sequela of human papilloma virus (HPV) infection. AIN is classified as low-grade squamous intraepithelial lesion or high-grade squamous intraepithelial lesion. Screening with anal cytology and anoscopy should be considered for high-risk populations. Diagnosis is made through high resolution anaoscopy and biopsy. Options for treatment include ablation and several topical therapies; however, recurrence rates are high for all treatment options, and an ongoing surveillance is necessary to prevent progression to anal squamous cell carcinoma. HPV vaccination is recommended to prevent disease.


Anus Neoplasms , Condylomata Acuminata , Papillomavirus Infections , Humans , Anus Neoplasms/diagnosis , Anus Neoplasms/therapy , Anus Neoplasms/pathology , Anus Neoplasms/virology , Condylomata Acuminata/diagnosis , Condylomata Acuminata/therapy , Condylomata Acuminata/virology , Papillomavirus Infections/complications , Papillomavirus Infections/diagnosis , Precancerous Conditions/diagnosis , Precancerous Conditions/pathology , Precancerous Conditions/therapy , Precancerous Conditions/virology , Squamous Intraepithelial Lesions/diagnosis , Squamous Intraepithelial Lesions/pathology , Squamous Intraepithelial Lesions/virology , Carcinoma in Situ/diagnosis , Carcinoma in Situ/therapy , Carcinoma in Situ/pathology , Carcinoma in Situ/virology
2.
J Acquir Immune Defic Syndr ; 96(2): 190-195, 2024 Jun 01.
Article En | MEDLINE | ID: mdl-38630441

BACKGROUND: People living with HIV (PLWH) have substantially increased incidence of anal precancer and cancer. There are very little data regarding genomic disturbances in anal precancers among PLWH. In this study, specific chromosomal variants were identified in anal squamous intraepithelial lesions. METHODS: Overall, 63 anal biopsy specimens (27 low-grade intraepithelial lesions [LSIL] and 36 high-grade intraepithelial lesions [HSIL]) were collected from PLWH obtained as part of anal cancer screening in our NYC-based health system. Data on patient demographics, anal cytological, and high-risk human papillomavirus (HR-HPV) diagnoses were collected. Specimens were tested for a panel of chromosomal alterations associated with HPV-induced oncogenesis using fluorescence in situ hybridization, and analyses compared the associations of these alterations with clinical characteristics. RESULTS: Gains of 3q26, 5p15, 20q13, and cen7 were detected in 42%, 31%, 31%, and 19% of HSIL compared with 7%, 0%, 4%, and 0% of LSIL, respectively. If at least 1 abnormality was observed, 89% had a 3q26 gain. In lesions with 5p15 gains, 20q13 gains co-occurred in 91% of cases, while cen7 gain only co-occurred with the other 3 alterations. The sensitivity and specificity of any alteration to predict HSIL were 47% (95% CI: 30%-65%) and 93% (95% CI: 76%-99%), respectively. CONCLUSIONS: Genomic alterations seen in HPV-associated cancers may help distinguish anal LSIL from HSIL. 3q26 amplification may be an early component of anal carcinogenesis, preceding 5p16, 20q13, and/or chr7. IMPACT: Insights into potential genomic biomarkers for discriminating high-risk anal precancers are shared.


Anus Neoplasms , DNA Copy Number Variations , HIV Infections , Precancerous Conditions , Humans , Anus Neoplasms/genetics , Anus Neoplasms/virology , Male , HIV Infections/complications , Female , Middle Aged , Adult , DNA Copy Number Variations/genetics , Precancerous Conditions/genetics , Precancerous Conditions/virology , Precancerous Conditions/pathology , Papillomavirus Infections/complications , Papillomavirus Infections/virology , Papillomavirus Infections/genetics , Squamous Intraepithelial Lesions/genetics , Squamous Intraepithelial Lesions/virology
3.
Cancer Causes Control ; 35(6): 935-942, 2024 Jun.
Article En | MEDLINE | ID: mdl-38368574

BACKGROUND: High-risk human papillomavirus (hrHPV) detection in self-collected urine samples (SeCUS) may be a promising alternative for cervical cancer screening because of its greater acceptability, as long as it can offer comparable sensitivity to clinician-collected cervical samples (CCoS) for detecting precancer lesions. OBJECTIVE: To evaluate the performance of the SeCUS compared to that of the CCoS for cervical intraepithelial neoplasia grade 3 (CIN3) detection among hrHPV-positive women receiving colposcopy in Mexico City using different specific extended HPV typing procedures: HPV16/18, HPV16/18/35/39/68 or HPV16/18/35/39/68/31. METHODS: From March 2017 to August 2018, 4,158 female users of the cervical cancer screening program at Tlalpan Sanitary Jurisdiction in Mexico City were invited to participate in the FRIDA-Tlalpan study. All participants provided ≥ 30 mL of SeCUS, and then a CCoS was obtained with Cervex-Brush®, which was used for hrHPV typing. Participants who tested positive for hrHPV in CCoS were referred for colposcopy for diagnostic confirmation, and all SeCUS of these women were also tested for hrHPV typing. RESULTS: In total, 561 hrHPV-positive women were identified by CCoS via colposcopy, and 82.2% of the SeCUS of these women were also hrHPV positive. From both CCoS and SeCUS, 7 cases of CIN3 were detected. Considering HPV16/18 typing, CCoS and SeCUS detected 4 cases of CIN3, but after HPV16/18/35/39/68/31 extension typing, both CCoS and SeCUS detected all 7 of the CIN3 cases among the hrHPV-positive women. CONCLUSIONS: Using extended hrHPV typing based on HPV16/18/35/39/68/31, our results suggest that the performance of SeCUS may be equivalent to that of CCoS for detecting CIN3 lesions. Although our results are inconclusive, they support the hypothesis that SeCUS may be an attractive alternative worthy of further research.


Colposcopy , Early Detection of Cancer , Papillomavirus Infections , Uterine Cervical Dysplasia , Uterine Cervical Neoplasms , Humans , Female , Papillomavirus Infections/diagnosis , Papillomavirus Infections/virology , Papillomavirus Infections/urine , Mexico/epidemiology , Adult , Uterine Cervical Neoplasms/virology , Uterine Cervical Neoplasms/diagnosis , Uterine Cervical Neoplasms/urine , Middle Aged , Early Detection of Cancer/methods , Uterine Cervical Dysplasia/virology , Uterine Cervical Dysplasia/diagnosis , Uterine Cervical Dysplasia/urine , Uterine Cervical Dysplasia/epidemiology , Precancerous Conditions/virology , Precancerous Conditions/diagnosis , Precancerous Conditions/urine , Papillomaviridae/isolation & purification , Papillomaviridae/genetics
4.
Int J Cancer ; 155(1): 61-70, 2024 Jul 01.
Article En | MEDLINE | ID: mdl-38418719

High-risk human papillomavirus (hrHPV) is the cause of virtually all cervical cancers, most vaginal and anal cancers, and some vulvar cancer cases. With HPV testing becoming the primary screening method for cervical cancer, understanding the link between cervical hrHPV infection and the risk of other anogenital cancers is crucial. We assessed the risk of vulvar, vaginal and anal cancer and precancer (VIN2+, VaIN2+ and AIN2+) in a prospective cohort study including 455,349 women who underwent cervical hrHPV testing in Denmark from 2005 to 2020. We employed Cox proportional hazard models, adjusting for age, calendar year and HPV vaccination status, and estimated hazard ratios (HRs) and 95% confidence intervals (CI). We used the Aalen Johansen estimator to calculate the absolute risks of VIN2+, VaIN2+ and AIN2+. In total, 15% of the women were hrHPV positive at baseline. A positive cervical hrHPV test was associated with increased incidence of vulvar, vaginal and anal squamous cell carcinoma (SCC). Five-year risk estimates of VIN2+, VaIN2+ and AIN2+ among hrHPV-positive women (0.45%, 0.14% and 0.12%) were higher than among hrHPV-negative women (0.14%, 0.01% and 0.05%). Particularly high risk was observed among the hrHPV-positive women of the oldest age, with a history of anogenital precancer and those not HPV vaccinated. In conclusion, our study confirms the association between cervical hrHPV infection and non-cervical anogenital precancers and cancers. Currently, no established risk threshold or guidelines for follow-up. As HPV testing becomes the primary method for cervical cancer screening, future data will help define high-risk groups and acceptable risk thresholds.


Anus Neoplasms , Papillomavirus Infections , Precancerous Conditions , Vaginal Neoplasms , Vulvar Neoplasms , Humans , Female , Papillomavirus Infections/virology , Papillomavirus Infections/epidemiology , Papillomavirus Infections/complications , Anus Neoplasms/virology , Anus Neoplasms/epidemiology , Vulvar Neoplasms/virology , Vulvar Neoplasms/epidemiology , Middle Aged , Prospective Studies , Adult , Precancerous Conditions/virology , Precancerous Conditions/epidemiology , Precancerous Conditions/pathology , Vaginal Neoplasms/virology , Vaginal Neoplasms/epidemiology , Vaginal Neoplasms/pathology , Uterine Cervical Neoplasms/virology , Uterine Cervical Neoplasms/epidemiology , Uterine Cervical Neoplasms/pathology , Denmark/epidemiology , Aged , Incidence , Carcinoma, Squamous Cell/virology , Carcinoma, Squamous Cell/epidemiology , Carcinoma, Squamous Cell/pathology , Papillomaviridae/isolation & purification , Early Detection of Cancer , Risk Factors , Cytology
5.
Infect Genet Evol ; 116: 105536, 2023 Dec.
Article En | MEDLINE | ID: mdl-38048896

Human papillomavirus type 16 (HPV-16) is the most prevalent HPV type worldwide and in Tunisia and the major carcinogenic HPV type found in cervical precancers and cancers. Previous studies have reported that genetic diversity of HPV16-E6 oncoprotein might be associated with cervical intraepithelial neoplasia progression. In this study we aimed to investigate the prevalence of HPV-16 E6 variants in precancerous lesions in Tunisian population to assess potential correlation with disease severity. Positive HPV cervical samples were obtained from the Laboratory of Anatomy Pathology of Pasteur Institute of Tunis. Cytological study was performed to identify cervical precancerous lesions. HPVs were typed using Reverse Line Hybridization. Only samples with HPV-16 single infection were selected for HP16-E6 genetic diversity investigation. HPV-16 E6 gene amplification was performed by PCR using specific primers and sequenced by Sanger Sequencing. The multiple alignment of generated sequences was performed using MEGAX software. Phylogenetic tree was constructed using Maximum Likehood method. The ternary complex of E6, E6AP and p53 core domain was used to perform in silico point mutations and thermodynamic calculations to assess stability and binding affinity. Genetic analysis of Tunisian E6-HPV16 sequences showed the presence of three lineages: European (A), African (C) and Asian American (D). Interestingly, the EUR variants were identified as the dominant lineage of HPV-16 and HPV-16 E6 350 G (L83V) was the most detected mutation in precancerous lesions. Modelling data showed that African variants induced the largest destabilizing effect on E6 structure and decreasing thereby in the affinity toward E6AP. Therefore, women infected with European variants are associated with low and high intraepithelial lesions. The findings give useful information for personalized decision algorithms of intra-epithelial cervical neoplasia in Tunisian women.


Oncogene Proteins, Viral , Papillomavirus Infections , Precancerous Conditions , Uterine Cervical Neoplasms , Female , Humans , Human papillomavirus 16/genetics , Oncogene Proteins, Viral/genetics , Oncogene Proteins, Viral/metabolism , Phylogeny , Polymorphism, Genetic , Precancerous Conditions/genetics , Precancerous Conditions/virology , Uterine Cervical Neoplasms/genetics , Uterine Cervical Neoplasms/virology
6.
BMC Cancer ; 23(1): 683, 2023 Jul 20.
Article En | MEDLINE | ID: mdl-37474918

BACKGROUND: High risk human papillomaviruses (HR-HPV) have a causal role in cervical oncogenesis, and HIV-mediated immune suppression allows HR-HPV to persist. We studied whether vaginal microbiome community state types (CSTs) are associated with high-grade precancer and/or invasive cervical cancer (HSIL/ICC). METHODS: This was a cross-sectional study of adult women with cervical cancer screening (CCS) at the Jos University Teaching Hospital (JUTH) in Jos, Nigeria, between January 2020 and February 2022. Cervical swabs underwent HPV genotyping (Anyplex™ II HPV28). Cervico-vaginal lavage (CVL) sample was collected for 16 S rRNA gene amplicon sequencing. We used multivariable logistic regression modelling to assess associations between CSTs and other factors associated with HSIL/ICC. RESULTS: We enrolled 155 eligible participants, 151 with microbiome data for this analysis. Women were median age 52 (IQR:43-58), 47.7% HIV positive, and 58.1% with HSIL/ICC. Of the 138 with HPV data, 40.6% were negative for HPV, 10.1% had low-risk HPV, 26.8% had single HR-HPV, and 22.5% had multiple HR-HPV types. The overall prevalence of any HR-HPV type (single and multiple) was 49.3%, with a higher proportion in women with HSIL/ICC (NILM 31.6%, LSIL 46.5%, HSIL 40.8%, and 81.5% ICC; p = 0.007). Women with HIV were more likely to have HSIL/ICC (70.3% vs. 29.7% among women without HIV). In crude and multivariable analysis CST was not associated with cervical pathology (CST-III aOR = 1.13, CST-IV aOR = 1.31). However, in the presence of HR-HPV CST-III (aOR = 6.7) and CST-IV (aOR = 3.6) showed positive association with HSIL/ICC. CONCLUSION: Vaginal microbiome CSTs were not significantly associated with HSIL/ICC. Our findings suggest however, that CST could be helpful in identifying women with HSIL/ICC and particularly those with HR-HPV. Characterization of CSTs using point-of-care molecular testing in women with HR-HPV should be studied as an approach to improve early detection and cervical cancer prevention. Future longitudinal research will improve our understanding of the temporal effect of non-optimal CST, HR-HPV, and other factors in cervical cancer development, prevention, and control.


Gardnerella , Human Papillomavirus Viruses , Lactobacillus , Microbiota , Precancerous Conditions , Uterine Cervical Neoplasms , Humans , Female , Adult , Uterine Cervical Neoplasms/epidemiology , Uterine Cervical Neoplasms/pathology , Uterine Cervical Neoplasms/virology , Precancerous Conditions/epidemiology , Precancerous Conditions/pathology , Precancerous Conditions/virology , Nigeria/epidemiology , Risk , Middle Aged , Cross-Sectional Studies , Human Papillomavirus Viruses/classification , Human Papillomavirus Viruses/genetics , Human Papillomavirus Viruses/isolation & purification , Lactobacillus/classification , Lactobacillus/genetics , Lactobacillus/isolation & purification , Gardnerella/classification , Gardnerella/genetics , Gardnerella/isolation & purification , Neoplasm Grading
7.
BMC Cancer ; 22(1): 42, 2022 Jan 06.
Article En | MEDLINE | ID: mdl-34991494

BACKGROUND: The aim of the study was to investigate the risk of human papillomavirus (HPV) genotyping particularly vaccine genotypes and multiple infections for cervical precancer and cancer, which might contribute to developing genotype-specific screening strategy and assessing potential effects of HPV vaccine. METHODS: The HPV genotypes were identified using the Seq HPV assay on self-collected samples. Hierarchical ranking of each genotype was performed according to positive predictive value (PPV) for cervical intraepithelial neoplasia 2/3 or worse (CIN2+/CIN3+). Multivariate logistic regression model was used to estimate the odds ratios (ORs) with 95% confidence interval (CI) of CIN2+ according to multiplicity of types and vaccine types. RESULTS: A total of 2811 HPV-positive women were analyzed. The five dominant HPV genotypes in high-grade lesions were 16/58/52/33/18. The overall ranking orders were HPV16/33/35/58/31/68/18/ 56/52/66/51/59/45/39 for CIN2+ and HPV16/33/31/58/45/66/52/18/35/56/51/68/59/39 for CIN3+. The risks of single infection versus co-infections with other types lower in the hierarchy having CIN2+ were not statistically significant for HPV16 (multiple infection vs. single infection: OR = 0.8, 95%CI = 0.6-1.1, P = 0.144) or other genotypes (P > 0.0036) after conservative Bonferroni correction. Whether HPV16 was present or not, the risks of single infection versus multiple infection with any number (2, ≥2, or ≥ 3) of types for CIN2+ were not significantly different. In addition, HPV31/33/45/52/58 covered by nonavalent vaccine added 27.5% of CIN2, 23.0% of CIN3, and 12.5% of cancer to the HPV16/18 genotyping. These genotype-groups were at significantly higher risks than genotypes not covered by nonavalent vaccine. Moreover, genotypes covered by nonavalent vaccine contributed to 85.2% of CIN2 lesions, 97.9% of CIN3 and 93.8% of cancers. CONCLUSIONS: Partial extended genotyping such as HPV33/31/58 but not multiplicity of HPV infections could serve as a promising triage for HPV-positive self-samples. Moreover, incidence rates of cervical cancer and precancer were substantial attributable to HPV genotypes covered by current nonavalent vaccination.


Genotyping Techniques , Papillomaviridae/genetics , Papillomavirus Vaccines/genetics , Precancerous Conditions/virology , Uterine Cervical Neoplasms/virology , Adult , Early Detection of Cancer/methods , Female , Genotype , Humans , Incidence , Logistic Models , Middle Aged , Papillomavirus Infections/prevention & control , Papillomavirus Infections/virology , Precancerous Conditions/epidemiology , Precancerous Conditions/prevention & control , Predictive Value of Tests , Uterine Cervical Neoplasms/epidemiology , Uterine Cervical Neoplasms/prevention & control , Uterine Cervical Dysplasia/epidemiology , Uterine Cervical Dysplasia/prevention & control , Uterine Cervical Dysplasia/virology
8.
Pan Afr Med J ; 40: 48, 2021.
Article En | MEDLINE | ID: mdl-34795828

INTRODUCTION: cervical precancer screening with same day treatment facilitates maximization of benefits of secondary prevention of cervical cancer. This is particularly important for women living with human immunodeficiency virus (WLHIV) infection because of their exceptional risk for cervical cancer. The availability of HIV programmes in low- and middle-income countries (LMICs) provide unique opportunity for possible introduction "human papillomavirus (HPV) screening followed by visual inspection after application of acetic acid (VIA) with same day treatment of eligible patients". This study piloted this concept. METHODS: in this prospective, cohort study, 98 WLHIV had HPV and VIA screening for cervical precancer lesions in a HIV clinic in Nigeria. Participants positive to HPV and/or VIA had biopsies from the visible lesions or quadrant of transformation zone. Participants positive to VIA and/or HPV16 or HPV18/45 had same-day thermal ablation treatment and the number of cases documented. The HPV, VIA and scenario of HPV followed by VIA results were compared with histologically confirmed cervical lesion grade 2 or worse statistically. RESULTS: same day treatment was achieved in 95.0% of eligible cases. Statistically, sensitivity and specificity of VIA was 25.0% and 50.0% and HPV had 95.5% and 75.0%, respectively. In the HPV screening with VIA triage, sensitivity dropped to 45.5% but specificity improved to 100.0%. CONCLUSION: triaging HPV positive test with VIA for same-day treatment in cervical precancer screening among PLWHIV looks feasible. The improved specificity will reduce the overtreatment rate, loss to follow-up associated with repeat clinic visits and improve completion of continuum of care.


HIV Infections/complications , Mass Screening/methods , Papillomavirus Infections/diagnosis , Uterine Cervical Neoplasms/prevention & control , Acetic Acid , Adult , Aged , Alphapapillomavirus/isolation & purification , Biopsy , Cohort Studies , Early Detection of Cancer/methods , Female , Humans , Middle Aged , Nigeria , Papillomavirus Infections/complications , Pilot Projects , Precancerous Conditions/diagnosis , Precancerous Conditions/virology , Prospective Studies , Sensitivity and Specificity , Triage/methods , Uterine Cervical Neoplasms/virology , Young Adult
9.
Acta Cytol ; 65(6): 494-500, 2021.
Article En | MEDLINE | ID: mdl-34515031

OBJECTIVES: This work is aimed to summarize the first year of the high-risk human papillomavirus (hrHPV) screening test and compare it to the cytology screening test, regarding positivity rates and premalignant lesions diagnosed in the Israeli population. A specific consideration is for the age group 25-30 that is not considered mandatory for the HPV primary screening testing. METHODS: A retrospective study was performed in women who were screened for prevention of cervical cancer in Maccabi HealthCare HMO from March 2017 to March 2019. Screening methods included hrHPV typing for types 16, 18, and the other 12 hrHPV types and the PAP LBC test. RESULTS: A total of 115,807 cervical samples were tested for HPV presence and 91% (105,225) were found negative for hrHPV. The other 9% (10,582) were positive for one or more of the 14 hrHPV types tested, and 37% (3,916) of them showed abnormal PAP LBC results. In the age group of 25-30, 3,104 (17.5%) women were found positive for hr-HPV (825 had hrHPV types 16 and/or 18), of which 42% (1,293) of them showed abnormal PAP LBC results. During the hrHPV versus PAP LBC screening era, 258 more women were diagnosed with precancerous cervical lesions (CIN2/3), 70% increased detection versus cytology screening. CONCLUSIONS: The hrHPV screening test is currently the best method for the detection of precancerous cervical lesions and cervical cancer, and it is better started at age 25.


DNA, Viral/genetics , Human Papillomavirus DNA Tests , Papanicolaou Test , Papillomaviridae/genetics , Papillomavirus Infections/virology , Precancerous Conditions/virology , Uterine Cervical Neoplasms/virology , Vaginal Smears , Adult , Aged , Female , Humans , Israel , Middle Aged , Papillomavirus Infections/pathology , Precancerous Conditions/pathology , Predictive Value of Tests , Program Evaluation , Reproducibility of Results , Retrospective Studies , Uterine Cervical Neoplasms/pathology , Young Adult
10.
Am J Surg Pathol ; 45(11): 1573-1578, 2021 11 01.
Article En | MEDLINE | ID: mdl-34231547

p16 is the most useful diagnostic marker for human papillomavirus (HPV)-associated anogenital lesions. In the cervix, the pattern of p16 immunoreactivity generally correlates with lesion severity. p16 expression in anal intraepithelial neoplasia (AIN) is far less studied. Whether such correlation holds true has to be determined. We correlated the degree and pattern of p16 immunohistochemistry (IHC) results with morphologic diagnoses of 1000 anal squamous and transitional zone biopsy specimens. Using the Lower Anogenital Squamous Terminology criteria, p16 IHC results were classified as block staining, partial staining, or negative. Among 150 samples without morphologic evidence of AIN, p16 was negative in 85% and partial staining in 15%. AIN 1 (n=400) revealed diverse results: 28% negative, 35% partial, and 37% block staining. Among AIN 2 (n=298), 89% were block, 9% partial staining, and 2% negative. AIN 3 (n=152) revealed block (95%) or partial staining (5%). For the detection of AIN 2/3, p16 block staining yielded 91% sensitivity, 73% specificity, 80% positive predictive value, 91% negative predictive value, and a Youden Index of 0.64. Combining block staining and partial staining slightly increased sensitivity (99%) and negative predictive value (98%), but significantly decreased specificity (43%), positive predictive value (59%) and Youden Index (0.42, P<0.001). As with the cervix, p16 immunoreactivity correlates with morphologic diagnoses of AIN. Block staining offers the optimal diagnostic value for AIN 2/3. Caution is required since AIN 1 frequently exhibits block staining; the prognostic value of p16 warrants further investigation.


Anus Neoplasms/chemistry , Biomarkers, Tumor/analysis , Carcinoma in Situ/chemistry , Cyclin-Dependent Kinase Inhibitor p16/analysis , Immunohistochemistry , Papillomaviridae/isolation & purification , Papillomavirus Infections/virology , Precancerous Conditions/metabolism , Squamous Intraepithelial Lesions/metabolism , Anus Neoplasms/pathology , Anus Neoplasms/virology , Biopsy , Carcinoma in Situ/pathology , Carcinoma in Situ/virology , Databases, Factual , Humans , In Situ Hybridization , Male , Neoplasm Grading , Papillomaviridae/genetics , Precancerous Conditions/pathology , Precancerous Conditions/virology , Predictive Value of Tests , RNA, Viral/genetics , Squamous Intraepithelial Lesions/pathology , Squamous Intraepithelial Lesions/virology
11.
Gynecol Oncol ; 162(3): 555-559, 2021 09.
Article En | MEDLINE | ID: mdl-34253387

OBJECTIVES: Human papillomavirus (HPV) testing for cervical screening has been shown to increase the yield of precancerous disease and reduce the incidence of cervical cancer more than cytology alone. Here we document the state-wide uptake of co-testing with HPV and cytology in women aged 30-64 years as recommended by national and international bodies. METHODS: Registry-based study of all screening cytology and HPV tests in New Mexico from 2008 to 2019 among women aged 21-64 years, with a focus on cytology negative tests to distinguish co-testing from reflex HPV testing to triage equivocal or mildly abnormal cytology. RESULTS: A total of 1,704,055 cervical screening tests from 681,440 women aged 21-64 years in the state of New Mexico were identified. The proportion of screening tests which were co-tests rose from 5.6% in 2008 to 84.3% in 2019 among women aged 30-64 years with a marked change from the near exclusive use of the Hybrid Capture II HPV test, (a signal amplified test method) to the use of target amplified HPV tests. The largest increases were seen between 2013 and 2015, reflecting the introduction and adoption of new clinical guidelines. Increases in co-testing were also seen in younger women. CONCLUSIONS: Co-testing is now well established in women aged 30-64 years, but smaller increases have also been seen at younger ages, although this is not currently recommended. The impact of co-testing on cervical disease outcomes and number of colposcopies and biopsies in routine population settings remain important, especially in young women.


Cervix Uteri/pathology , Cervix Uteri/virology , Papillomavirus Infections/diagnosis , Precancerous Conditions/diagnosis , Uterine Cervical Neoplasms/diagnosis , Adult , Early Detection of Cancer/statistics & numerical data , Female , Humans , Middle Aged , Papillomaviridae/isolation & purification , Papillomavirus Infections/epidemiology , Papillomavirus Infections/pathology , Papillomavirus Infections/virology , Precancerous Conditions/epidemiology , Precancerous Conditions/pathology , Precancerous Conditions/virology , Registries , United States , Uterine Cervical Neoplasms/epidemiology , Uterine Cervical Neoplasms/pathology , Uterine Cervical Neoplasms/virology , Young Adult
12.
Virol J ; 18(1): 144, 2021 07 10.
Article En | MEDLINE | ID: mdl-34246302

BACKGROUND: Regard to this fact that the main transmission route of HPV and HHV-8 is via sexual activity, it is reasonable to speculate that coinfection of HPV and HHV-8 may have been played an important role in the development of cervical cancer. The aim of this study was to estimate the prevalence of HHV-8 and the frequency of HPV and HHV-8 coinfection in cervical samples of patients with cervical cancer and healthy individuals. METHODS: In total, 364 samples from 61 patients with cervical cancer, 124 women with premalignant lesions, and 179 healthy individuals were investigated by nested-PCR. RESULTS: The frequency of HHV-8 was found to be 22.9%, 17.7%, and 14.5% in cervical cancer, premalignant lesions, and normal specimens, respectively (P = 0.308). The overall prevalence of coinfection between HHV-8 and HPV was shown to be 16.2%. The HPV prevalence was higher in HHV-8 positive samples than HHV-8 negative specimens in all three studied groups and this difference was reached a statistically significant level (P = 0.002). However, no significant differences were found between HHV-8 positivity and HPV genotypes (P = 0.08). CONCLUSIONS: Our results showed the higher rate of HHV-8 genome detection in cervical cancer group than control group. However, future studies with larger sample sizes and evaluation of expression of HHV-8 proteins are warranted.


Coinfection , Herpesvirus 8, Human , Papillomavirus Infections , Precancerous Conditions , Uterine Cervical Neoplasms , Coinfection/epidemiology , Coinfection/virology , DNA, Viral/genetics , Female , Humans , Iran/epidemiology , Papillomaviridae/genetics , Papillomavirus Infections/complications , Papillomavirus Infections/epidemiology , Precancerous Conditions/epidemiology , Precancerous Conditions/virology , Prevalence , Uterine Cervical Neoplasms/epidemiology , Uterine Cervical Neoplasms/virology
13.
Gynecol Oncol ; 162(3): 569-574, 2021 09.
Article En | MEDLINE | ID: mdl-34226019

OBJECTIVE: The purpose of this study was to evaluate the role of HPV genotyping and previous cytology result to predict the evolution of CIN2 histological lesions managed conservatively. METHODS: A prospective observational study was conducted at Hospital del Mar in Barcelona from January 2012 to May 2017. Women with new diagnosis of CIN2 were invited to undergo conservative management for 24 months. Complete regression, partial regression, persistence and progression to CIN3 were defined as final outcomes. Univariate and multivariate analyses combining HPV genotyping and cytology were used to establish progression predictors of CIN2. RESULTS: A total of 300 patients were included in the study, and 291 patients completed the 24-months follow-up. Of them, 214 patients (73.5%) showed regression; 43 (14.8%) persistence to CIN2, and 34 (11.7%) progression to CIN3. In multivariable analysis, HPV-16 infection (odds ratio [OR] 1.97, [95% confidence interval {CI} 1.13-3.43]) and previous HSIL cytology (OR 3.46, [95% CI 1.99-6.02]) significantly increased the risk of persistence or progression (CIN2+) of CIN2 lesions. In contrast, all HPV-negative lesions regressed (p < 0.001). CONCLUSIONS: The regression rate of CIN2 lesions supports conservative management in selected patients regardless of their age. Patients with a CIN2 biopsy and negative HPV test had a high rate of regression and should be offered follow-up without excisional treatment. In contrast, patients with HPV-16 and HSIL cytology had an increased risk of CIN2+, their treatment should be individualized and excisional treatment should be considered. The age may not be considered a criterion to decide the best management. New markers may help in the future to select the best management of CIN2.


Papillomavirus Infections/pathology , Papillomavirus Infections/virology , Uterine Cervical Dysplasia/pathology , Uterine Cervical Dysplasia/virology , Uterine Cervical Neoplasms/pathology , Uterine Cervical Neoplasms/virology , Adult , Conservative Treatment , Female , Genotype , Human papillomavirus 16/genetics , Human papillomavirus 16/isolation & purification , Humans , Neoplasm Grading , Papillomavirus Infections/therapy , Precancerous Conditions/pathology , Precancerous Conditions/virology , Predictive Value of Tests , Prospective Studies , Squamous Intraepithelial Lesions of the Cervix/pathology , Squamous Intraepithelial Lesions of the Cervix/virology , Uterine Cervical Neoplasms/therapy , Young Adult , Uterine Cervical Dysplasia/therapy
14.
Gynecol Oncol ; 162(3): 584-589, 2021 09.
Article En | MEDLINE | ID: mdl-34226020

OBJECTIVE: to profile patients with vaginal intraepithelial neoplasia (VAIN), to evaluate natural history and to identify risk factors for persistence, progression and recurrence. METHODS: At West China Second University Hospital, all patients with histologically confirmed VAIN over a five-year period with minimum follow-up of 6 months were retrospectively identified. Demographics, medical history and clinical information related to the diagnosis and treatment were extracted. Clinical outcomes included normalization, persistence, progression and recurrence. We evaluated risk factors by univariate and multivariate analyses. RESULTS: A total of 1478 patients fulfilled the inclusion criteria with a median follow-up of 14 months (range, 6-60 months). In 86.6% of patients, VAIN went into normalization, 6.4% persisted, 3.5% progressed and 3.5% recurred. Besides, 24 (7.1%) VAIN 3 patients and 4 (0.8%) progressed to cancer, accounting for 85.7% and 14.3% of cancer cases, respectively. VAIN 3 patients treated with excision yielded superior outcomes. Risk factors for persistence were HPV 16, 56, 59 and 43 infections, for progression were prior hysterectomy for cervical lesions and HPV 56 infection, for recurrence were HPV 61 infection. CONCLUSION: Although VAIN will regress in most patients, there are still risks of persistence, recurrence and progression, even malignancy. Therefore, a long-term follow-up is recommended. Patients with VAIN 3 are at higher risk of progressing to cancer and excision is preferred. HPV 16, 56, 59 and 43 infections might associate with an increased risk of persistence and patients with prior hysterectomy for cervical lesions tend to progress.


Carcinoma in Situ/pathology , Precancerous Conditions/pathology , Vaginal Neoplasms/pathology , Adolescent , Adult , Aged , Carcinoma in Situ/virology , DNA, Viral/genetics , Disease Progression , Female , Humans , Middle Aged , Papillomaviridae/genetics , Papillomaviridae/isolation & purification , Precancerous Conditions/virology , Risk Factors , Uterine Cervical Neoplasms/surgery , Vaginal Neoplasms/virology , Young Adult
15.
Cancer Invest ; 39(10): 885-892, 2021 Nov.
Article En | MEDLINE | ID: mdl-34279158

The aim of this study is to analyze the correlation between clinically significant histologic results and HPV in women with AGC in pap test. Of the 311 women confirmed as AGC, 111 women (35.7%) was identified as positive for HPV. In the AGC analysis, cervical lesions were significantly more common in HPV positive group compared to HPV negative group (61.2 vs. 10.5%, p < 0.001). In contrast, endometrial lesions were not associated with HPV infection (8.1 vs. 4.5%, p = 0.12). The HPV-DNA testing in women with AGC may be a useful tool for predicting clinically significant cervical lesions.


Cervix Uteri/pathology , DNA, Viral/analysis , Papanicolaou Test , Papillomaviridae/isolation & purification , Precancerous Conditions/virology , Uterine Cervical Neoplasms/virology , Adult , Aged , Female , Humans , Middle Aged , Papillomaviridae/genetics , Young Adult
16.
BMC Cancer ; 21(1): 688, 2021 Jun 10.
Article En | MEDLINE | ID: mdl-34112111

BACKGROUND: Low-risk human papillomavirus (HPV), such as types 6 and 11, is considered non-oncogenic, but these types have been detected in oral cancer tissue samples, suggesting their possible involvement in oral carcinogenesis. Because double infection of high-risk HPV and Epstein-Barr virus (EBV) is known to be involved in oral carcinogenesis, we hypothesized that low-risk HPV and EBV co-infection can transform the oral cells. To verify our hypothesis, we evaluated the transformation activity of cell lines expressing both low-risk HPV E6/E7 and EBV LMP-1. METHODS: We transduced HPV6, 11 and 16 E6/E7 genes and EBV LMP-1 gene into primary mouse embryonic fibroblasts. The cell lines were examined for indices of transformation activity such as proliferation, induction of DNA damage, resistance to apoptosis, anchorage-independent growth, and tumor formation in nude mice. To evaluate the signaling pathways involved in transformation, NF-κB and p53 activities were analyzed. We also assessed adhesion signaling molecules associated with anchorage-independent growth such as MMP-2, paxillin and Cat-1. RESULTS: Co-expression of low-risk HPV6 E6 and EBV LMP-1 showed increased cell proliferation, elevated NF-κB activity and reduced p53 induction. Moreover, co-expression of low-risk HPV6 E6 and EBV LMP-1 induced DNA damage, escaped from apoptosis under genotoxic condition and suppression of DNA damage response (DDR). Co-expression of low-risk HPV11 E6/E7 and EBV LMP-1 demonstrated similar results. However, it led to no malignant characteristics such as anchorage-independent growth, invasiveness and tumor formation in nude mice. Compared with the cells co-expressing high-risk HPV16 E6 and EBV LMP-1 that induce transformation, co-expression of low-risk HPV6 E6 and EBV LMP-1 was associated with low MMP-2, paxillin and Cat-1 expression. CONCLUSIONS: The co-expression of low-risk HPV E6/E7 and EBV LMP-1 does not induce malignant transformation, but it allows accumulation of somatic mutations secondary to increased DNA damage and suppression of DDR. Thus, double infection of low-risk HPV and EBV could lead to precancerous lesions.


Coinfection/pathology , Epstein-Barr Virus Infections/pathology , Mouth Neoplasms/genetics , Papillomavirus Infections/pathology , Precancerous Conditions/pathology , Animals , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/pathology , Coinfection/genetics , Coinfection/virology , DNA Damage , DNA Repair , Disease Models, Animal , Epstein-Barr Virus Infections/virology , Female , Fibroblasts , Herpesvirus 4, Human/pathogenicity , Host-Pathogen Interactions/genetics , Human papillomavirus 11/pathogenicity , Human papillomavirus 6/metabolism , Humans , Mice , Mouth Mucosa/pathology , Mouth Mucosa/virology , Mouth Neoplasms/pathology , Mouth Neoplasms/virology , Mutation , Oncogene Proteins, Viral/metabolism , Papillomavirus Infections/virology , Precancerous Conditions/genetics , Precancerous Conditions/virology , Primary Cell Culture , Viral Matrix Proteins/metabolism
17.
J Med Virol ; 93(11): 6089-6099, 2021 11.
Article En | MEDLINE | ID: mdl-34180541

The role of human papillomavirus (HPV) in the development of oral lesions is controversial. There has been no comprehensive study about HPV prevalence in Iran. This systematic review and meta-analysis were aimed at finding HPV prevalence of oral lesions and normal oral mucosa in Iran. International (PubMed, Web of Science, and Scopus) and national (Iranmedex, Irandoc, and SID) databases were searched systematically until October 2020. Studies that examined the prevalence of HPV in oral lesions by polymerase chain reaction method were included. The heterogeneity of articles was assessed with the Cochran test and I-Square statistics. The prevalence rate of HPV was calculated using a random-effect model. Of 3729 initially searched articles, 29 articles were eligible for inclusion. The overall prevalence of HPV in oral lesions was 21%. The prevalence was the highest in Rasht (50%) city. Lip lesions had the highest HPV prevalence (40%). According to the classification of lesions, the highest prevalence was of precancerous lesions (29%) and the lowest in normal mucosa (8%). Well-differentiated tumors showed a higher prevalence than poorly-differentiated ones. The highest prevalence of HPV was hairy leukoplakia (70%) and the lowest was of pyogenic granuloma (6%). Also, the prevalence was 31% in oral squamous cell carcinoma. There are differences between HPV prevalence according to the geographical area, intraoral location, type of lesion, and grading. As HPV prevalence was fairly high, further attention to vaccination and treatment for HPV in Iran, as a potential risk factor for oral precancerous and cancerous lesions is recommended.


Alphapapillomavirus/genetics , Alphapapillomavirus/physiology , Carcinoma, Squamous Cell/virology , Mouth Neoplasms/virology , Papillomavirus Infections/complications , Granuloma, Pyogenic/virology , Humans , Iran/epidemiology , Leukoplakia, Oral/virology , Mouth Mucosa/virology , Papillomavirus Infections/epidemiology , Precancerous Conditions/virology , Prevalence
18.
Asian Pac J Cancer Prev ; 22(6): 1875-1881, 2021 Jun 01.
Article En | MEDLINE | ID: mdl-34181346

OBJECTIVES: The main objectives of this study were to investigate the detection rate of high-risk human papillomavirus types 16 and 18 (high-risk HPV16/18) in oral potentially malignant disorders (OPMDs) including oral leukoplakia (OL) and oral lichen planus (OLP) in a Thai population and their associations with demographic, risk habits, and clinicopathologic features. METHODS: Paraffin-embedded formalin-fixed specimens from 101 OL and 59 OLP patients with patients' demographic, risk habits, and clinicopathologic data were collected. Conventional qualitative polymerase chain reaction was used to detect high-risk HPV16/18 DNA. Associations between high-risk HPV type 16/18 and demographic, clinicopathologic, risk factors (tobacco and alcohol uses) of OPMDs were analysed by Chi-square or Fisher's exact test. The results with p value less than 0.05 were considered statistically significant. RESULTS: HPV16/18 DNA was found in both OL and OLP groups with the detection rate of 19.8% and 18.6%, respectively. Approximately 90% of high-risk HPV were HPV18 subtype. Additionally, in OL group, high-risk HPV was found more frequently in patients with moderate/severe dysplasia than that in mild dysplasia. Interestingly, in OLP group, high-risk HPV was only detected in atrophic/ulcerative subtypes. None of risk factors was associated with high-risk HPV. CONCLUSIONS: Approximately 19% of OPMDs were HPV16/18-positive. HPV18 DNA was predominantly detected in both OL and OLP patients (90%). Additionally, the detection rate of high-risk HPV was higher in more severe dysplastic cases of OL and more clinically severe cases of OLP.


Human papillomavirus 18/isolation & purification , Leukoplakia, Oral/virology , Lichen Planus, Oral/virology , Papillomavirus Infections/virology , Precancerous Conditions/virology , Adult , Aged , Female , Human papillomavirus 16/isolation & purification , Humans , Leukoplakia, Oral/epidemiology , Lichen Planus, Oral/epidemiology , Male , Middle Aged , Papillomavirus Infections/epidemiology , Precancerous Conditions/epidemiology , Prevalence , Risk Factors , Thailand/epidemiology
19.
J Med Virol ; 93(8): 5118-5125, 2021 08.
Article En | MEDLINE | ID: mdl-33913528

This study investigates the epidemiological characteristics of high-risk human papillomavirus (hrHPV) and analyzes the risk of cervical lesions among women in Zhejiang province, China. HPV data were collected retrospectively from a cohort of 67 742 women who underwent routine cervical cancer screening from 2010 to 2019. Precancerous and cervical cancer cases (n = 980) were histologically diagnosed as a low-grade squamous intraepithelial lesion (LSIL; n = 341) or a high-grade squamous intraepithelial lesion (HSIL; n = 499) and invasive cervical cancer (ICC) (n = 140) groups. Disordered logistic regression analysis was used to test the relationship between different degrees of cervical lesions, HPV16/18 infection status, positive rate of p16INK4a (p16), Ki-67 expression, and patient's age in SIL and ICC (270/980 cases) patients. HPV52 (4.7%) was the most prevalent HPV type, followed by HPV16 (3.3%) and HPV58 (2.6%). HPV16 was the most common HPV in SIL, peaking at the age of 30-39. The HPV16 infection rate was significantly higher in HSIL than in LSIL patients; moreover, HPV16, HPV18, and HPV51 infection rates were significantly higher in ICC patients than in HSIL (Bonferroni-adjusted p < 0.0167). The presence of HPV16/18 was also associated with a higher risk of developing HSIL from LSIL (odds ratio [OR] = 9.198, 95% confidence interval [CI]: 2.76-127.49). The increased p16 expression and HPV16/18 were associated with the increased risk of cancer progression (OR = 1.092, 95% CI: 1.03-1.36; OR = 1.495, 95% CI: 1.23-2.19, respectively). The identified hrHPV genotypes in cervical lesions can serve as a baseline indicator for future vaccine assessment in Zhejiang, China.


Cervix Uteri/pathology , Papillomaviridae/isolation & purification , Papillomavirus Infections/virology , Adult , Aged , Cervix Uteri/virology , China/epidemiology , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Female , Genotype , Humans , Middle Aged , Papillomaviridae/classification , Papillomaviridae/genetics , Papillomavirus Infections/diagnosis , Papillomavirus Infections/epidemiology , Papillomavirus Infections/pathology , Precancerous Conditions/epidemiology , Precancerous Conditions/pathology , Precancerous Conditions/virology , Prevalence , Retrospective Studies , Risk Factors , Squamous Intraepithelial Lesions of the Cervix/epidemiology , Squamous Intraepithelial Lesions of the Cervix/pathology , Squamous Intraepithelial Lesions of the Cervix/virology , Uterine Cervical Neoplasms/epidemiology , Uterine Cervical Neoplasms/pathology , Uterine Cervical Neoplasms/virology , Young Adult
20.
Front Immunol ; 12: 624230, 2021.
Article En | MEDLINE | ID: mdl-33868241

Cervical cancer is the fourth most common cancer and fourth leading cause of cancer death among women worldwide. In low Human Development Index settings, it ranks second. Screening and surveillance involve the cytology-based Papanicolaou (Pap) test and testing for high-risk human papillomavirus (hrHPV). The Pap test has low sensitivity to detect precursor lesions, while a single hrHPV test cannot distinguish a persistent infection from one that the immune system will naturally clear. Furthermore, among women who are hrHPV-positive and progress to high-grade cervical lesions, testing cannot identify the ~20% who would progress to cancer if not treated. Thus, reliable detection and treatment of cancers and precancers requires routine screening followed by frequent surveillance among those with past abnormal or positive results. The consequence is overtreatment, with its associated risks and complications, in screened populations and an increased risk of cancer in under-screened populations. Methods to improve cervical cancer risk assessment, particularly assays to predict regression of precursor lesions or clearance of hrHPV infection, would benefit both populations. Here we show that women who have lower risk results on follow-up testing relative to index testing have evidence of enhanced T cell clonal expansion in the index cervical cytology sample compared to women who persist with higher risk results from index to follow-up. We further show that a machine learning classifier based on the index sample T cells predicts this transition to lower risk with 95% accuracy (19/20) by leave-one-out cross-validation. Using T cell receptor deep sequencing and machine learning, we identified a biophysicochemical motif in the complementarity-determining region 3 of T cell receptor ß chains whose presence predicts this transition. While these results must still be tested on an independent cohort in a prospective study, they suggest that this approach could improve cervical cancer screening by helping distinguish women likely to spontaneously regress from those at elevated risk of progression to cancer. The advancement of such a strategy could reduce surveillance frequency and overtreatment in screened populations and improve the delivery of screening to under-screened populations.


Alphapapillomavirus/immunology , Early Detection of Cancer , Genes, T-Cell Receptor beta , Papanicolaou Test , Papillomavirus Infections/diagnosis , Precancerous Conditions/diagnosis , T-Lymphocytes/immunology , Uterine Cervical Neoplasms/diagnosis , Vaginal Smears , Adult , Alphapapillomavirus/genetics , Alphapapillomavirus/pathogenicity , Complementarity Determining Regions/genetics , Female , Gene Expression Profiling , High-Throughput Nucleotide Sequencing , Human Papillomavirus DNA Tests , Humans , Machine Learning , Middle Aged , Papillomavirus Infections/immunology , Papillomavirus Infections/virology , Precancerous Conditions/immunology , Precancerous Conditions/virology , Predictive Value of Tests , Proof of Concept Study , Reproducibility of Results , Risk Assessment , Risk Factors , T-Lymphocytes/virology , Transcriptome , Uterine Cervical Neoplasms/immunology , Uterine Cervical Neoplasms/virology
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