Grade Cervical Lesions Research Articles

Association between human papillomavirus (HPV) 16, HPV18, and other HR-HPV viral load and the histological classification of cervical lesions: Results from a large-scale cross-sectional study.

The relationship between HPV viral load and histological grades in the development of cervical cancer is in argument. It is helpful to better understand the association by quantitatively detecting viral load of HPV16, 18, and a pool of 12 other high-risk HPV type (OT) independently on the samples of precancer and cancer. A cross-sectional study was performed in five medical centers of China. Histological diagnosis made by local pathologists was adjudicated via a pathology expert panel. A fully automated real-time PCR test was used for the measurement of HPV16, 18, OT, and human β-globin gene. A total of 2,513 women [1,341 normal, 209 low grade intraepithelial lesion (LSIL), 392 high grade intraepithelial lesion (HSIL), 520 squamous cell carcinoma (SCC), and 51 adenocarcinoma (ADC)] were included. There is a linear increase in the total 14 HPV viral load with histological grade from normal to SCC. This trend was not observed in HPV18 infection but HPV16. The viral load for OT was low in normal, peaked in LSIL and HSIL, and declined in SCC and ADC. In the co-infection of HPV16 and HPV18, HPV16 viral load was significantly higher than HPV18 in LSIL and HSIL. In co-infection of HPV16 and OT, higher HPV16 viral load was also seen in SCC and ADC. Viral load of HPV16 increases with cervical lesion grade and is predominant in cervical cancer. HPV18 viral load is low in precancer, but going up in cancer. OT viral load shows inverse trend of HPV18. J. Med. Virol. 89:535-541, 2017. © 2016 Wiley Periodicals, Inc.

Viral load and integration status of HPV58 associated with cervical lesion severity in women of Northeast China.

We aimed to evaluate the viral load and integration status of human papillomavirus 58 in women with different grades of cervical lesions to determine whether viral load and integration status are related to malignant transformation in HPV58-infected women. A total of 212 cervical specimens were collected from women in Northeast China who had undergone human papillomavirus genotyping and were HPV58-positive. The HPV58 viral load was determined using real-time polymerase chain reaction, and the integration status was discriminated using the ratio of HPV58 E2 gene copy number to E6 gene copy number. The median HPV58 viral load in women with normal cervix or cervicitis, low-grade squamous cell intraepithelial lesion, high-grade squamous cell intraepithelial lesion and cervical cancer was 352.12, 864.21, 1199.75 and 693.04 copies/genome, respectively. High significance was obtained when comparing the viral load of infected women presenting normal/cervicitis with that of the women either with precancerous cervical lesions or cervical cancer (P < 0.05). The HPV58 genome was in the episomal form in 35 samples (16.5%), mixed episomal and integrated forms in 165 (77.8%) samples, and completely integrated into the host genome in 12 (5.7%) samples. The HPV58 E2/E6 copy number ratio in the cervical cancer group was significantly lower than that in the other groups (P < 0.01). The HPV58 viral load in patients with precancerous cervical lesions or cervical cancer increases significantly with disease progression. The HPV58 E2/E6 copy number ratio in patients with cervical cancer is lower than that for less severe cervical lesions, suggesting a high degree of viral integration may be a considerable risk factor for cervical cancer.

Analysis of E2 gene integrity in HPV16 and HPV58 viruses isolated from women with cervical pathology.

Integration of human papillomavirus (HPV) DNA into human cells accompanied by the disruption of the viral genome has been described as a prerequisite for cancer development. This study aimed to investigate E2 gene integrity of HPV16 and HPV58 viruses isolated from infected women with cervical lesions. Forty-two HPV16- and 31 HPV58-positive samples were analysed. E2 integrity was assumed when all fragments covering the E2 gene were amplified with specific polymerase chain reaction primers. Overall, in 59% of the samples, at least one fragment was not amplified in HPV16- (57%) and HPV58-positive samples (61%). Samples from high-grade squamous intraepithelial lesions had the highest frequency of E2 gene disruptions (73%), followed by samples from low-grade squamous intraepithelial lesions (63%) and, finally, samples from invasive cervical cancer (35%). Association between the integrity status of the E2 gene, and lesion grade was assessed by the chi-squared test applied to the combined set of viruses (p = 0.6555) or to populations of the same virus type (HPV58, p = 0.3101; HPV16, p = 0.3024). In conclusion, in this study, no association was found between the presence of E2 gene disruptions and the grade of cervical lesions caused by HPV16 and HPV58.

Validity parameters of the HPV detection tests HC2 and APTIMA with and without cytology smears after surgical treatment of high grade cervical intraepithelial neoplasia lesions

Validity parameters of the HPV detection tests HC2 and APTIMA with and without cytology smears after surgical treatment of high grade cervical intraepithelial neoplasia lesions

HPV 16 and 18 viral loads are greater in patients with high-grade cervical epithelial lesions.

Cervical cancer is the second most common cancer in women worldwide. High-risk infection with HPV type 16 or type 18 is the most important risk factor associated with the development of cervical cancer. To determine the viral load of HPV-16 and HPV-1 8 in samples from women with cervical epithelial lesion in the State of Colima, Mexico. A cross-sectional analytic study was conducted that included 45 samples positive for HPV- 16 and 45 samples positive for HPV-1 8 from patients with cervical cancer or precursor lesion. Real time PCR was employed to determine the number of copies /101 cells. Viral load was determined in the two groups of patients and correlated with tumor grade. THe authors found that the HPV-1 6 viral load was greater than that of HPV-18 through a Mann-Whitney U analysis, resulting in ap = 0.000; as the malignancy of the cervical lesion progressed, the viral load increased, and HPV-16 showed a moderate positive association with an r = 0.509 and a p = 0.000, whereas HPV-18 showed a weak positive correlation with an r = 0.372 and a p = 0.0 12. The viral load of HPV-16 was greater than that of HPV-18. The HPV-16 viral load had a moderate positive association in relation to cervical lesion severity, whereas the viral load of HPV- 18 had a weak positive correlation with respect to the cervical lesion grade.

Association of human papillomavirus type 16 and its genetic variants with cervical lesion in Korea.

Persistent human papillomavirus type 16 (HPV16) is the major risk factor for cervical cancer. HPV16 intratypic variants differ in their geographical distribution and oncogenic potential. This study aimed to analyze the distribution of HPV16 variants and their association with cervical lesion histopathology in Korean women. In total, 133 HPV16-positive cervical samples from women admitted to Seoul National University Boramae Hospital were analyzed by sequencing E6, E7, and L1 genes and the long control region (LCR), and the variant distribution according to cervical lesion grade was determined. Isolates were grouped into a phylogenetic lineage, and A1-3, A4, C, and D sublineages were detected in 54.1, 37.8, 0.7, and 7.4% of samples, respectively. The most commonly observed LCR variations were 7521G>A (91.5%), 7730A>C (59.6%), and 7842G>A (59.6%). Furthermore, A4 or D sublineage-positive women had a higher risk for cervical cancer than women who were positive for A1-3. Among HPV phylogenetic clusters, A1-3 was the predominant sublineage, and within A1-3, the 350G polymorphism was highly frequent. These results differed from those of previous studies in Korea and other Asian countries. The findings suggest that cervical neoplasia incidence in HPV16-infected patients could be affected by the distribution of HPV16 variants in the population.

Industry-academic partnerships: an approach to accelerate innovation

BackgroundBiotechnology companies are process-driven organizations and often struggle with their ability to innovate. Universities, on the other hand, thrive on discovery and variation as a source of innovation. As such, properly structured academic-industry partnerships in medical technology development may enhance and accelerate innovation. Through joint industry-academic efforts, our objective was to develop a technology aimed at global cervical cancer prevention. MethodsOur Center for Medical Innovation assembled a multidisciplinary team of students, surgical residents, and clinical faculty to enter in the University of Utah's annual Bench-to-Bedside competition. Bench-to-Bedside is a university program centered on medical innovation. Teams are given access to university resources and are provided $500.00 for prototype development. Participation by team members are on a volunteer basis. Our industry partner presented the validated need and business mentorship. The team studied the therapeutic landscape, environmental constraints, and used simulation to understand human factors design and usage requirements. A physical device was manufactured by first creating a digital image (SOLIDWORKS 3D CAD). Then, using a 3-dimensional printer (Stratasys Objet30 Prime 3D printer), the image was translated into a physical object. Tissue burn depth analysis was performed on raw chicken breasts warmed to room temperature. Varying combinations of time and temperature were tested, and burn depth and diameter were measured 30 min after each trial. An arithmetic mean was calculated for each corresponding time and temperature combination. User comprehension of operation and sterilization was tested via a participant validation study. Clinical obstetricians and gynecologists were given explicit instructions on usage details and then asked to operate the device. Participant behaviors and questions were recorded. ResultsOur efforts resulted in a functional battery-powered hand-held thermocoagulation prototype in just 72 d. Total cost of development was <$500. Proof of concept trials at 100°C demonstrated an average ablated depth and diameter of 4.7 mm and 23.3 mm, respectively, corresponding to treatment efficacy of all grades of precancerous cervical lesions. User comprehension studies showed variable understanding with respect to operation and sterilization instructions. ConclusionsOur experience with using industry-academic partnerships as a means to create medical technologies resulted in the rapid production of a low-cost device that could potentially serve as an integral piece of the “screen-and-treat” approach to premalignant cervical lesions as outlined by World Health Organization. This case study highlights the impact of accelerating medical advances through industry-academic partnership that leverages their combined resources.

Association between p21 Ser31Arg polymorphism and the development of cervical lesion in women infected with high risk HPV

Infection by high-risk human papillomavirus (HR-HPV) and single nucleotide polymorphism (SNP) in genes involved in cell cycle control, as p21 and p27, are important factors in the development of different types of human cancers. This study aims at investigating whether both the p21 Ser31Arg and p27 V109G polymorphisms are associated with susceptibility to the development of cervical lesions in women HR-HPV positive. We analyzed 132 women HPV positive and with cervical lesions or CC and 154 healthy control (HPV negative and without cervical lesions). p21 Ser31Arg and p27 V109G polymorphisms were analyzed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method and sequencing. The p21 31Arg allele was associated with susceptibility for the development of cervical lesions (P* = 0.0009), while p27 V109G polymorphism showed no significant differences for this association (P* = 0.89). However, the combined effect of the polymorphisms showed that the presence of the CC genotype (SNP p21 Ser31Arg) conferred protection for the development of cervical lesions (OR = 0.39). p21 Ser31Arg and p27 V109G polymorphisms were not associated with the grade of cervical lesions (CINI, CINII, and CINIII) or CC (P* > 0.05). The HR-HPV more frequent in this study were of 16 (57.6%) and 18 (37.1%) types; however, no association was observed when both polymorphisms and risk factors analyzed were compared (P* > 0.05). Our findings suggest a possible association between p21 Ser31tabArg polymorphism and susceptibility to the development of cervical lesions in women from Pernambuco. Brazil.

Prevalence of Human Papillomavirus Genotypes Among Women With High-Grade Cervical Lesions in Beijing, China.

The aim of the study is to investigate the prevalence of high-risk human papillomavirus (hr-HPV) genotypes among Han women with high-grade cervical lesions in Beijing, China.Cervical cell specimens from patients with histopathologically confirmed cervical lesions at 7 hospitals in Beijing were examined with a validated HPV kit for 13 hr-HPV genotypes during the study period. The patients were divided into a low-grade cervical lesions group (cervical intraepithelial neoplasia grade 1, CIN1) and a high-grade cervical lesions group (CIN2+, including cervical intraepithelial neoplasia grade 2, CIN2; cervical intraepithelial neoplasia grade 3, CIN3; squamous cervical cancer, SCC; and adenocarcinoma of the cervix, ACC) based on the histopathology results.A total of 2817 eligible patients were enrolled, including 610 cases identified as CIN1 and 2207 as CIN2+. The hr-HPV positive rates in the CIN1 and CIN2+ groups were 78.2% (477/610) and 93.3% (2060/2207), respectively. The most frequently detected genotypes were HPV16, 58, 52 and18 in the CIN1 group and HPV16, 58, 33, and 52 in the CIN2+ group, in descending order of prevalence. In addition, the prevalence of HPV18 among the patients with ACC was 28.6% (14/49), significantly >7.2% (54/752) prevalence among the SCC patients (P < 0.001). Additionally, significantly more women in the CIN2+ group had multiple infections compared with those in the CIN1 group (38.1% and 24.9%, respectively; P < 0.001). However, as the cervical lesion grade increased, the prevalence of multiple hr-HPV infections gradually deceased to 44.2% in the CIN2 patients, 36.7% in the CIN3 patients, and 35.3% in the cervical cancer (CC) patients, which included SCC and ACC patients. In cases of multiple hr-HPV infections in the CIN2+ group, double infections accounted for ∼76.6%, and HPV16+58, HPV16+52, and HPV16+18 were the most common combinations, in descending order. The most frequent combination for triple infections was HPV16+58+31, with a rate of 4.2%. The highest positive rate occurred in the ≤24 year-old group for all types of cervical lesions.The prevalence of HPV genotypes in the targeted population with high-grade cervical lesions differs from that of other countries. This information could be helpful for the prevention of CC in Beijing, China.

Significance of p53, pRb and Ki-67 markers in Cervical intraepithelial lesion and Malignancy

To study and to derive the significance of expression of p53, pRb and Ki-67 markers in various grades of cervical intraepithelial lesions and malignancy in a tertiary hospital situated in southern part of India which caters the rural and semi-urban population. A total of 120 cervical tissue samples were included. These represented normal, dysplasia and malignancy. Immunohistochemical staining was performed for p53, Ki-67 and pRb in formalin-fixed, paraffin-embedded tissue sections of the uterine cervix using horse-peroxidase method. Descriptive statistical analysis was done; significance was assessed at 5% level of significance. The mean value of the markers was compared between normal and pathological lesions separately using Independent “t” test. There was significant association of p53 expression between normal cervical epithelium and low grade squamous intraepithelial lesion (LSIL) (p=0.023), squamous cell carcinoma (SCC) (p<0.001) and adenocarcinoma AC (p=0.004), but no significant association with high grade squamous intraepithelial lesion (HSIL) (p=0.09). In case of pRb(n) (n=nuclear) expression significant association was found when normal was compared with LSIL (p<0.001) and HSIL (p=0.001), no association was found with SCC (p=0.207) and AC (p=0.322). pRb(c) (c=cytoplasmic) expression showed significant association when normal was compared with HSIL(p=0.03), SCC (p<0.001) and AC (p<0.001), but no association was found with LSIL. Whereas Ki-67 expression showed highly significant association with LSIL (p=0.012), HSIL (p<0.001), SCC (p<0.001) and AC (p<0.001). p53 expression progressively increased from normal cervical epithelium to intraepithelial lesion to malignant lesion. pRb expression showed shift of expression of pRb(n) in intraepithelial lesions to expression of pRb(c) in HSIL to frank malignancy. Ki-67 expression was directly proportional to the degree of dysplasia to malignant lesion.

Correlation of plasma nitrite/nitrate levels and inducible nitric oxide gene expression among women with cervical abnormalities and cancer

Cervical cancer is caused by infection with high risk human papillomavirus (HR-HPV). Inducible nitric oxide synthase (iNOS), a soluble factor involved in chronic inflammation, may modulate cervical cancer risk among HPV infected women. The aim of the study was to measure and correlate plasma nitrite/nitrate levels with tissue specific expression of iNOS mRNA among women with different grades of cervical lesions and cervical cancer. Tissue biopsy and plasma specimens were collected from 120 women with cervical neoplasia or cancer (ASCUS, LSIL, HSIL and invasive cancer) and 35 women without cervical abnormalities. Inducible nitric oxide synthase (iNOS) mRNA from biopsy and plasma nitrite/nitrate levels of the same study subjects were measured. Single nucleotide polymorphism (SNP) analysis was performed on the promoter region and Ser608Leu (rs2297518) in exon 16 of the iNOS gene. Differences in iNOS gene expression and plasma nitrite/nitrate levels were compared across disease stage using linear and logistic regression analysis. Compared to normal controls, women diagnosed with HSIL or invasive cancer had a significantly higher concentration of plasma nitrite/nitrate and a higher median fold-change in iNOS mRNA gene expression. Genotyping of the promoter region showed three different variations: A pentanucleotide repeat (CCTTT) n, −1026T > G (rs2779249) and a novel variant −1153T > A. These variants were associated with increased levels of plasma nitrite/nitrate across all disease stages. The higher expression of iNOS mRNA and plasma nitrite/nitrate among women with pre-cancerous lesions suggests a role for nitric oxide in the natural history of cervical cancer.

Comparative study of HPV16 integration in cervical lesions between ethnicities with high and low rates of infection with high-risk HPV and the correlation between integration rate and cervical neoplasia.

The etiology of a high incidence of cervical cancer in populations with a low human papillomavirus (HPV) infection rate is unclear. The current study aimed to investigate the role of HPV16 DNA integration in cervical lesions in women of Han and Uygur ethnicity and to explore the association between viral integration and a high cervical cancer morbidity with a low HPV infection rate. DNA was extracted from the biopsy specimens of cervical lesions of 379 patients of Uygur ethnicity and 464 patients of Han ethnicity, and multiple quantitative polymerase chain reaction (qPCR) assays were performed to determine the copy numbers of the HPV16 E2 and E6 genes. The copy number of the HPV16 DNA was evaluated according to the E2/E6 ratio. Among these cases, 122 Uygur and 121 Han specimens were found to be HPV16 positive. In the two populations, the percentage of cases with HPV16 integration (the sum of integrated-type infection only or a mixture of free-and integrated-type infection) increased with the grade of the cervical lesions (P<0.001). Within groups with the same cervical lesion grade, no significant differences in HPV16 integration were found between women of Uygur and Han ethnicity (rank sum test, P>0.05). No significant differences in the distribution of the HPV16 integration rate according to lesion grade were found in either population (P>0.05). When the two subpopulations were considered as one sample population, the integration rate significantly increased with lesion grade (P=0.02). These results indicate that the integration rate of HPV16 E2 may serve as a molecular biological marker for the development of cervical lesions.

HPV16 RNA patterns defined by novel high-throughput RT-qPCR as triage marker in HPV-based cervical cancer precursor screening

ObjectiveCervical cancer precursor screening by HPV testing has a low positive predictive value for advanced lesion. HPV16 RNA patterns characteristic for HPV16-transformed cells but based on laborious, cost-intensive singleplex NASBA reactions promised high value in triaging HPV16 DNA-positive women. MethodsWe developed two high-throughput reverse transcriptase quantitative (RT-q) PCR assays for the HPV16 transcripts E6*I, E1^E4 and E1C and the cellular transcript ubiquitin C and analysed RNA of 158 singly HPV16 DNA-positive cervical cell samples archived in PreservCyt buffer for the presence of transformation-associated HPV16 RNA patterns, i.e., upregulation of E6*I relative to E1^E4 and/or presence of E1C. ResultsHPV16 RNA pattern analyses classified 85% of 58 samples diagnosed ≤CIN1 (no cytologically and histologically detectable cervical lesion or CIN grade 1) as negative and 90% of 59 samples diagnosed as ≥CIN3 (CIN grade 3 or invasive cancer) as positive. Among 41 CIN grade 2 samples representing an intermediate lesion group, 49% were HPV16 RNA patterns-positive. Interestingly, 3 of 4 HPV16 RNA patterns-positive lesions initially diagnosed as ≤CIN1 at follow-up 5–24months later had progressed to ≥CIN2. ConclusionsWe successfully developed and validated a second generation of HPV16 RNA patterns assay by rapid RT-qPCR as triage marker for HPV16 DNA-positive women offering clinical utility to distinguish between the need for immediate colposcopy and continued observation. Limited follow-up data suggests that HPV16 RNA patterns-positivity in ≤CIN1 lesions can predict disease progression.

Tissue Detection and Typisation of Human Papillomavirus in Women with Squamous Intraepithelial Lesions and Squamous Invasive Carcinoma of the Cervix

AbstractIntroduction. The most common risk factor for intraepithelial lesions and cervical carcinoma is infection with human papillomavirus (HPV), especially with high-risk HPV genotypes. Only persistent, high-risk HPV infections represent a major risk factor for intraepithelial lesions and cervical cancer. The aims of the study were: detection and typisation of HPV genotypes, which are the most common causes of intraepithelial lesions and cervical cancer, determination of the correlation between HPV infection and histopathological diagnosis, and the correlation between the grade of lesion of the cervix and oncogenic potential of the virus as well as determination of the most affected age group of patients.Methods. This cross-sectional study included 100 sexually active patients with an abnormal Pap test at the age from 20 to 69 years (39±10.77), and was conducted at the University Clinic of Gynecology and Obstetrics in Skopje and University Clinic of Radiotherapy and Oncology in Skopje in the period from January 2014 to August 2014. In all patients colposcopic cervical biopsy was made with endocervical curettage for histopathological analysis and cervical biopsy for detection and HPV typisation. HPV detection and typisation were done using polymerase chain reaction (PCR) and reverse hybridization.Results. HPV DNA was detected in 81.0% (81/100) of the examined women. The relationship between the prevalence of high-risk and low-risk HPV DNA genotypes was 72.0%:9.0%. The frequency of high-risk HPV DNA genotypes ranged from: 54.5% (12/22) in productive HPV infection-mild dysplasia, 86.4% (19/22) with moderate dysplasia, 91.2% (21/23) in severe dysplasia to 100% of squamous cell carcinoma in situ (6/6) and invasive squamous cell carcinoma (5/5). Mixed HPV infection was detected in 19.0% (19/100) of all patients, in 23.5% (19/81) of HPV DNA positive patients. The most common HPV DNA genotypes, in descending order, were HPV 16 (43.2%), HPV 31 (28.4%), HPV 18 (14.8%), etc. The highest frequency of HPV infection was found in patients under 30 years of age.Conclusion. There was an association between HPV infection and squamous intraepithelial lesions and squamous invasive carcinoma of the cervix. There was a correlation between the grade of cervical lesion and the oncogenic potential of the virus. The results of this study may be useful for building a national strategy in the fight against cervical cancer.

P16INK4a immunohistochemical and histopathologic study of Pap test cases interpreted as HSIL without CIN2-3 identification in subsequent cervical specimens.

Tissue biopsy following a pap test diagnosis of high grade squamous intraepithelial lesion (HSIL) sometimes fails to confirm the presence of a corresponding high grade cervical intraepithelial lesion (CIN 2-3), leading to confusion as to how best to manage the patient. It has been shown that these patients are still at higher risk for future detection of CIN 2-3 even if the initial biopsy fails to detect it. It has also been shown that immunohistochemical staining for p16INK4a can be reliably used as a surrogate marker for infection with high risk human papillomavirus in cervical samples, and that it can be used to enhance detection of CIN2-3 in cases where suspicion is high. To evaluate the use of p16INK4a staining in cases of HSIL which were not confirmed on initial biopsy, two pathologists rereviewed Pap and hematoxylin and eosin preparations from all such cases seen within the preceding 3 years. Immunohistochemical study for p16INK4a was performed and graded on representative sections. The results were tabulated and analyzed. Of the identified 596 HSIL Pap cases, 82% had HSIL on initial cervical specimens. Table 1 shows the 56 cases included in the study with graded and stratified p16INK4a results. On review of the p16INK4a slides, only 2 cases could be upgraded to HSIL/CIN2-3 from the original diagnosis. p16INK4a 2-3+ was expressed more frequently in cases initially interpreted on Pap as low-grade cervical lesion as compared with benign (24 of 35 cases). In the younger than 24-yr-old group p16 2-3+ reactivity was more frequent in benign and low-grade cervical lesion/CIN1 groups (benign: 3 of 5 cases, and CIN1: 6 of 8), and p16 negative reactivity was not seen. p16INK4a was graded 0-1+ more frequently in specimens interpreted as benign in the older than 25 yr olds (10 of 16 cases). The study suggests some diagnostic benefit from the use of p16INK4a immunohistochemical study on cervical specimens from women with a HSIL Pap test without HSIL/CIN2-3 on original hematoxylin and eosin review.

Sociodemographic and clinical factors of women with HPV and their association with HIV.

OBJECTIVE: to identify the association between HIV-seropositive or HIV-seronegative status and the sociodemographic and clinical variables of women with genital HPV infection. METHOD: cross-sectional, retrospective study in a reference service in Ribeirão Preto. A total of 824 women undergoing HIV testing who had high or low grade cervical intraepithelial lesions or condylomatous genital lesions caused by HPV were studied. The chi-square test and logistic regression analysis with the calculation of the odds ratio and a confidence interval of 95% were conducted to verify the association. RESULTS: a higher probability of seropositivity was identified for non-white women; with low education; widowed; who consumed alcohol, tobacco or illicit drugs; with hepatitis C; who had multiple partners; and that worked as prostitutes. CONCLUSION: the increasing impairment of women due to sexually transmitted infections, considering the influence of the socioeconomic and behavioral context on the course of these infections, highlights the importance of public policies that establish intervention strategies involving the prevention, early diagnosis and timely treatment of these diseases, so that there is the promotion of quality of life in this population.

Genetic characterization and clinical implications of human papillomavirus type 16 (HPV16) variants from northeastern Argentina

BackgroundHuman papillomavirus type 16 (HPV16) plays a central role in the development of cervical cancer. Worldwide studies indicate the existence of HPV16 variants that show different geographic distributions and oncogenic potential. ObjectiveOur goal was to describe the genetic variation of HPV16 isolates identified in urban women with different grades of cervical lesions living in northeastern Argentina. Study designWe analyzed 116 HPV16-positive cervical samples (16 NLIM, 62 L-SIL, 16 H-SIL and 22 cervical cancer) from patients attending health centers in Misiones (Argentina) during 2006–13. HPV16 isolates were genetically characterized through PCR amplification and direct sequencing of 364bp within the long control region, and the resulting sequences classified into variants based on phylogenetic analysis (lineages A, B, C and D). A potential association between HPV16 variants and lesion grade was evaluated through an odds ratio (OR) test. A temporal framework for the origin of HPV16 variants was assessed through coalescence analysis (BEAST v 1.7.5). ResultsPhylogenetic analysis of HPV16 sequences showed that 92.1% of the samples clustered with lineage A, and 6.9% to lineage D. HPV16 variants from lineage D were more frequently associated with high-grade lesions and cancer (HSIL+) than lineage A variants at an OR of 13.8 (1.6–117.0). The time to most common recent ancestor (tMCRA) of all variants was 119,103years before present (HPD 95%=48,486–197,239), a date consistent with the time frame for modern human evolution. ConclusionOur results suggest that HPV16 variants from lineage D may represent an additional risk factor for the development of cervical cancer in women living in northeastern Argentina. This study provides new information about viral isolates present in Argentina that will contribute to the monitoring of HPV16 infection in the vaccine era.

Potential impact of a 9-valent HPV vaccine in HPV-related cervical disease in 4 emerging countries (Brazil, Mexico, India and China)

BackgroundWe estimated the potential impact of an investigational 9-valent human papillomavirus (HPV) vaccine (HPVs 6/11/16/18/31/33/45/52/58) in HPV-related cervical disease in Brazil, Mexico, India and China, to help to formulate recommendations on cervical cancer prevention and control. MethodsEstimations for invasive cervical cancer (ICC) were based on an international study including 1356 HPV-positive cases for the four countries altogether, and estimations for precancerous cervical lesions were extracted from a published meta-analysis including 6 025 HPV-positive women from the four mentioned countries. Globocan 2012 and 2012 World Population Prospects were used to estimate current and future projections of new ICC cases. ResultsCombined proportions of the 9 HPV types in ICC were 88.6% (95%CI: 85.2–91.3) in Brazil, 85.7% (82.3–88.8) in Mexico, 92.2% (87.9–95.3) in India and 97.3% (93.9–99.1) in China. The additional HPV 31/33/45/52/58 proportions were 18.8% (15.3–22.7) in Brazil, 17.6% (14.2–21.2) in Mexico, 11.3% (7.5–16.1) in India and 11.9% (7.5–17.2) in China. HPV6 and 11 single types were not identified in any of the samples.Proportion of the individual 7 high risk HPV types included in the vaccine varied by cytological and histological grades of HPV-positive precancerous cervical lesions. HPV 16 was the dominant type in all lesions, with contributions in low grade lesions ranging from 16.6%(14.3–19.2) in Mexico to 39.8% (30.0–50.2) in India, and contributions in high grade lesions ranging from 43.8% (36.3–51.4) in Mexico to 64.1% (60.6–67.5) in Brazil. After HPV 16, variations in other majors HPV types were observed by country, with an under representation of HPV 18 and 45 compared to ICC. ConclusionThe addition of HPVs 31/33/45/52/58 to HPV types included in current vaccines could increase the ICC preventable fraction in a range of 12 to 19% across the four countries, accounting the 9-types altogether 90% of ICC cases. Assuming the same degree of efficacy of current vaccines, the implementation of the 9-valent HPV vaccine in Brazil, Mexico, India and China would substantially impact on the reduction of the world cervical cancer burden.

Association between cervical lesion grade and micronucleus frequency in the Papanicolaou test.

The aim of this study was to evaluate the association between the frequency of micronuclei (MN) and the cellular changes detected in the conventional Papanicolaou test. One hundred and seventy-four Papanicolaou test smears with cellular changes were examined. MN screening was done in cytopathological smears by counting 1,000 cervical cells in a light microscope. MN frequencies were significantly higher in the group with cellular changes compared to the control group (p < 0.001). The mean MN frequencies were 0.95 ± 1.12 (mean ± SD) in the control group (n = 223), 2.98 ± 1.20 in individuals with atypical squamous cells of undetermined significance (ASC-US) (n = 50), 4.04 ± 1.45 in cervical intraepithelial neoplasia (CIN) I (n = 52), 5.97 ± 1.83 in CIN II (n = 30), 7.29 ± 1.55 in CIN III (n = 17) and 8.64 ± 1.55 in invasive cancer (n = 25). These findings suggest that MN monitoring should be included as an additional criterion for the early detection of cytogenetic damage in routine examinations. This monitoring should be done in the same smear as used for cytopathological examination. More specific and systematic studies are necessary to confirm this proposal.

The expression of GLTSCR2 in cervical intra-epithelial lesion and cancer.

GLTSCR2 was originally identified as a candidate tumor suppressor in several types of cancers. The present study was to investigate the expression pattern of GLTSCR2 in different cervical lesion tissues, appraise its potential role in cervical cancerogenesis. 225 histologically confirmed samples representing a wide range of cervical disease processes were studied in this study using immunohistochemistry (IHC). Compared with normal cervix and low-grade cervical intra-epithelial neoplasia (CIN I), cervical cancer and high-grade cervical intra-epithelial neoplasia (CIN II-III) tissues had lower expression scores of IHC staining of GLTSCR2. The positive staining signals of GLTSCR2 in CIN were decreased according to the grades of the intra-epithelial lesions. The IHC scores of GLTSCR2 in cervical cancer tissues were significantly lower than that in adjacent normal tissues. Different from previous report, we also found that GLTSCR2 was expressed in both nucleus and cytoplasm of cervical tissues, and the cytoplasmic expression of GLTSCR2 was observed in almost all tissues. We demonstrated the GLTSCR2 expression decreased with the rise of the grade of cervical lesions. GLTSCR2 may play an important role in carcinogenesis of cervical cancer.