Study of Expression of p16 and Ki-67 in Cervical Squamous Intraepithelial Lesion and Cervical Carcinoma and Its Role as a Predictive Marker in Human Papilloma Virus Infection

Human Papillomavirus and Vaccination

Human papillomavirus (HPV) infection is a common sexually transmitted disease worldwide and the leading cause of cervical cancer. Current vaccines do not cover all HPV genotypes whereas the distribution of HPV genotypes varies in different geographic regions. The study aimed to investigate the distribution of HPV genotypes in patients with cervical squamous intraepithelial lesion (SIL) and cervical squamous cell carcinoma (SCC) in Taizhou City of Jiangsu Province, China. A total of 940 patients including 489 cases with cervical low-grade squamous intraepithelial lesions (LSIL), 356 cases with cervical high-grade squamous intraepithelial lesions (HSIL), and 95 cases with cervical SCC, underwent a biopsy or surgery in Taizhou People's Hospital between January 2019 and December 2019. The HPV testing results were retrospectively analyzed. The overall prevalence of any, high-risk, and low-risk HPV was 83.83%, 81.91%, and 12.13%, respectively. The 5 most common HPV genotypes were HPV16 (35.64%), HPV52 (16.91%), HPV58 (13.94%), HPV33 (8.94%), and HPV18 (7.98%). The prevalence of any and HR-HPV in SCC was significantly higher than those in LSIL and HSIL, while the prevalence of LR-HPV in SCC was significantly lower than those in LSIL and HSIL (P < .01). Single and dual HPV infections were prevalent in SCC, LSIL, and HSIL. Furthermore, the prevalence of dual HPV infection in SCC was significantly higher than those in LSIL and HSIL (P = .002). The HPV prevalence varied by age, being highest among women with SCC, LSIL, and HSIL aged 40 to 49 years, 40 to 49 years, and 50 to 59 years, respectively. In conclusion, the findings revealed a very high prevalence of HPV in women with cervical lesions in Taizhou. Routine HPV tests must cover all common HPV genotypes in clinical practice.

To investigate the prevalence of high risk human papillomavirus (HPV) genital infection and cervical cancer in adult women from Shenzhen. Cluster sampling was used to investigate the prevalence of HPV infection and cervical cancer from women aged 20 - 59 years old living in Luohu, Futian, Nanshan, Longgang and Baoan districts in Shenzhen from April 2006 to April 2010. All women were detected for liquid-based cytology test (LCT) or Thinprep cytologic test (TCT) and high-risk HPV-DNA test with hybrid capture II (HC-II). All women with ≥ ASC-US by cytology and/or a positive HC-II test were asked to return for colposcopy and four-quadrant biopsy. Endocervical curettage was performed. Pathological finding were used as the gold standard of the diagnosis of cervical intraepithelial neoplasia. 10 210 women were involved in the study and 10 017 of them having completed data. The overall positive rate of high-risk HPV-DNA was 16.29%. HPV positive rates in 20-, 30-, 35-, 40-, 45-, 50-59 age groups were 17.37%, 15.59%, 16.33%, 14.74%, 17.16% and 17.98%, respectively. The curve of HPV infection rates in different age groups appeared a 'W' shape. HPV infection rates in the 25-years-olds and 50-59 year-olds groups were significantly higher than the other age groups (χ(2) = 4.50, P = 0.03). The overall prevalence rate of cervical intraepithelial lesions (CIN) was 7.52%, of which the prevalence rates of low-grade cervical intraepithelial lesions (CIN I) was 5.32% high-grade cervical intraepithelial lesions (CIN II/III) was 2.21%, cervical cancer was 0.12%. The prevalence of CIN I was significantly higher than the CIN II/III (χ(2) = 134.15, P < 0.001). The prevalence of cervical cancer in 45-age group was 0.12%, the highest. HPV infection rates increased with the grades of cervical lesions including women without CIN as 44.31%, in CINI as 70.73%, in CINII as 86.73%, and in CIN III as 96.75% and in cancer as 100.00%. The HPV infection rates were different in districts (χ(2) = 17.81, P = 0.03), with Futian and Luohu higher than those of Nanshan, Longgang and Baoan district. The prevalence rate of CIN in Baoan was lower than other districts. The CIN prevalence rates were not significantly different among the other districts of Shenzhen (χ(2) = 4.84, P = 0.18). The prevalence of cervical cancer was low in adult women living in Shenzhen, with cervical lesions still in the early stage. Prevention of HPV infection and treatment of CIN were the key points for the prevention of cervical cancer.

Chromosomal Biomarkers for Detection of Human Papillomavirus Associated Genomic Instability in Epithelial Cells of Cervical Cytology Specimens

Objective To study the relationship between female genital human papilloma virus (HPV) infection and Chlamydia trachomatis (CT) infection, and its correlation with cervical precancerous lesions and cervical cancer. Methods A total of 540 female outpatients were recruited. All the patients were given HPV, CT and cervical scraping examination. Cervical biopsy was conducted in patients with suspected cervical lesions. According to the results of HPV examination, 140 patients with confirmed HPV infection were designated as the observation group, and 400 patients negative to HPV were designated as control group. The relationship between HPV infection and CT infection, and its correlation with cervical lesions was analyzed. Results The incidence of cervical lesions in the observation group (21.4%) was significantly higher than that in control group (1.3%, P<0.000 1). According to type of HPV infection, patients in the observation group were divided into the high-risk group (78 cases), low risk group (32 cases) and mixed infection group (30 cases). The incidence of cervical lesions in the high-risk group (25.6%) and mixed infection group (26.7%) was significantly higher than that in the low-risk group (6.3%, P=0.009; P=0.019). The incidence of CT infection in the observation group (27.1%) was significantly higher than that in control group (3.3%, P<0.000 1). The incidence of CT infection in the high-risk group (33.3%) and the mixed infection group (36.7%) was significantly higher than that in the low-risk group (3.1%, P=0.021; P=0.019). Based on the presence of CT infection, the patients in the observation group were divided into HPV infection group and CT mixed infection group. The incidene of cervical lesions in the latter (57.8%) was significantly higher than that in the former (25.5%, P=0.046). And in CT mixed infection group, the incidence of cervical lesions in patients with high risk of HPV infection and mixed HPV were 39.3% and 50.0%, it was significantly higher than that of pure HPV and mixed infection in patients with high-risk HPV infection group, the incidence rate was 16.0% and 15.4%, the differences were statistically significant (P=0.026, P=0.017). Logistic regression analysis showed that high-risk HPV infection (OR=2.180, P=0.018), mixed infection of HPV and CT (OR=6.690, P=0.012) were risk factors for cervical lesions. Conclusion CT infection in female genital tract is closely related to HPV infection. Mixed infection of HPV and CT is an independent risk factor of cervical precancerous lesion and cancer. It is of important significance to further reduce the incidence of cervical cancer and precancerous lesions through the early screening of female genital HPV infection and CT infection, timely and effective treatment of mixed microbial infections. Key words: Genital tract; Human papilloma virus (HPV); Chlamydia trachomatis (CT); Cervical precancerous lesions; Cervical cancer

Distribution of HPV genotypes in 282 women with cervical lesions: evidence for three categories of intraepithelial lesions based on morphology and HPV type

ABSTRACTCervical cancer is an important health concern worldwide and is one of the leading causes of death in Mexican women. Previous studies have shown changes in the female genital tract microbe community related to human papillomavirus (HPV) infection and cervical cancer; yet, this link remains unexplored in many human populations. This study evaluated the vaginal bacterial community among Mexican women with precancerous squamous intraepithelial lesions (SIL). We sequenced the V3 region of the 16S rRNA gene in cervical samples from 228 Mexican women, including 121 participants with SIL, most of which were HPV positive, and 107 healthy women without HPV infection or SIL. The presence of SIL was associated with changes in composition (beta diversity) and with a higher species richness (Chao1). A comparison of HPV-positive women with and without SIL showed that microbiota changes occurred even in the absence of SIL. Multivariate association with linear models (MaAsLin) analysis yielded independent associations between HPV infection and an increase in the relative abundance of Brachybacterium conglomeratum and Brevibacterium aureum as well as a decrease in two Lactobacillus iners operational taxonomic units (OTUs). We also identified a positive independent association between HPV-16, the most common HPV subtype linked to SIL, and Brachybacterium conglomeratum. Our work indicates that HPV infection leading to SIL is primarily associated with shifts in vaginal microbiota composition, some of which may be specific to this human population.IMPORTANCE Human papillomavirus (HPV) plays a critical role in cervical carcinogenesis but is not sufficient for cervical cancer development, indicating the involvement of other factors. The vaginal microbiota is an important factor in controlling infections caused by HPV, and, depending on its composition, it can modulate the microenvironment in vaginal mucosa against viral infections. Ethnic and sociodemographic factors influence differences in vaginal microbiome composition, which underlies the dysbiotic patterns linked to HPV infection and cervical cancer across different populations of women. Here, we provide evidence for associations between vaginal microbiota patterns and HPV infection linked to ethnic and sociodemographic factors. To our knowledge, this is the first report of the species Brevibacterium aureum and Brachybacterium conglomeratum linked to HPV infection or squamous intraepithelial lesions (SIL).

To determine the effect of HIV-1 and HIV-2 infection on the prevalence of cervical human papillomavirus (HPV) and squamous intraepithelial lesions (SIL) in a population of high-risk women in Senegal. Cross-sectional study among 759 female commercial sex workers, including 68 with HIV-1, 58 with HIV-2, 14 with HIV-1 and 2, and 619 without HIV infection. Overall, HPV was detected in 43% of women by polymerase chain reaction (PCR), and in 7% by Southern transfer hybridization, with 7.4% of all women having SIL. The mean CD4 count was 820, 1205, and 727 x 10(6)/l for those with HIV-1, HIV-2, and dual HIV-1 and 2 infections, respectively, and 1447 x 10(6)/l for those without HIV infection. Both HIV-1 and HIV-2 were associated with HPV, as detected by PCR [HIV-1 odds ratio (OR), 2.9; 95% confidence interval (Cl), 1.7-4.9; HIV-2 OR, 1.7; 95% Cl, 1.0-2.9]. HIV-2 was also associated with cervical SIL, and although the association between HIV-1 and SIL did not attain statistical significance, a trend was apparent (HIV-1 OR, 1.8; 95% Cl, 0.7-4.7; HIV-2 OR, 2.9; 95% Cl, 1.2-7.2). Despite less immunosuppression with HIV-2, both HIV-1 and HIV-2 were associated with detection of HPV. HIV-2 was also associated with SIL. Further studies are needed to examine the risks of high-grade SIL and invasive cervical cancer with HIV-1 versus HIV-2 infection.

Our study assessed the factors associated with cervical squamous intra-epithelial lesions (SILs) and invasive cervical cancer, with special attention to human immunodeficiency virus (HIV) and human papillomavirus (HPV) infections. Women from 3 outpatient gynecology clinics of Abidjan, Côte d'Ivoire, were screened for cervical abnormalities: 151 women with low-grade SILs and 151 controls, 60 with high-grade SILs and 240 controls, and 13 with invasive cancer and 65 controls were enrolled in 3 case-control studies. Controls were chosen at random among the women without lesions, with a frequency matching for age and center. We used the PCR method for the detection of cervical HPV DNA and the restriction fragment length polymorphism analysis for HPV typing. HIV antibody testing and CD4 cell count were performed. In multivariate analyses, factors associated with cervical lesions were: for low-grade SILs, HPV positivity, HIV-1 seropositivity and parity >3; for high-grade SILs, HPV positivity, chewing tobacco, HIV-1 seropositivity and illiteracy, and for invasive cancer, HPV positivity only. We found a diversity of HPV types associated with SILs. In HIV-1-infected women, SILs occurred at an early stage of HIV disease. Women infected with both HIV-1 and HPV were at much higher risk of SILs than women infected with each of these 2 viruses separately. Invasive cancer was linked to HIV-2 infection in univariate analysis only. Our results suggest that the relation of SILs with HIV-1 infection is mainly explained by HPV infection and that HIV-1-infected African women may not often reach the invasive stage of cervical cancer.

Human papillomavirus (HPV) infection is a necessary but not sufficient factor for the development of invasive cervical cancer (ICC) and high-grade intraepithelial lesion (HSIL). Oxidative stress is known to play a crucial role in HPV infection and carcinogenesis. In this study, we comprehensively investigate the modulation of HPV infection, HSIL and ICC, and ICC through an exploration of oxidative stress-related genes: CβS, MTHFR, NOS3, ACE1, CYBA, HAP, ACP1, GSTT1, GSTM1, and CYP1A1. Notably, the ACE1 gene emerges as a prominent factor with the presence of the I allele offering protection against HPV infection. The association of NOS3 with HPV infection is perceived with the 4a allele showing a protective effect. The presence of the GSTT1 null mutant correlates with increased susceptibility to HPV infection, HSIL and ICC, and ICC. This study also uncovers intriguing epistatic interactions among some of the genes that further accentuate their roles in disease modulation. Indeed, the epistatic interactions between the BB genotype (ACP1) and DD genotype (ECA1) were shown to increase the risk of HPV infection, and the interaction between BB (ACP1) and 0.0 (GSTT1) was associated with HPV infection and cervical lesions. These findings underscore the pivotal role of four oxidative stress-related genes in HPV-associated cervical lesions and cancer development, enriching our clinical understanding of the genetic influences on disease manifestation. The awareness of these genetic variations holds potential clinical implications.

Colposcopic correlates of cervical papillomavirus infection

Little is known about the duration of precancerous cervical lesions in relation to human papillomavirus (HPV) infection. We estimated rates of progression and regression and sojourn times of cervical squamous intraepithelial lesions (SILs) according to HPV status. We used data from a longitudinal study of HPV infection and cervical neoplasia in São Paulo, Brazil. Cervical specimens were taken from 2404 women for Pap cytology and polymerase chain reaction-based HPV testing every 4-6 months over a period of 8 years. We used actuarial and non-actuarial analyses to measure time to and rates of lesion progression and regression according to status and type of HPV infection. During follow-up, 118 low-grade SIL (LSIL), 24 high-grade SIL (HSIL), and 173 atypical squamous cells of undetermined significance (ASCUS) events were detected. Mean time to progression from ASCUS to LSIL or worse and from LSIL to HSIL or worse was shorter in women with oncogenic HPV types than in women with no HPV infection (mean times for ASCUS progression were 67.0 and 88.0 months, respectively, in women with oncogenic HPV and no HPV, difference = 21.0 months, 95% confidence interval [CI] = 11.3 to 30.7 months; mean times for LSIL progression were 73.3 and 83.5 months, respectively, difference = 10.2 months, 95% CI = -0.15 to 20.6 months). Half of the LSILs regressed to normal or ASCUS within 6 months. Mean times for regression from ASCUS to normal, from LSIL to ASCUS or normal, and from HSIL/cervical intraepithelial neoplasia 2 to ASCUS or normal were longer for women with oncogenic HPV types (16.8 months, 95% CI = 7.5 to 26.2 months; 13.8 months, 95% CI = 8.8 to 18.7 months; and 17.1 months, 95% CI = 4.1 to 30.1 months, respectively) than for women with non-oncogenic HPV types (7.7 months, 95% CI = 5.2 to 10.2 months; 7.8 months, 95% CI = 5.3 to 10.2 months; 8.9 months, 95% CI = 3.3 to 14.6 months) or for women with no HPV infection (7.6 months, 95% CI = 6.9 to 8.4 months; 7.6 months, 95% CI = 6.4 to 8.7 months; and 7.0 months, 95% CI = 5.0 to 8.9 months, respectively). Precursor lesions of the cervix persist longer and progress more quickly in women with oncogenic HPV infections than in women with non-oncogenic infections or without HPV. Testing cervical lesions for oncogenic HPVs may help identify those that are likely to progress rapidly.

Data suggest that in adults, human papillomavirus (HPV) infections and their sequalae, squamous intraepithelial lesions (SILs), occur more commonly among human immunodeficiency (HIV)-infected women because of the HIV-associated CD4+ T-cell immunosuppression. Since adolescents are more likely to be early in the course of HIV and HPV infections, the study of both infections in this age group may help elucidate their initial relationship. To examine the prevalence of and risks for cervical HPV infection and SILs by HIV status in a population of adolescent girls. Subjects recruited at each of the 16 different US sites participating in a national study of HIV infection in adolescents. Cervical HPV DNA findings using polymerase chain reaction detection techniques and Papanicolaou smear from baseline visits. Infection with HPV was categorized into low- (rarely associated with cancer) and high- (commonly associated with cancers) risk types. Of 133 HIV-infected girls, 103 (77.4%) compared with 30 (54.5%) of 55 noninfected girls were positive for HPV (relative risk [RR], 1.4; 95% confidence interval [CI], 1.1-1.8). The risk was for high-risk (RR, 1.8; 95% CI, 1.2-2.7) but not low-risk (RR, 1.2; 95% Cl, 0.4-3.9) HPV types. Among the girls with HPV infection, 21 (70.0%) of the non-HIV-infected girls had normal cytologic findings compared with only 29 (29.9%) of the HIV-infected girls (P<.001). Multivariate analysis showed that HIV status was a significant risk for HPV infection (odds ratio [OR], 3.3; 95% CI, 1.6-6.7) and SIL (OR, 4.7; 95% CI, 1.8-14.8), but CD4 cell count and viral load were not associated with infection or squamous intraepithelial lesions. Only 9 girls had a CD4+ T-cell count of less than 0.2 cell X 10(9)/L. High prevalence of HPV infection in both groups underscores the risky sexual behavior in this adolescent cohort. Rates of HPV infection and SILs were higher among HIV-infected girls, despite similar sexual risk behaviors and the relatively healthy state of our HIV-infected group. Infection with HIV may enhance HPV proliferation through mechanisms other than CD4 immunosuppression, particularly early in the course of HIV infection.

Human papillomavirus (HPV) infection and cervical squamous intraepithelial lesions (SILs) were studied in 379 high-risk women. Human papillomavirus DNA was detected in 238 of 360 (66.1%) of the beta-globin-positive cervical samples, and 467 HPV isolates belonging to 35 types were identified. Multiple (2–7 types) HPV infections were observed in 52.9% of HPV-infected women. The most prevalent HPV types were HPV-52 (14.7%), HPV-35 (9.4%), HPV-58 (9.4%), HPV-51 (8.6%), HPV-16 (7.8%), HPV-31 (7.5%), HPV-53 (6.7%), and HPV-18 (6.4%). Human immunodeficiency virus type 1 (HIV-1) seroprevalence was 36.0%. Human papillomavirus prevalence was significantly higher in HIV-1-infected women (87 vs 54%, prevalence ratio (PR)=1.61, 95% confidence interval (CI): 1.4–1.8). High-risk HPV types (71 vs 40%, PR=1.79, 95% CI: 1.5–2.2), in particular HPV-16+18 (22 vs 9%, PR=2.35, 95% CI: 1.4–4.0), and multiple HPV infections (56 vs 23%, PR=2.45, 95% CI: 1.8–3.3) were more prevalent in HIV-1-infected women. High-grade SIL (HSIL) was identified in 3.8% of the women. Human immunodeficiency virus type 1 infection was strongly associated with presence of HSIL (adjusted odds ratio=17.0; 95% CI 2.2–134.1, P=0.007) after controlling for high-risk HPV infection and other risk factors for HSIL. Nine of 14 (63%) HSIL cases were associated with HPV-16 or HPV-18 infection, and might have been prevented by an effective HPV-16/18 vaccine.

Since the implementation of the cervical cancer screening program in Lithuania in 2004, cervical cancer incidence rates have stabilized during a 4-year period: in 2006 and 2007, 508 and 485 new cases, respectively, were diagnosed. Human papillomavirus (HPV) infection is one of the main risk factors for cervical cancer and development of intraepithelial lesions. However, not only HPV, but also HPV type, is a very important factor for malignant transformation. Cervical intraepithelial lesions with HPV 16 and 18 more frequently progress to cancer. To date, in Lithuania, studies only on HPV prevalence and risk factors have been carried out, and less attention has been paid to the identification of HPV types. The aim of this study was to identify the most common HPV types in women with various cytological lesions. A total of 246 women with various cytological lesions (atypical squamous cells of undetermined significance [ASCUS], low-grade squamous intraepithelial lesion [LSIL], and high-grade squamous intraepithelial lesion [HSIL]) were included into the study. All the women were screened for HPV infections followed by HPV typing for types 6, 11, 16, 18, 31, 33, 45, and 59. Polymerase chain reaction was used. Less than half (45.5%) of women with cytological lesions were infected with HPV. The highest prevalence of HPV was detected in women with HSILs (62.1%) and CIN2 (86.7%). HPV typing revealed that the most frequent type was HPV 16 (64.3%); HPV 18 and HPV 33 accounted for 5.4% and 4.5% of cases, respectively. Based on cytologic diagnosis, HPV 16 was more frequently found in women with HSILs than women with ASCUS (77.8% vs. 50.0%). The prevalence of HPV infection in women with cytological lesions was 45.5%. The highest prevalence of HPV was detected in women with HSILs (cytologic investigation) and CIN2 (histologic investigation). HPV 16 is the most common type in women with various cervical intraepithelial lesions.