Stages Of Cervical Disease Research Articles

Age, absolute CD4 count, and CD4 percentage in relation to HPV infection and the stage of cervical disease in HIV-1-positive women.

A subgroup of women who are co-infected with human immunodeficiency virus type 1 (HIV-1) and human papillomavirus (HPV), progress rapidly to cervical disease. We characterized HPV genotypes within cervical tumor biopsies, assessed the relationships of cervical disease stage with age, HIV-1 status, absolute CD4 count, and CD4 percentage, and identified the predictive power of these variables for cervical disease stage in a cohort of South African women.We recruited 181 women who were histologically diagnosed with cervical disease; 87 were HIV-1-positive and 94 were HIV-1-seronegative. Colposcopy-directed tumor biopsies were confirmed by histology and used for genomic DNA extraction. The Roche Linear Array HPV genotyping test was used for HPV genotyping. Peripheral whole blood was used for HIV-1 rapid testing. Fully automated FC500MPL/CellMek with PanLeucogate (PLG) was used to determine absolute CD4 count, CD4 percentage, and CD45 count. Chi-squared test, a logistic regression model, parametric Pearson correlation, and ROC curves were used for statistical analyses. We used the Benjamini-Horchberg test to control for false discovery rate (FDR, q-value). All tests were significant when both P and q were <.05.Age was a significant predictor for invasive cervical cancer (ICC) in both HIV-1-seronegative (P < .0001, q < 0.0001) and HIV-1-positive women (P = .0003, q = 0.0003). Sixty eight percent (59/87) of HIV-1-positive women with different stages of cervical disease presented with a CD4 percentage equal or less than 28%, and a median absolute CD4 count of 400 cells/μl (IQR 300-500 cells/μl). Of the HIV-1-positive women, 75% (30/40) with ICC, possessed ≤28% CD4 cells vs 25% (10/40) who possessed >28% CD4 cells (both P < .001, q < 0.001). Furthermore, 70% (28/40) of women with ICC possessed CD4 count >350 compared to 30% (12/40) who possessed CD4 count ≤ 350 (both P < .001, q < 0.001).Age is an independent predictor for ICC. In turn, development of ICC in HIV-1-positive women is independent of the host CD4 cells and associates with low CD4 percentage regardless of absolute CD4 count that falls within the normal range. Thus, using CD4 percentage may add a better prognostic indicator of cervical disease stage than absolute CD4 count alone.

Učestalost i histološko-citološka korelacija premalignih i malignih promena na grliću materice kod žena različitog životnog doba

Introduction: Cervical cancer is the fourth most common and accounts for about 6.6% of all cancers in women. Aim: The aim was to determine the frequency of premalignant and malignant changes in the cervix, to examine the histological-cytological correlation of premalignant and malignant changes in the cervix and the correlation of the women's age with the stage of cervical disease. Material and Methods: A retrospective study analyzed 186 cervical biopsy specimens and cervical smears (Papanicolau test) at the Institute of Pathology of the Faculty of Medicine in Pristina, based in Kosovska Mitrovica, over a three-year period from 2016 to 2018. Results: Of the 186 subjects, 62 had mild premalignant changes of type LSIL, 22 HSIL, and as many as 20 (10.75%) cervical cancer. There was a statistically significant positive association between histological and cytological findings (r = 0.854; p &lt;0.001). There was a statistically significant difference in the age of the subjects with regard to histological findings (F = 11,327; p &lt;0.001). Subjects with HSIL were significantly older than those diagnosed with cervicitis chronica (p = 0.029). Subjects diagnosed with planocellular carcinoma were significantly older than women with cervicitis chronica (p &lt;0.001) and LSIL (p &lt;0.001). Conclusion: There is an increasing trend of cervical cancer in Northern Kosovo and in the Serbian enclaves in central Kosovo and Metohija. Subjects with cervical cancer were significantly older than subjects with mild premalignant cervical changes. There is a significant histologic-cytological correlation of cervical findings, so we believe that more massive cervical screening, especially in younger women, could reduce the incidence of premalignant and malignant diseases of the cervix.

HPV16-Related Cervical Cancers and Precancers Have Increased Levels of Host Cell DNA Methylation in Women Living with HIV.

Data on human papillomavirus (HPV) type-specific cervical cancer risk in women living with human immunodeficiency virus (WLHIV) are needed to understand HPV–HIV interaction and to inform prevention programs for this population. We assessed high-risk HPV type-specific prevalence in cervical samples from 463 WLHIV from South Africa with different underlying, histologically confirmed stages of cervical disease. Secondly, we investigated DNA hypermethylation of host cell genes ASCL1, LHX8, and ST6GALNAC5, as markers of advanced cervical disease, in relation to type-specific HPV infection. Overall, HPV prevalence was 56% and positivity increased with severity of cervical disease: from 28.0% in cervical intraepithelial neoplasia (CIN) grade 1 or less (≤CIN1) to 100% in invasive cervical cancer (ICC). HPV16 was the most prevalent type, accounting for 9.9% of HPV-positive ≤CIN1, 14.3% of CIN2, 31.7% of CIN3, and 45.5% of ICC. HPV16 was significantly more associated with ICC and CIN3 than with ≤CIN1 (adjusted for age, ORMH 7.36 (95% CI 2.33–23.21) and 4.37 (95% CI 1.81–10.58), respectively), as opposed to non-16 high-risk HPV types. Methylation levels of ASCL1, LHX8, and ST6GALNAC5 in cervical scrapes of women with CIN3 or worse (CIN3+) associated with HPV16 were significantly higher compared with methylation levels in cervical scrapes of women with CIN3+ associated with non-16 high-risk HPV types (p-values 0.017, 0.019, and 0.026, respectively). When CIN3 and ICC were analysed separately, the same trend was observed, but the differences were not significant. Our results confirm the key role that HPV16 plays in uterine cervix carcinogenesis, and suggest that the evaluation of host cell gene methylation levels may monitor the progression of cervical neoplasms also in WLHIV.

Human Papillomavirus 16, 18, 31 and 45 viral load, integration and methylation status stratified by cervical disease stage.

BackgroundPersistent infection with oncogenic Human Papillomavirus (HPV) is associated with the development of cervical cancer with each genotype differing in their relative contribution to the prevalence of cervical disease. HPV DNA testing offers improved sensitivity over cytology testing alone but is accompanied by a generally low specificity. Potential molecular markers of cervical disease include type-specific viral load (VL), integration of HPV DNA into the host genome and methylation of the HPV genome. The aim of this study was to evaluate the relationship between HPV type-specific viral load, integration and methylation status and cervical disease stage in samples harboring HPV16, HPV18, HPV31 or HPV45.MethodsSamples singly infected with HPV16 (n = 226), HPV18 (n = 32), HPV31 (n = 75) or HPV45 (n = 29) were selected from a cohort of 4,719 women attending cervical screening in England. Viral load and integration status were determined by real-time PCR while 3’L1-URR methylation status was determined by pyrosequencing or sequencing of multiple clones derived from each sample.ResultsViral load could differentiate between normal and abnormal cytology with a sensitivity of 75% and a specificity of 80% (odds ratio [OR] 12.4, 95% CI 6.2–26.1; p < 0.001) with some variation between genotypes. Viral integration was poorly associated with cervical disease. Few samples had fully integrated genomes and these could be found throughout the course of disease. Overall, integration status could distinguish between normal and abnormal cytology with a sensitivity of 72% and a specificity of 50% (OR 2.6, 95% CI 1.0–6.8; p = 0.054). Methylation levels were able to differentiate normal and low grade cytology from high grade cytology with a sensitivity of 64% and a specificity of 82% (OR 8.2, 95% CI 3.8–18.0; p < 0.001). However, methylation varied widely between genotypes with HPV18 and HPV45 exhibiting a broader degree and higher magnitude of methylated CpG sites than HPV16 and HPV31.ConclusionsThis study lends support for HPV viral load and CpG methylation status, but not integration status, to be considered as potential biomarkers of cervical disease.

Human papillomavirus type 16 long control region and E6 variants stratified by cervical disease stage

ObjectiveCertain intra-type variants of HPV16 have been shown to be associated with an increased risk of developing high grade cervical disease, but their potential association is confounded by apparent geographic and phylogenetic lineage dependency. The objective of this study was to evaluate the relationship between HPV16 sequence variants and cervical disease stage in monospecific infection samples from a single lineage (European, EUR) in England. MethodsOne hundred and twelve women singly infected with HPV16 and displaying normal and abnormal cytology grades were selected. An 1187bp fragment encompassing the entire LCR and a portion of the E6 open reading frame was sequenced to identify intra-type variants. Intra-type diversity was estimated using Shannon entropy. ResultsAlmost all samples (110/112; 98%) were assigned to the EUR lineage, one sample was classified as European-Asian (EAS) and another African (Afr1a). The mean pairwise distance of the EUR sequences in this study was low (0.29%; 95%CI 0.13–0.45%) but there were nevertheless several sites in the LCR (n=5) and E6 (n=2) that exhibited a high degree of entropy. None of these sites, however, including the T350G non-synonymous (L83V) substitution in E6, alone or in combination, were found to be associated with cervical disease stage. ConclusionsDespite using single infection samples and samples from a single variant lineage, intra-type variants of HPV16 were not differentially associated with cervical disease. Monitoring intra-lineage, site-specific variants, such as T350G, is unlikely to be of diagnostic value.

Cancer-initiating cells as target for prevention of recurring disease etiology: role of these malignant putative progenitor cells in relapse or metastasis of human cervical carcinoma.

Evidence suggests that there is a link between high-risk human papillomaviruses (HPVs) and cervical cancer. Studies indicate that persistence of high risk HPVs may determine progression to more severe stages of cervical disease, while the majority of HPV infections are transient and do not seem to be important in cervical carcinogenesis. Earlier studies in different cancers have shown that tumor initiating cells TICs are responsible for tumor formation and progression and interestingly, they are endowed with stem/ progenitor cell properties. In particular, TICs share with stem cells the key feature of self-renewal. The most efficacious therapeutic intervention for cervical cancer is probably vaccination. This review gives an overview on cervical cancer and its potential therapeutic interventions.

The role of co-factors in the progression from human papillomavirus infection to cervical cancer

ObjectiveCo-factors for cervical cancer, including oral contraceptive (OC) use, smoking and multiparity have been identified; however, the stage at which they act in cervical carcinogenesis is not clear. We compared established risk factors among women with CIN2 and CIN3 to evaluate the heterogeneity of these factors in precancer and also assessed their role during cervical carcinogenesis. MethodsThe current analysis included 2783 women with various stages of cervical disease who were enrolled in the Study to Understand Cervical Cancer Early Endpoints and Determinants (SUCCEED) and the Biopsy Study. Associations of co-factors within cervical precancer and at different stages of cervical carcinogenesis were estimated using logistic regression. ResultsLong-term OC use (10+years vs. never: OR=2.42, 95% CI: [1.13–5.15]), multiparity (3+ births vs. nulliparous: OR=1.54 [1.04–2.28]), smoking (ever vs. never: OR=1.95 [1.48–2.58]), and no Pap test in the previous five years (2.05 [1.32–3.17]) were positively associated with CIN3 compared to CIN2. We observed that long-term OC use, parity and smoking were associated with an increased risk of CIN3 compared to <CIN2 (1.97 [1.12–3.46]; 2.23 [1.59–3.11]; 2.60 [2.04–3.30], respectively), whereas associations were not significantly different (OC use, parity) or showed decreased risk (smoking) when comparing cancer to CIN3. ConclusionsDifferences in established risk factors suggest that CIN3 is a more specific definition of precancer than CIN2. Hormonally-related factors and smoking play a role in the transition from human papillomavirus infection to precancer.

Human papillomavirus genotype detection and viral load in paired genital and urine samples from both females and males

The ability to detect type-specific high risk HPV (HR-HPV) infections in samples from females and males is important for monitoring the epidemiology of HPV and the impact of vaccination. Type-specific detection concordance between paired urine and genital samples from females (n = 264) undergoing routine colposcopy and males (n = 88) attending a genito-urinary medicine clinic was evaluated using an in-house genotyping assay. The overall inter-rater agreement (κ) was 0.781 for female pairs and 0.346 for male pairs. Female urine had sensitivity for detection of HPV16/18 and HR-HPV of 75% and 84%, respectively, while male urine had sensitivities of 13% and 28%, respectively. Genital samples had a higher HPV DNA copy number than urine although a small proportion (10%) of urine samples had a higher copy number than the corresponding genital sample. The proportion of females with normal cytology positive for HPV16/18 was 19%, increasing to 57% in moderate or severely dyskaryotic samples. The same trend was seen in the corresponding urine (19-43%) compounded by the reduced sensitivity of this sample type. The HPV16 viral load in female genital samples, but not in urine, was weakly associated with cervical disease stage. Despite reduced sensitivity, urine appears to be an appropriate surrogate sample for type-specific HPV detection in females for epidemiological objectives. The lower sensitivity and lack of association between viral load and disease stage in urine suggest that urine may not be useful for clinical management of HPV infection. The utility of urine for type-specific detection in males is less certain.

Deregulated expression of superoxide dismutase-2 correlates with different stages of cervical neoplasia.

Objective: Superoxide dismutase-2 (SOD2) is considered one of the most important antioxidant enzymes that regulate cellular redox state in normal and tumorigenic cells. Overexpression of this enzyme may be involved in carcinogenesis, particularly in lung, gastric, colorectal and breast cancer. Methods: In the present study, we have evaluated SOD2 protein levels by immunohistochemistry (IHC) in 331 cervical histological samples including 31 low-grade cervical intraepithelial neoplasia (LSIL), 51 high-grade cervical intraepithelial neoplasia (HSIL), 197 squamous cervical carcinomas (SCC) and 52 cervical adenocarcinomas (ADENO). Results: We observed that SOD2 staining increases with cervical disease severity. Intense SOD2 staining was found in 13% of LSIL, 25.5% of HSIL and 40% of SCC. Moreover, 65.4% of ADENO exhibited intense SOD2 staining. Conclusions: Differences in the expression of SOD2 could potentially be used as a biomarker for the characterization of different stages of cervical disease.

Deregulated Expression of Superoxide Dismutase-2 Correlates with Different Stages of Cervical Neoplasia

Objective: Superoxide dismutase-2 (SOD2) is considered one of the most important antioxidant enzymes that regulate cellular redox state in normal and tumorigenic cells. Overexpression of this enzyme may be involved in carcinogenesis, particularly in lung, gastric, colorectal and breast cancer.Methods: In the present study, we have evaluated SOD2 protein levels by immunohistochemistry (IHC) in 331 cervical histological samples including 31 low-grade cervical intraepithelial neoplasia (LSIL), 51 high-grade cervical intraepithelial neoplasia (HSIL), 197 squamous cervical carcinomas (SCC) and 52 cervical adenocarcinomas (ADENO).Results: We observed that SOD2 staining increases with cervical disease severity. Intense SOD2 staining was found in 13% of LSIL, 25.5% of HSIL and 40% of SCC. Moreover, 65.4% of ADENO exhibited intense SOD2 staining.Conclusions: Differences in the expression of SOD2 could potentially be used as a biomarker for the characterization of different stages of cervical disease.

Analysis of human kallikrein 7 expression as a potential biomarker in cervical neoplasia

Overexpression of kallikrein 7, a proteolytic enzyme important for epithelial cell shedding, may be causally involved in carcinogenesis, particularly in tumor metastasis and invasion. In this study, we have evaluated hK7 (human kallikrein 7) protein levels by immunohistochemistry in 367 cervical histological samples including 35 cases of cervicitis, 31 low-grade cervical intraepithelial neoplasia, 51 high-grade cervical intraepithelial neoplasia (H-SIL), 197 squamous cervical carcinomas (SCC) and 53 cervical adenocarcinomas. We have observed that hK7 staining increased with the severity of cervical disease. Intense hK7 staining was found in 15.2% of cervicitis samples, in contrast to 55% of H-SIL and 68% of SCC. Moreover, 92.5% of adenocarcinomas also exhibited intense hK7 staining. Differences in the expression of hK7 could potentially be used as a biomarker for the characterization of different stages of cervical disease.

A shift to a peripheral Th2-type cytokine pattern during the carcinogenesis of cervical cancer becomes manifest in CIN III lesions

Background: A shifted balance between T helper 1 (Th1)-type and Th2-type cytokines has been hypothesised in cervical dysplasia Aims: To evaluate possible deregulation of the cytokine network by estimating the...

The c- myc activation in cervical carcinomas and HPV 16 infections

Despite the prominent role for Human Papillomavirus (HPV) infection in the development of genital cancer, other genetic or environmental co-factors have also been involved. Studies of c- myc activation in cervical carcinomas have reported that gene over-expression (mainly gene amplification) are common in cervical squamous cell carcinomas and may correlate with the biologic behavior of the neoplasm. Using PCR based technology, DNAs from 79 normal cervical samples and 225 abnormal cervical tissue scrapes were analyzed for HPV detection and typing and for c- myc gene amplification. Significant differences were found between the different cyto/histology groups ( P<0.0001) and also with HPV high-risk infected samples ( P<0.0002). In this sense, we showed that the average c- myc copy number increased according to the histological grade of the lesion (OR=6.3, CI=2.1–18.8). Also, the results showed that the infection with HPV 16 was tightly associated with c- myc amplification (OR=10.6, CI=3.1–36). These results could indicate that oncogene amplification take place in pre-invasive stages of cervical disease and could cooperate not only in tumor progression but also in cell transformation. Moreover, the results strongly associate the c- myc gene amplification to the infection with the oncogenic HPV 16, showing that the pattern of virus infection and oncogene activation could be specific for different viral genotypes.

Human Papillomaviruses and cervical Cancer

Molecular and epidemiological studies conducted over the last 20 years led to the recognition of certain types of human papillomavirus (HPV) as the etiological agents of cervical cancer, a very common neoplasia, particularly in developing countries. More than 70 HPVs have been described, including both cutaneous and mucosal types. About half of the known HPVs, and an even higher number of variants, have been isolated from genital mucosas. The association of certain types primarily with normal tissues and benign lesions, as opposed to cancer-associated types, has led to the concept of low and high oncogenic risk HPVs, respectively. The latter express oncogenic proteins that interfere with cell growth control functions. As a consequence of the continuous expression of these viral genomes, chromosome instability may occur, leading to fully transformed cells. Studies indicate that persistence of high-risk HPVs may determine progression to more severe stages of cervical disease, while the majority of HPV infections are transient and do not seem to be important in cervical carcinogenesis. The risk for disease progression seems also to be associated with viral burden. Prospective epidemiological studies will contribute to the knowledge of the natural history of HPV infections and provide information on the determinants of viral persistence. Data derived from these studies may define the clinical utility of HPV testing and its use in cervical cancer prevention programs.