Natural History Of Cervical Neoplasia Research Articles

Research of the potential biomarkers in vaginal microbiome for persistent high-risk human papillomavirus infection

Vaginal dysbiosis may paly role in increased risk of human papillomavirus (HPV) infection. This study aims to explore potential vaginal microbiome biomarkers, to predict persistent high-risk HPV (HR-HPV) infection and cervical intraepithelial neoplasia (CIN) 2+, and to find novel treatment targets for HPV infection. A total of 329 women aged 20-69 were enrolled in this study, including 59 with cervical persistent HPV infection irrespective of cytology status (group A), 139 with incident HPV infection (group B), and 131 without HPV infection (group C). Vaginal microbiome composition was determined by sequencing of barcoded 16S rDNA gene fragments (V4) on Illumina HiSeq2500. In genus level, the relative abundance of Prevotella, Porphyromonas and Enterococcus were significantly the highest in group A, while Bacteroides was the lowest in group A. In species level, we found the relative abundance of Prevotella bivia, Enterococcus durans and Porphyromonas uenonis were the highest in group A while Lactobacillus iners was significantly under-represented in group A than the other two, and Prevotella disiens was over-represented in group C than the other two groups. A predominance of Prevotella bivia, Enterococcus durans and Porphyromonas uenonis with a concomitant paucity of Lactobacillus iners and Prevotella disiens may relate to HPV persistent infection. Furthermore, the relative abundance of Prevotella bivia being over 0.05554% with Prevotella disiens being under 0.02196% may be a good predictor for appearance CIN2+ for those diagnosed with the other 12 types of HR-HPV persistent infection but normal ThinPrep cytology test (TCT) testing. The exact molecular mechanism of the vaginal microbiome in the course of persistent HR-HPV infection and cervical neoplasia should be further explored. Future research should include intervention of vaginal microbiome composition to reverse the course of HR-HPV infection and the natural history of cervical neoplasia.

Correlation between the diversity of vaginal microbiota and the risk of high-risk human papillomavirus infection.

Since other genital infections enhance HIV susceptibility by inducing inflammation and evidence suggests that the vaginal microbiome plays a functional role in the persistence or regression of high-risk human papillomavirus (HPV) infections, we investigated the relationship between the composition of the vaginal microbiota and the risk of high-risk HPV infection. The study included 151 healthy women (65 HPV-positive and 86 HPV-negative) aged 20-65 at enrollment. Total genome DNA from samples was extracted using the hexadecyltrimethylammonium bromide (CTAB) CTAB method. The vaginal microbiota composition was determined by sequencing barcoded 16S rDNA gene fragments (V4) on Illumina HiSeq2500. Of the 30 most abundant bacteria at the genus level, we found only six bacteria with a statistical difference between HPV-positive and HPV-negative women: Bacteroides, Acinetobacter, Faecalibacterium, Streptococcus, Finegoldia, and Moryella. Lactobacillus was the predominant genus and was detected in all women, but there was no significant difference between the two groups for L. iners, L. jensenii, and L. gasseri. Furthermore, we found 26 types of bacteria with a statistical difference at the species level between the two groups. Anaerobic bacteria such as Bacteroides plebeius, Acinetobacter lwoffii, and Prevotella buccae were found significantly more frequently in HPV-positive women, which is the most important finding of our study. Our findings suggest a possible role for the composition of the vaginal microbiota as a modifier of high-risk HPV infection, and specific microbiota species may serve as sensors for changes in the cervical microenvironment associated with high-risk HPV infection. The exact molecular mechanism of the vaginal microbiota in the course of high-risk HPV infection and cervical neoplasia should be further explored. Future research should include intervention in the composition of the vaginal microbiota to reverse the course of high-risk HPV infection and the natural history of cervical neoplasia.

Bacterial vaginosis and inflammatory response showed association with severity of cervical neoplasia in HPV-positive women.

Vaginal infections may affect susceptibility to and clearance of human papillomavirus (HPV) infection and chronic inflammation has been linked to carcinogenesis. This study aimed to evaluate the association between bacterial vaginosis (BV) and inflammatory response (IR) with the severity of cervical neoplasia in HPV-infected women. HPV DNA was amplified using PGMY09/11 primers and genotyping was performed using a reverse line blot hybridization assay in 211 cervical samples from women submitted to excision of the transformation zone. The bacterial flora was assessed in Papanicolaou stained smears, and positivity for BV was defined as ≥ 20% of clue cells. Present inflammatory response was defined as ≥ 30 neutrophils per field at 1000× magnification. Age higher than 29 years (OR:1.91 95% CI 1.06-3.45), infections by the types 16 and/or 18 (OR:1.92 95% CI 1.06-3.47), single or multiple infections associated with types 16 and/or 18 (OR: 1.92 CI 95% 1.06-3.47), BV (OR: 3.54 95% CI 1.62-7.73) and IR (OR: 6.33 95% CI 3.06-13.07) were associated with severity of cervical neoplasia (CIN 2 or worse diagnoses), while not smoking showed a protective effect (OR: 0.51 95% CI 0.26-0.98). After controlling for confounding factors, BV(OR: 3.90 95% CI 1.64-9.29) and IR (OR: 6.43 95% CI 2.92-14.15) maintained their association with the severity of cervical neoplasia. Bacterial vaginosis and inflammatory response were independently associated with severity of cervical neoplasia in HPV-positive women, which seems to suggest that the microenvironment would relate to the natural history of cervical neoplasia.

Incidence and progression of cervical lesions in women with HIV: a systematic global review

Global data on cervical lesion incidence and progression in HIV-positive women are essential for understanding the natural history of cervical neoplasia and informing screening policy. A systematic review was performed summarizing the incidence and progression of cervical lesions in HIV-positive women. Of 5882 HIV-positive women from 15 studies, incidence ranged from 4.9 to 21.1 cases per 100 woman-years for any cervical lesion and 0.4 to 8.8 cases per 100 woman-years for high-grade cervical lesions. HIV-positive women showed a median three-fold higher incidence of cervical lesions compared to HIV-negative women. Of 1099 HIV-positive women from 11 studies, progression from low- to high-grade lesions ranged from 1.2 to 26.2 cases per 100 woman-years. Both incidence and progression rates increased with lower CD4 counts. The effect of antiretroviral therapy on the natural history of cervical neoplasia remains unclear. HIV-positive women have higher incidence and progression of cervical neoplasia. Cervical cancer screening should be integrated into HIV treatment programmes.

A large, population-based study of age-related associations between vaginal pH and human papillomavirus infection

BackgroundVaginal pH is related to genital tract inflammation and changes in the bacterial flora, both suggested cofactors for persistence of human papillomavirus (HPV) infection. To evaluate the relationship between vaginal pH and HPV, we analyzed data from our large population-based study in Guanacaste, Costa Rica. We examined vaginal pH and the risk of HPV infection, cytological abnormalities, and C. trachomatis infection.MethodsOur study included 9,165 women aged 18-97 at enrollment with a total of 28,915 visits (mean length of follow-up = 3.4 years). Generalized estimating equations were used to evaluate the relationship between vaginal pH and HPV infection (both overall and single versus multiple types) and low-grade squamous intraepithelial lesions (LSIL), the cytomorphic manifestation of HPV infection. The relationship between enrollment vaginal pH and C. trachomatis infection was assessed by logistic regression. Results were stratified by age at visit.ResultsDetection of HPV was positively associated with vaginal pH, mainly in women < 35 years (p-trend = 0.009 and 0.007 for women aged < 25 and 25-34 years, respectively). Elevated vaginal pH was associated with 30% greater risk of infection with multiple HPV types and with LSIL, predominantly in women younger than 35 and 65+ years of age. Detection of C. trachomatis DNA was associated with increased vaginal pH in women < 25 years (OR 2.2 95% CI 1.0-5.0).ConclusionsOur findings suggest a possible association of the cervical microenvironment as a modifier of HPV natural history in the development of cervical precancer and cancer. Future research should include studies of vaginal pH in a more complex assessment of hormonal changes and the cervicovaginal microbiome as they relate to the natural history of cervical neoplasia.

The Prevention of Cervical Cancer in Africa

In this article we aim to draw attention to the burden of cervical cancer in Africa for reproductive health and review strategies for prevention, including appropriate noncytology-based cervical screening and prophylactic human papillomavirus vaccination. We consider the heavy burden of disease attributable to human papillomavirus infection borne by developing countries, particularly in Africa. Following identification of the human papillomavirus as the infectious etiological agent and elucidation of the long natural history of cervical neoplasia, cervical cancer is now one of the most preventable of all cancers. Opportunities for primary prevention by prophylactic vaccination and secondary prevention by appropriate cervical screening are discussed, together with the importance of population coverage. Qualitative work on attitudes towards cervical cancer prevention, education needs, the creation of an environment for informed choice and uptake are essential aspects of effective prevention programs. Cervical cancer poses a huge health burden in Africa. It is a disease that is eminently preventable given political will, the availability of affordable vaccines, appropriate cervical screening and access to cheap, point-of-care human papillomavirus testing. There are a number of unanswered questions for the prevention of cervical cancer and a need for demonstration projects to address these and further develop prevention strategies.

Natural history of cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: a retrospective cohort study

The invasive potential of cervical intraepithelial neoplasia 3 (CIN3; also termed stage 0 carcinoma) has been poorly defined. At the National Women's Hospital, Auckland, New Zealand, treatment of CIN3 was withheld from a substantial number of women between 1965 and 1974 as part of an unethical clinical study. The resulting variation in management allows comparison of the long-term risk of invasive cancer of the cervix in women whose lesion was minimally disturbed with those who had adequate initial treatment followed by conventional management. We aimed to estimate the long-term risk of invasive cancer in these two groups of women. A judicial inquiry referred for independent clinical review in 1988 all women for whom there remained doubt about the adequacy of their management. Between February, 2001, and December, 2004, medical records, cytology, and histopathology were reviewed for all women with CIN3 diagnosed between 1955 and 1976, whose treatment was reviewed by judicial inquiry and whose medical records could be located, and linkages were done with cancer and death registers and electoral rolls. To take into account the probability that the CIN3 lesion had been completely removed, we classified adequacy of treatment by type of procedure, presence of CIN3 at the excision margin, and subsequent cytology. The primary outcome was cumulative incidence of invasive cancer of the cervix or vaginal vault. Follow-up continued until death or Dec 31, 2000, whichever came first. Analyses accounted for procedures during follow-up. 1229 women whose treatment was reviewed by the judicial inquiry in 1987-88 were included. Of these, 48 records (4%) could not be located and 47 women (4%) did not meet the inclusion criteria. At histopathological review, a further 71 (6% of 1134) women were excluded because the review diagnosis was not CIN3. We identified outcomes in the remaining 1063 (86% of 1229) women diagnosed with CIN3 at the hospital in 1955-76. In 143 women managed only by punch or wedge biopsy, cumulative incidence of invasive cancer of the cervix or vaginal vault was 31.3% (95% CI 22.7-42.3) at 30 years, and 50.3% (37.3-64.9) in the subset of 92 such women who had persistent disease within 24 months. However, cancer risk at 30 years was only 0.7% (0.3-1.9) in 593 women whose initial treatment was deemed adequate or probably adequate, and whose treatment for recurrent disease was conventional. This study provides the most valid direct estimates yet available of the rate of progression from CIN3 to invasive cancer. Women with untreated CIN3 are at high risk of cervical cancer, whereas the risk is very low in women treated conventionally throughout.

Loop electrosurgical excision of the cervix and the subsequent risk of preterm delivery

To investigate the association between loop electrosurgical excision procedure (LEEP) and other potential risk factors, and subsequent preterm delivery (<37 weeks), using data from a large cohort study of Danish women. The Danish prospective cohort study was initiated in 1991, with the original aim of investigating the role of human papillomavirus in the natural history of cervical neoplasia. The study included 11,088 women aged 20-29. The cohort was invited for 2 follow-up examinations in 1993-1995 and 1999-2000, respectively. At all 3 examinations, the women answered questions about a number of different lifestyle variables. We assessed the relationship between preterm delivery and potential risk factors, such as previous LEEP treatments, smoking during pregnancy, age, parity and previous preterm delivery. The cohort was followed until 2004, through linkages with the nationwide Pathology Data Bank and the Medical Birth Registry. Of the 14,982 deliveries in the cohort during follow up, 542 were preterm (21-37 weeks). Among deliveries with no previous LEEP, 3.5% ended as a preterm delivery, whereas this applied to 6.6% among deliveries following a LEEP, yielding a significantly increased risk of preterm birth after LEEP (OR=1.8; 95% CI: 1.1-2.9). The strongest risk factor for preterm delivery was a previous preterm delivery (OR=2.3; 95% CI: 1.4-3.7). Other significant risk factors were smoking during pregnancy and low educational status. Our study showed an almost 2-fold increase in the risk of preterm delivery after LEEP treatment. Thus, women in their reproductive age should be informed about the increased risk of preterm delivery, if treated with LEEP.

Toward a reduction of the global burden of cervical cancer

Of the 190,000 deaths from cervical cancer that occur annually worldwide, the majority take place in developing countries. Recent advances in our understanding of the causes and natural history of cervical neoplasia and, in particular, the establishment of the central role of human papilloma virus (HPV) infection have created opportunities for the primary and secondary prevention of cervical cancer. In the future, prevention efforts will include the incorporation of HPV testing as an adjunct to or replacement for cytology-based screening programs and the use of recombinant DNA technologies for the development of prophylactic vaccines.

The epidemiology of cervical cancer.

Cervical cancer is one of the most common neoplastic diseases affecting women, with a combined worldwide incidence of almost half a million new cases annually, second only to breast cancer. Basic and epidemiologic research conducted during the past 15-20 years have provided overwhelming evidence for an etiologic role for infection with certain types of sexually-transmitted human papillomavirus (HPV) as the primary cause of cervical cancer. The relative risks of cervical cancer following HPV infection as ascertained in case-control and cohort studies are among the highest in cancer epidemiology. The available evidence indicates that the HPV-cervical cancer association satisfies all relevant causal criteria for public health action. Other cervical cancer risk factors, such as smoking, parity, use of oral contraceptives, diet, other infections, and host susceptibility traits must be understood in the context of mediation of acquisition of HPV infection or in influencing events of the natural history of cervical neoplasia that occur following the establishment of a persistent HPV infection. Virtually all cervical carcinoma specimens contain HPV DNA, which suggests that HPV infection is a necessary cause of cervical neoplasia. This is the first instance in which a necessary cause has been demonstrated in cancer epidemiology--a realization that has obvious implications for primary and secondary prevention of this neoplastic disease.

Toward a reduction of the global burden of cervical cancer

Of the 190000 deaths from cervical cancer that occur annually worldwide the majority take place in developing countries. Recent advances in our understanding of the causes and natural history of cervical neoplasia and in particular the establishment of the central role of human papilloma virus (HPV) infection have created opportunities for the primary and secondary prevention of cervical cancer. In the future prevention efforts will include the incorporation of HPV testing as an adjunct to or replacement for cytology-based screening programs and the use of recombinant DNA technologies for the development of prophylactic vaccines. (authors)

Natural history of cervical neoplasia: defining progression and its consequence.

Natural history of cervical neoplasia: defining progression and its consequence.

Differences in serological IgA responses to recombinant baculovirus-derived human papillomavirus E2 protein in the natural history of cervical neoplasia.

Infection with certain types of human papillomavirus (HPV) presents a high risk for the subsequent development of cervical intraepithelial neoplasia (CIN) and cervical carcinoma. Immunological mechanisms are likely to play a role in control of cervical HPV lesions. The HPV E2 protein has roles in virus replication and transcription, and loss of E2 functions may be associated with progression of cervical neoplasia. Accordingly, it is of interest to monitor immune responses to the E2 protein, and previous studies have reported associations between serological reactivity to E2 peptide antigens and cervical neoplasia. In order to investigate serological responses to native, full-length E2 protein, we expressed HPV-16 E2 proteins with and without an N-terminal polyhistidine tag using the baculovirus system. Purified HPV-16 E2 protein was used to develop enzyme-linked immunosorbent assays to detect serological IgG and IgA responses in cervical neoplasia patients and controls. We found that serum IgA levels against the E2 protein were elevated in CIN patients relative to normal control subjects but were not elevated in cervical cancer patients. Moreover, there appeared to be a gradient of response within cervical neoplasia such that the highest antibody levels were seen in lower grades of neoplasia up to CIN 2, whereas lower levels were observed in CIN 3 and still lower levels in cervical carcinoma. These findings suggest that the IgA antibody response to E2 may associate with stage and progression in cervical neoplasia.

Natural history of cervical neoplasia: Overview and update

Current cervical cancer control strategies and specifically, the screening and treatment policies that have been used during the past 30 years, are based on an understanding of the natural history of cervical neoplasia that does not take into account the important role of human papillomavirus in cervical cancer pathogenesis. This survey presents a review of new data on the causes of cervical cancer and the role of human papillomavirus and recommends the integration of these data. Incorporation of new information on the role of human papillomavirus as the causative agent of most cervical cancers will allow the design of more efficient and more cost-effective strategies for cervical cancer control. (Am J Obstet Gynecol 1996;175:1099-104.)

Optimization of cervical cancer screening.

The aim of this study was to investigate how a screening program interacts with the dynamic natural history of cervical neoplasia in order to learn how screening for cervical cancer should be carried out most cost-effectively. For the purpose of optimization, the fundamental quantities of the natural history are the shape of the curve of age-specific prevalence rates of cancer in situ, and the duration of this stage before progression to invasive cancer. Since these quantities seem similar in different populations, the results probably can be generalized. Simulation studies revealed that optimal screening implies a nonperiodic schedule, and that this schedule is dependent not only on the number of screenings, but also on the efficiency of the screening rounds. With lower efficiency, the schedule should be concentrated into a shorter period. The effect of screening is also especially sensitive to the choice of age at the first and--to a smaller extent--last screening. The results concerning three different objectives also were compared, namely reduction of the cumulative number of invasive cancers, reduction of deaths due to cervical cancer, and reduction of years-of-life lost. The choice of objective also plays a role in the design of an optimal screening program. The theoretical approach in this analysis easily can be developed and accommodated to more complex individual situations such as prior screening histories and differing screening schedules in high- and low-risk women.

Natural history of cervical neoplasia: consistent results obtained by an identification technique.

Swedish population-based incidence and mortality rates for cancer of the uterine cervix, both in situ and invasive, during the period 1958 to 1981 were determined by means of a dynamic model. This new approach describes without any preconceptions the development of the disease as a sequential process over the stages cancer in situ, invasive cancer before and after diagnosis, and death. The strong disturbance of the steady-state situation that occurred after the introduction of cytological mass screening in the early 1960s permitted the use of a computerized identification technique. The whole natural history of cervical cancer could thus be identified and described consistently, with the mutual compatibility between statistical data, structure, parameters, and the states and flows between the states. The estimated age-specific incidence of cancer in situ increased rapidly to a maximum of 650 per 10(5) woman-years at the age of 30 years, after which it declined, and that of invasive cancer to a maximum of 55 per 10(5) at the age of 43. The natural history of cervical neoplasia did not differ appreciably between eight successive 5-year birth cohorts. The proportion of cases of new cancer in situ that progressed to invasive cancer was 12.2%, with a mean duration of the in situ stage in these cases of 13.3 years. The preclinical phase of the invasive stage (without screening) lasted on average about 4 years.