Detection of persistent cervical carcinogenic human papillomavirus (HPV) DNA is used as a marker for cervical cancer risk in clinical trials. The authors performed a systematic review and meta-analysis of the association between persistent HPV DNA and high-grade cervical intraepithelial neoplasia (CIN2-3), high-grade squamous intraepithelial lesions (HSIL), and invasive cervical cancer (together designated CIN2-3/HSIL+) to evaluate the robustness of HPV persistence for clinical use. MEDLINE and Current Contents were searched through January 30, 2006. Relative risks (RRs) were stratified by HPV comparison group. Of 2,035 abstracts, 41 studies were eligible for inclusion in the meta-analysis. Over 22,500 women were included in calculation of RRs for persistent HPV DNA detection and cervical neoplasia. RRs ranged from 1.3 (95% confidence interval: 1.1, 1.5) to 813.0 (95% confidence interval: 168.2, 3,229.2) for CIN2-3/HSIL+ versus 12 months), wider testing intervals, CIN2-3/HSIL+, and use of an HPV-negative reference group were consistently associated with higher RRs. Thus, HPV persistence was consistently and strongly associated with CIN2-3/HSIL+, despite wide variation in definitions and study methods. The magnitude of association varied by duration of persistence and testing interval. Precise definition and standardization of HPV testing, sampling procedure, and test interval are needed for reliable clinical testing. These findings validate HPV persistence as a clinical marker and endpoint.
human papillomavirus 16; human papillomavirus 18; longitudinal studies; papillomavirus infections; uterine cervical neoplasms
Bacterial vaginosis (BV), an alteration of vaginal flora involving a decrease in Lactobacilli and predominance of anaerobic bacteria, is among the most common cause of vaginal complaints for women of childbearing age. It is well known that BV has an influence in acquisition of certain genital infections. However, association between BV and cervical human papillomavirus (HPV) infection has been inconsistent among studies. The objective of this meta-analysis of published studies is to clarify and summarize published literature on the extent to which BV is associated with cervical HPV infection.
Medline and Web of Science were systematically searched for eligible publications until December 2009. Articles were selected based on inclusion and exclusion criteria. After testing heterogeneity of studies, meta-analysis was performed using random effect model.
Twelve eligible studies were selected to review the association between BV and HPV, including a total of 6,372 women. The pooled prevalence of BV was 32%. The overall estimated odds ratio (OR) showed a positive association between BV and cervical HPV infection (OR, 1.43; 95% confidence interval, 1.11-1.84).
This meta-analysis of available literature resulted in a positive association between BV and uterine cervical HPV infection.
Bacterial vaginosis is characterized by a shift from the predominant lactobacillus vaginal flora to an overgrowth of anaerobic bacteria. Bacterial vaginosis is associated with an increased risk of gynecologic complications, including pelvic inflammatory disease, postoperative infection, cervicitis, human immunodeficiency virus (HIV), and possibly cervical intraepithelial neoplasia (CIN). The obstetrical risks associated with bacterial vaginosis include premature rupture of membranes, preterm labor and delivery, chorioamnionitis and postpartum endometritis. Despite the health risks associated with bacterial vaginosis and its high prevalence in women of childbearing age, bacterial vaginosis continues to be largely ignored by clinicians, particularly in asymptomatic women.
To assess the association between MTHFR polymorphism and cervical cancer risk, a meta-analysis was performed.
Based on comprehensive searches of the PubMed, Embase, and Web of Science databases, we identified outcome data from all articles estimating the association between MTHFR polymorphism and cervical cancer risk. The pooled odds ratio (OR) with 95% confidence intervals (CIs) were calculated.
A total of 12 studies with 2,924 cases (331 cervical intraepithelial neoplasia (CIN) I, 742 CIN II/III, 1851 invasive cervical cancer) and 2,581 controls were identified. There was no significant association between MTHFR C677T polymorphism and CIN I risk (T vs. C, OR = 1.10, 95% CI = 0.92–1.31; TT vs. CC, OR = 1.14, 95% CI = 0.78–1.68; TT+CT vs. CC, OR = 1.22, 95% CI = 0.94–1.58; TT vs. CT+CC, OR = 0.99, 95% CI = 0.70–1.40). For the CIN II/III, lack of an association was also found (T vs. C, OR = 1.08, 95% CI = 0.95–1.23; TT vs. CC, OR = 1.15, 95% CI = 0.87–1.52; TT+CT vs. CC, OR = 1.13, 95% CI = 0.94–1.35; TT vs. CT+CC, OR = 1.07, 95% CI = 0.83–1.38). The T allele had significant association to susceptibility of invasive cervical cancer in recessive model (TT vs. CT+CC, OR = 1.23, 95% CI = 1.02–1.49). On subgroup analysis by ethnicity, similarly significant differences in T vs. C, TT vs. CC, and recessive model were found in Asians.
The present meta-analysis suggested that MTHFR C677T polymorphism were to substantially contribute to invasive cervical cancer in recessive model.
Human papillomavirus (HPV) infection plays an etiological role in the development of cervical dysplasia and cancer. Amplification of human telomerase gene (hTERC) and over expression of telomerase were found to be associated with cervical tumorigenesis. This study was performed to analyze genomic amplification of hTERC gene, telomerase activity in association with HPV infection in different stages of cervical intraepithelial neoplasia (CIN) and cervical cancer. We were studying the role of hTERC in the progression of uterine cervical dysplasia to invasive cancer, and proposed an adjunct method for cervical cancer screening.
Exfoliated cervical cells were collected from 114 patients with non neoplastic lesion (NNL, n=27), cervical intraepithelial neoplasia (CIN1, n=26, CIN2, n=16, CIN3, n=24) and cervical carcinoma (CA, n=21), and analyzed for amplification of hTERC with two-color fluorescence in situ hybridization (FISH) probe and HPV-DNA with Hybrid Capture 2.
From these patients, 53 were taken biopsy to analyze telomerase activity by telomeric repeat amplification protocol (TRAP) and expression of human telomerase reverse transcriptase (hTERT), with immunohistochemistry (IHC). All biopsies were clinically confirmed by phathologists.
Amplification of hTERC was significantly associated with the histologic diagnoses (p<0.05). The positive correlation was found between the level of hTERC amplification and histologic grading of dysplasia (CIN2/3 from CIN1 or normal, P=0.03). A profounding increase in the accumulation of HPV and hTERC positive cases was observed in the CIN3 subgroup compared with the CIN2 group, 25% versus 62.96%, respectively (p=0.007).
hTERC ampliffication can be detected with FISH technique on exfoliated cervical cells. Amplification of hTERC and HPV infection are associated with more progressive CIN3 and CA. The testing of hTERC amplification might be a supplementary to cytology screening and HPV test, especially high-risk patients.
The virtual slide(s) for this article can be found here:
Cervical cancer; Telomerase; hTERT; hTERC; HR-HPV
A number of studies have explored the association between methyl enetetrahydrofolate reductase (MTHFR) C677T polymorphism and susceptibility to cervical cancer and cervical intraepithelial neoplasia (CIN). However, results remained controversial. To address this gap, we decided to conduct a meta-analysis of all available published studies.
Electronic literature searches of the PubMed, EmBase and Medline databases were performed up to April 30, 2012. Fixed-effects or random-effects model was used to calculate the pooled ORs for different genetic models.
A total of 12 case-control studies were ultimately identified. No statistical correlation was found between C677T variants and cervical cancer for the overall population. However, subgroup analyses on the White women pointed to a significant protective effect for individuals heterozygous or homozygous for the T-allele (for CT vs. CC: OR = 0.72, 95% CI 0.59–0.88; for TT vs. CC: OR = 0.69, 95% CI = 0.49–0.97; for CT+TT vs. CC: OR = 0.71, 95% CI 0.59–0.86). C677T variants were associated with neither combined nor stratified CIN among the overall population.
This meta-analysis suggests that White women with mutant C677T genotypes might have a lower risk of cervical cancer, yet lacking enough statistical robustness. Further investigations are needed to get more insight into the role of this polymorphism in cervical carcinogenesis.
The aim of this study was to determine whether the presence of bacterial vaginosis (BV) is associated with cervical intraepithelial neoplasia (CIN) and human papilloma virus (HPV) infection.
A total of 588 women who had abnormal Pap smears and had finally undergone loop electrosurgical excision procedure (LEEP) in our institute from September 2002 to May 2006 were selected. The screening tests for BV were done in 552 of the 588, and BV was diagnosed if three of the following four findings were satisfied: presence of abnormal discharge, vaginal pH>4.5, presence of clue cells, positive amine or whiff test. Five hundred and five patients had HPV typing tests by the HPV DNA chip. Forty two patients diagnosed with invasive cancer were excluded from this study. CIN was subdivided into low-grade CIN (CIN I) and high-grade CIN (CIN II/III) groups.
There was no statistically significant difference in patient characteristics between BV-present and BV-absent group. The incidence of CIN was significantly higher in the BV-present group (p=0.043), however, no statistical significance of BV on CIN was observed on multivariate analysis. HPV infection showed no significant relationship with BV. BV with or without HPV infection did not influence the incidence of CIN, regardless of the severity.
There was significant correlation between BV and the presence of CIN, regardless of the severity of CIN. In addition, there was no significant association between the presence of BV and HPV infection.
Bacterial vaginosis; Cervical intraepithelial neoplasia; Human papilloma virus
Since the mid-1990s, there have been growing efforts to prevent cervical cancer in less-developed countries through the development of innovative screening approaches such as visual inspection of the cervix associated with same day management of cervical lesions with cryotherapy or loop electrosurgical excision procedure (LEEP). In the past, promising cancer screening interventions have been widely promoted despite incomplete evidence, only to become the subject of intense controversies about ensuing net health benefit. Because the efficacy and effectiveness of the new protocols for global cervical cancer screening have not been well characterized yet, and as a contribution to the evaluation of the balance between the benefits and risks of these protocols, we reviewed the literature on the safety of cryotherapy and LEEP for cervical intraepithelial neoplasia (CIN) in low- and middle-income countries.
We searched 12 databases (Medline, Google Scholar, Scopus, Cochrane Library, Web of Science, OCLC, PAIS International Database, WHO Global Health Library, CINAHL, Science.gov, NYAM Grey Literature Report, and POPLINE) for original research published between January 1995 and April 2009. Both peer-reviewed publications and items of "grey" literature were retrieved; no language restriction was applied. We calculated the median (minimum, maximum) reported rate for each harm considered. Because of limitations and heterogeneity in the data, no formal meta-analysis was performed.
The search identified 32 articles that reported safety data from 24 cryotherapy and LEEP studies. The combined sample consisted of 6,902 women treated by cryotherapy and 4,524 women treated by LEEP. Most studies were conducted in reference or research settings in Asia and Africa. Short-term harms of cryotherapy and LEEP appeared to be similar to those described in the literature from high-income countries. Information was sparse on HIV-related harms and long-term reproductive outcomes of treatment.
When performed in resource-limited settings by qualified providers, cryotherapy and LEEP are not associated with excess harm. However, available data are insufficient to propose fully evidence-based protocols for routine screening of HIV-infected women and women of reproductive age.
The association between cervical cancers and human papillomavirus (HPV) is now well established. To estimate the extent of infection with common HPVs among Korean women, we have examined 224 cervical scrapes of various cervical lesions. Detection and typing of HPVs were done by polymerase chain reaction (PCR) using consensus primers followed by restriction enzyme digestion and PCR using type-specific primers. The prevalence of total HPV infection in patients with cervical intraepithelial neoplasia (CIN) and cervical cancer were significantly higher than those in healthy women and patients with atypical squamous cells of undetermined significance (ASCUS). HPV typing in 41 invasive carcinomas of the cervix revealed the prevalence of HPV 16 in 15 cases, followed by HPV 58, 18, 33, 31, 52 and 35. The distribution pattern of HPV types in CIN were not much different from carcinomas. HPV types except HPV 18 had a tendency to show higher prevalence in high-grade squamous intraepithelial lesion (HSIL) than low-grade squamous intraepithelial lesions (LSIL), however, HPV 18 was detected in LSIL but not in HSIL. HPV 18 tended to have the worse clinical stage, although it was not statistically significant. These findings suggest the importance of HPV typing other than HPV 16 and 18 and a different clinicopathologic significance of HPV 18.
Studies of cervical cancer and its immediate precursor, cervical intraepithelial neoplasia 3 (CIN3), have identified genes that often show aberrant DNA methylation and therefore, represent candidate early detection markers. We used quantitative PCR assays to evaluate methylation in five candidate genes (TNFRSF10C, DAPK1, SOCS3, HS3ST2 and CDH1) previously demonstrated as methylated in cervical cancer.
In this analysis, we performed methylation assays for the five candidate genes in 45 invasive cervical cancers, 12 histologically normal cervical specimens, and 23 liquid-based cervical cytology specimens confirmed by expert review as unequivocal demonstrating cytologic high-grade squamous intraepithelial lesions, thus representing the counterparts of histologic CIN3.
We found hypermethylation of HS3ST2 in 93% of cancer tissues and 70% of cytology specimens interpreted as CIN3; hypermethylation of CDH1 was found in 89% of cancers and 26% of CIN3 cytology specimens. Methylation of either HS3ST2 or CDH1 was observed in 100% of cervical cancer tissues and 83% of CIN3 cytology specimens. None of the five genes showed detectable methylation in normal cervical tissues.
Our data support further evaluation of HS3ST2 and CDH1 methylation as potential markers of cervical cancer and its precursor lesions.
cervical cancer; promoter methylation; tumor suppressor genes
Objectives: This study intends to analyze some statistical data concerning Cervical Intraepithelial Neoplasia diagnosed in our hospital.
Material and Methods: Our study concerning the incidence of Cervical Intraepithelial Neoplasia (CIN) covers the 2000-2009 time-span, the data being collected from the Histopathology Exams (HPE) registers.
Results: During this period, CIN lesions were discovered in 1256 cases and Cervical Intraglandular Dysplasia (CIGD) in 53 cases. CIN I, CIN II and CIN III lesions represented 65.92%(828 cases), 19.67% (247 cases), and 14.41% (181 cases) of the total CIN cases, respectively. There were 26 cases combined with cervical carcinoma (2.07% of all CIN cases, 3.56% of the 731 cervical cancer cases). The mean patients' age was 44.65± 9.83 years for all cervical dysplasia cases, 44.58± 9.75 years for all CIN cases, 43.81±9.22, 46.50±10.17, and 45.46±11.05 years for CIN I, CIN II, and CIN III, respectively, and 46.45 ± 11.63 years for CIGD. The t-test revealed the following significant differences: all cases versus CIN I (p<0.05) and CIN II (p<0.01), CIGD versus CIN I (p<0.05), all cases versus CIN II (p<0.01), CIN I versus CIN II (p<0.0001) and versus CIN III (p<0.05). The mean age of the 731 cervical cancer cases diagnosed in our hospital during that same period was 52.94±12.96 years,and it was statistically significantly different from the mean ages of patients with CIN I, II and III (p <0.00000001) and with CIGD (p<0.0005).
Conclusions: Early detection of CIN is of utmost importance for preventing cervical cancer, a serious and frequent health problem in Romania.
cervical intraepithelial neoplasia; cervical intraglandular dysplasia; cervical biopsy; cervical cancer
Recent studies have described premalignant changes in the endocervical epithelium, but morphological criteria for the diagnosis of cervical glandular atypia of lesser severity than adenocarcinoma in situ have not been established. Adenocarcinoma in situ is often associated with cervical intraepithelial neoplasia (CIN). The endocervical mucosa in 105 cases of CIN grade III was evaluated and compared with that of 100 controls. Sixteen cases of cervical glandular atypia and one case of adenocarcinoma in situ were identified, and it was possible to discriminate between these and a range of benign glandular lesions. Interestingly, the control series included two patients with cervical glandular atypia, one of whom on review had had a cone biopsy for CIN. The progression of cervical glandular atypia through adenocarcinoma in situ to invasive adenocarcinoma is known, but the natural history of cervical glandular atypia is as yet uncertain.
Heat shock protein (HSP) is thought to play important roles in the cell cycle and various process of carcinogenesis. This study was performed to evaluate the expression of heat shock protein (HSP70) and estrogen receptor (ER) and Ki-67 and to assess relationship between them in cervical squamous cell neoplasia. The materials were 50 cervical squamous cell lesions, consisted of 30 cervical intraepithelial neoplasia (CIN) (6 moderate dysplasia, 11 severe dysplasia, 13 carcinoma in situ), and 20 invasive squamous cell carcinoma (ISCC) cases. These specimens were immunohistochemically stained for HSP70, ER and Ki-67. The score of HSP70 was significantly higher in ISCC than CIN. Expression rate of the ER was not significantly higher in CIN than in ISCC. Ki-67 labelling index was significantly higher in the ISCC and high HSP70 positive staining group. These results suggested that HSP70 may play an important role in tumor cell proliferation and is related with ISCC than CIN, but ER may be not related with tumor cell proliferation and differentiation. HSP70 may be a useful prognostic factor in cervical dysplasia and cancer.
Regauer S & Reich O (2007) Histopathology50, 629–635 CK17 and p16 expression patterns distinguish (atypical) immature squamous metaplasia from high-grade cervical intraepithelial neoplasia (CIN III)
Atypical immature metaplasia (AIM) refers to a full-thickness intraepithelial basaloid lesion in the uterine cervix that features both metaplasia and atypia and is therefore difficult to distinguish from high-grade cervical intraepithelial neoplasia (CIN III). p16 is a marker for human papillomavirus (HPV)-induced dysplasia. Cytokeratin (CK) 17 is a marker for cervical reserve (stem) cells, which give rise to metaplasia. The aim was to determine whether AIM can be reclassified into metaplasia and CIN III based on p16 and CK17 immunohistochemistry.
Material and results
Seventy-five cervical biopsy specimens, curettings and cone excisions containing varying proportions of dysplasia and metaplasia and 20 cases regarded as AIM were analysed immunohistochemically with antibodies to CK17, p16 and p63. In immature metaplasia all proliferating cells were immunoreactive with antibodies to CK17 and p63, while p16 was negative. All dysplastic cells of CIN III demonstrated uniform immunoreactivity for p16 and p63, but were CK17–. Based on the reciprocal immunoreactivity of p16 and CK17, 17/20 cases of AIM were reclassified as metaplasia (n = 10) and CIN III (n = 7). Three cases of AIM stained for both CK17 and p16 and were classified as CIN III.
‘AIM’ is a helpful histological descriptor but it should not be used as a final diagnosis. Immunohistochemistry for p16 and CK17 allows distinction between metaplasia and high-grade CIN.
HPV; reactive atypia; squamous intraepithelial lesions
Cervical cytology by Papanicolaou (Pap) smears is an effective means of screening for cervical premalignant and malignant conditions. Cervical intra-epithelial neoplasia (CIN) and cervical cancer remain important health problems for women worldwide.
To study the role of Pap smear in detecting premalignant and malignant lesions of cervix; and to determine the prevalence of various lesions.
Materials and Methods:
This study is based on 300 patients who attended the out-patient Department of Obstetrics and Gynaecology. Pap smears were prepared from patients presenting with complaints like vaginal discharge, post-coital bleeding, inter-menstrual bleeding, dyspareunia, and pain lower abdomen. After fixation and staining, each smear was carefully examined.
Epithelial cell abnormalities were found in 5% smears, atypical squamous cells of undetermined significance (ASCUS) in 0.3%, squamous intraepithelial lesion (SIL) in 3.4% which includes low grade squamous intraepithelial lesion (LSIL) (2.7%) and high grade squamous intraepithelial lesion (HSIL) 0.7%. Invasive carcinoma was seen in 1.3% cases. Mean age of the patients with diagnosis of LSIL was 32.3 years and for HSIL, it was 40.5 years. The mean age of the patients with invasive carcinoma was 57 years.
Premalignant and malignant lesions of cervix are not uncommon in our set up and can be diagnosed early by Pap smears.
Cervical cancer; cervical intraepithelial neoplasia; papanicolaou smear
Objective: The cure rate after treatment of bacterial vaginosis (BV) differs in various investigations, but most studies report a cure rate of 70% after 1 month.
Methods: A long-term observation study after successful treatment of BV has been undertaken. The original study was a treatment study of BV and included 50 patients.
Results: We were able to identify 44 of the original 50 patients. The mean follow-up time was 6.9 years (range 4.7–9 years). During this time, 21 women (48%) had been free of BV while 23 women had had relapses. There was no difference in the use of broad-spectrum antibiotics, episodes of candida vaginitis, bleeding disturbances, family planning method, development of cervical intraepithelial neoplasia (CIN), or gynecological operations between women with and without relapses. The women with relapses had had a new sexual contact more often during the observation period than women without relapses. There was no difference in hydrogen peroxide production of the lactobacilli among women with or without relapses, and survival analysis shows that most relapses occur during the first year after treatment.
Conclusions: If patients are successfully treated, half of the patients will stay cured indicating that treatment is of benefit. Most relapses occur during the first year. Our results indicate that the etiology of BV might have something to do with new sexual contacts.
Cervical metaplastic squamous epithelium exhibiting atypia insufficient for a diagnosis of cervical intraepithelial neoplasia (CIN) is usually reported as “atypical squamous metaplasia” (ASM). Stratification impacts treatment since the differential is often between reactive and high grade CIN (CIN II, III). Diagnosis with H&E is associated with low intra/interobserver concurrence. P16/Ki-67 immunostains are helpful to assess cervical biopsies for HPV-associated lesions but staining in metaplastic squamous epithelium has received little attention. This study aims to establish staining characteristics of metaplastic squamous epithelium and determine if p16/Ki-67 is useful in ASM stratification. 80 cervical biopsies containing morphologically normal and dysplastic squamous metaplasia were retrieved to determine the staining characteristics of metaplastic epithelium utilizing p16/Ki-67 immunostains. These included 21 benign squamous metaplasia (BSM) from benign cervices, 15 BSM present adjacent to HPV/CIN lesions, and 44 CIN involving squamous metaplasia. Serial sections with controls were stained for p16 and Ki-67 and in-situ hybridization (ISH) for low-risk (LR) and high-risk (HR) HPV was performed. P16 was recorded as negative, spotty, or band-like. Ki-67 was recorded as positive when present in >50% of lesional nuclei. Results were correlated with H&E diagnosis. 95% of the BSMs, whether from normal cervices or adjacent to HPV/CIN were p16/Ki-67 negative. 81% HG CINs involving squamous metaplasia were p16 band/Ki-67 positive. Low grade CIN (CIN I) involving metaplastic epithelium showed a broad distribution of p16/Ki-67 staining patterns. Based on these criteria, 20 ASM were evaluated. 10% of the ASM cases were p16 band/Ki-67 positive indicating HG CIN. 60% of the ASMs were p16/Ki-67 negative indicating reactive change (all with the exception of one case being HPV negative). The remaining 30% of the ASM cases showed variable positivity for p16 and Ki-67 and could not be stratified into the two categories. Thus p16/Ki-67 staining is helpful in stratification of ASM as reactive or CIN.
P16; Ki-67; cervical intraepithelial neoplasia (CIN); human papilloma virus (HPV); atypical squamous metaplasia
Increased angiogenesis leads to invasion in cervical cancer. Vascular endothelial growth factors (VEGFs) are involved in angiogenesis, but molecular links to the most important aetiological agent, human papillomavirus (HPV), need clarifying.
Archival samples—150 squamous cell carcinomas (SCCs) and 152 cervical intraepithelial neoplasia (CIN) lesions—were examined immunohistochemically for anti‐VEGF‐C antibody and for HPV by polymerase chain reaction (PCR). Follow up data were available for all SCC cases, and 67 CIN lesions were monitored with serial PCR to assess HPV clearance/persistence after treatment.
High risk (HR) HPV types were closely associated with CIN (odds ratio, 19.12; 95% confidence interval, 2.31 to 157.81) and SCC (27.25; 3.28 to 226.09). There was a linear increase of VEGF‐C expression—weak in CIN1 and intense in CIN3 and SCC (20.49; 8.69 to 48.26). VEGF‐C upregulation was a sensitive (93.5%; 95% CI, 90.1% to 96.9%) marker of HR‐HPV type (4.70; 2.17 to 10.21), but lost its significance in multivariate regression—p16INK4a and survivin were equally strong independent predictors of HR‐HPV. Aberrant expression of VEGF‐C did not predict clearance/persistence of HR‐HPV after treatment of CIN. In cervical cancer, VEGF‐C had no prognostic value in univariate or multivariate survival analysis. After adjustment for HR‐HPV, FIGO stage, age, and tumour grade, only FIGO stage and age remained independent prognostic predictors.
VEGF‐C is an early marker of cervical carcinogenesis, with linearly increasing expression starting from low grade CIN. VEGF‐C expression is closely related to HR‐HPV in cervical lesions, probably because of its p53 independent upregulation by the E6 oncoprotein of HR‐HPV.
vascular endothelial growth factor C; angiogenesis; human papillomavirus; cervical intraepithelial neoplasia; cervical cancer; prognosis; virus clearance; high risk human papillomavirus; conisation
U.S. cervical cancer screening guidelines for HIV-uninfected women 30 years of age and older have recently been revised, increasing the suggested interval between Pap tests from three years to five years among those with normal cervical cytology (the Pap test) who test negative for oncogenic human papillomavirus (HPV). Whether a three-year or five-year screening interval might be used in HIV-infected women who are cytologically normal and oncogenic HPV-negative is unknown.
To determine the risk of cervical pre-cancer or cancer defined cytologically (high-grade squamous intraepithelial lesions or greater [HSIL+]) or histologically (cervical intraepithelial neoplasia 2 or greater [CIN-2+]), as two separate endpoints, in HIV-infected women and HIV-uninfected women who at baseline had a normal Pap test and were negative for oncogenic HPV.
Design, Setting and Participants
Participants included 420 HIV-infected women and 279 HIV-uninfected women with normal cervical cytology at their enrollment in a multi-institutional cohort, between October 1, 2001 and September 30, 2002, with follow-up through April 30, 2011. Clinical sites were in the Bronx, Brooklyn, Chicago, Los Angeles, San Francisco, and Washington, DC. Semi-annual visits included Pap testing and, if indicated, cervical biopsy. Cervicovaginal lavage specimens from enrollment were tested for HPV DNA using PCR. The primary analysis was truncated at five years of follow-up.
Main Outcome Measure
The five-year cumulative incidence of cervical pre-cancer and cancer.
No oncogenic HPV was detected in 369 (88%; 95% CI, 84%-91%) of the HIV-infected women and 255 (91%; 95% CI, 88%-94%) of the HIV-uninfected women with normal cervical cytology at enrollment. Among these oncogenic HPV-negative women two cases of HSIL+ were observed; an HIV-uninfected woman and an HIV-infected woman with a CD4 cell count of 500/μL or greater. Histologic data were obtained from four of the six sites. There were six cases of CIN-2+ in N=145 HIV-uninfected women (cumulative incidence = 5% [95% CI, 1%-8%]) and nine cases in N=219 HIV-infected women (cumulative incidence = 5% [95% CI, 2%-8%]). This included one case of CIN-2+ in N=44 oncogenic HPV-negative HIV-infected women with CD4 cell counts less than 350/μL (cumulative incidence = 2% [95% CI, 0%-7%]), one case in N=47 women with CD4 cell counts of 350 to 499/μL (cumulative incidence = 2% [95% CI, 0%-7%]), and seven cases in N=128 women with CD4 cell counts of 500/μL or greater (cumulative incidence = 6% [95% CI, 2%-10%]). One HIV-infected and one HIV-uninfected woman had CIN-3, but none had cancer.
The five-year cumulative incidence of HSIL+ and CIN-2+ was similar in HIV-infected women and HIV-uninfected women who were cytologically normal and oncogenic HPV-negative at enrollment.
The highest rates of cervical cancer are found in developing countries. Frontline monitoring has reduced these rates in developed countries and present day screening programs primarily identify precancerous lesions termed cervical intraepithelial neoplasias (CIN). CIN lesions described as mild dysplasia (CIN I) are likely to spontaneously regress while CIN III lesions (severe dysplasia) are likely to progress if untreated. Thoughtful consideration of gene expression changes paralleling the progressive pre invasive neoplastic development will yield insight into the key casual events involved in cervical cancer development.
In this study, we have identified gene expression changes across 16 cervical cases (CIN I, CIN II, CIN III and normal cervical epithelium) using the unbiased long serial analysis of gene expression (L-SAGE) method. The 16 L-SAGE libraries were sequenced to the level of 2,481,387 tags, creating the largest SAGE data collection for cervical tissue worldwide. We have identified 222 genes differentially expressed between normal cervical tissue and CIN III. Many of these genes influence biological functions characteristic of cancer, such as cell death, cell growth/proliferation and cellular movement. Evaluation of these genes through network interactions identified multiple candidates that influence regulation of cellular transcription through chromatin remodelling (SMARCC1, NCOR1, MRFAP1 and MORF4L2). Further, these expression events are focused at the critical junction in disease development of moderate dysplasia (CIN II) indicating a role for chromatin remodelling as part of cervical cancer development.
We have created a valuable publically available resource for the study of gene expression in precancerous cervical lesions. Our results indicate deregulation of the chromatin remodelling complex components and its influencing factors occur in the development of CIN lesions. The increase in SWI/SNF stabilizing molecule SMARCC1 and other novel genes has not been previously illustrated as events in the early stages of dysplasia development and thus not only provides novel candidate markers for screening but a biological function for targeting treatment.
The colposcopic vision guided loop electrosurgical excisional procedure (LEEP) was studied for the effective diagnosis of cervical cancer and cervical intraepithelial neoplasia (CIN).
A total of 199 patients participated in this study. Individual cases were from gynecologic outpatients at Thammasat University Hospital, Thailand. These had diagnoses for CIN and were selected for treatment with colposcopic guided LEEP. The average age of patients in this study was 45. Menopausal women represented 31%, (61/199) of the patients. The most frequently found Pap smear result among these women (44%, 88/199), was that of high-grade squamous intraepithelial lesion. The next most frequent Pap smear result (32%, 64/199) was low-grade squamous intraepithelial lesion. Patients' medical records and outcomes were evaluated for consistency of pathological examination between colposcopic directed biopsy and LEEP. Discrepancies between initial diagnosis and the final diagnosis were also analyzed.
The colposcopic guided LEEP accurately determined 100% of the cervical cancer cases and 84.8 % of the high-grade squamous intraepithelial lesion cases. Involvement of the ectocervical or endocervical margin regions was found to be 5% and 10% respectively, in this study. Excessive bleeding complication, either during the excision and/or postoperative recovery was found in 3% and 6% of cases, respectively.
LEEP under colposcopic vision is a recommended technique for ambulatory management of precancerous lesion and early diagnosis of cervical cancer. This technique significantly reduces rate of positive ectocervical cone margin involvement.
Cervical cancer; Cervical intraepithelial neoplasia; Loop electrosurgical excision procedure (LEEP); Colposcopic vision
Essentially all squamous cervical cancers and their precursor lesions, high grade cervical intraepithelial neoplasia (CIN2/3), are caused by persistent human papil-lomavirus (HPV) infection. However, not all CIN2/3 lesions progress to cancer. In a brief, observational study window monitoring subjects with CIN2/3 from protocol entry (biopsy diagnosis) to definitive therapy (cervical conization) at week 15, in a cohort of 50 subjects, we found that 26% of CIN2/3 lesions associated with HPV16, the genotype most commonly associated with disease, underwent complete histologic regression. Nonetheless, HPV16-specific T cell responses measured in peripheral blood obtained at the time of study entry and at the time of conization were marginally detectable directly ex vivo, and did not correlate with lesion regression. This finding suggests that, in the setting of natural infection, immune responses which are involved in elimination of cervical dysplastic epithelium are not represented to any great extent in the systemic circulation.
Human papillomavirus (HPV); Cervical dysplasia; Regression; Systemic immune response
The effectiveness of screening programs for cervical cancer has benefited from the inclusion of Human papillomavirus (HPV) DNA assays; which assay to choose, however, is not clear based on previous reviews. Our review addressed test accuracy of Hybrid Capture II (HCII) and polymerase chain reaction (PCR) assays based on studies with stronger designs and with more clinically relevant outcomes. We searched OvidMedline, PubMed, and the Cochrane Library for English language studies comparing both tests, published 1985–2012, with cervical dysplasia defined by the Bethesda classification. Meta-analysis provided pooled sensitivity, specificity, and 95% confidence intervals (CIs); meta-regression identified sources of heterogeneity. From 29 reports, we found that the pooled sensitivity and specificity to detect high-grade squamous intraepithelial lesion (HSIL) was higher for HCII than PCR (0.89 [CI: 0.89–0.90] and 0.85 [CI: 0.84–0.86] vs. 0.73 [CI: 0.73–0.74] and 0.62 [CI: 0.62–0.64]). Both assays had higher accuracy to detect cervical dysplasia in Europe than in Asia-Pacific or North America (diagnostic odd ratio – dOR = 4.08 [CI: 1.39–11.91] and 4.56 [CI: 1.86–11.17] for HCII vs. 2.66 [CI: 1.16–6.53] and 3.78 [CI: 1.50–9.51] for PCR) and accuracy to detect HSIL than atypical squamous cells of undetermined significance (ASCUS)/ low-grade squamous intraepithelial lesion (LSIL) (HCII-dOR = 9.04 [CI: 4.12–19.86] and PCR-dOR = 5.60 [CI: 2.87–10.94]). For HCII, using histology as a gold standard results in higher accuracy than using cytology (dOR = 2.87 [CI: 1.31–6.29]). Based on higher test accuracy, our results support the use of HCII in cervical cancer screening programs. The role of HPV type distribution should be explored to determine the worldwide comparability of HPV test accuracy.
Human papillomavirus; hybrid capture II; meta-analysis; polymerase chain reaction; test accuracy
To describe (1) prevalence and (2) estimated attribution of human papillomavirus (HPV) types in U.S. cervical, vaginal and vulvar precancers and cancers.
U.S. studies reporting HPV typing for cervical (CIN), vulvar (VIN) and vaginal (VaIN) intraepithelial neoplasias and/or invasive cancers of those sites were gathered from the PubMed database (http://www.ncbi.nlm.nih.gov/sites/entrez/). Selected studies had polymerase chain reaction testing data for ≥10 cases for a disease endpoint. Analytic methods augmented prior reviews of cervical disease with an updated and expanded analysis (including vulvar and vaginal disease), new selection criteria for specimens, and adjustment for histologic type, where possible, among pooled cancer cases. In addition, for analyses of estimated attribution of HPV types, we incorporated accounting methods for lesions infected with multiple HPV types.
Data from 22 U.S. studies meeting review eligibility criteria were tabulated. Following adjustment for the presence of multiple HPV types in a single specimen, the top two HPV types contributing to disease were: CIN 1 (HPV 16/66) [15.3%], CIN 2/3 (16/31) [61.9%], cervical cancer (16/18) [79.2%], VIN 1 (6/11) [41.7%], VIN 3 (16/18) [84.0%], vulvar cancer (16/33) [55.5%], VaIN 3 (16/18) [65.1%], vaginal cancer (16/18) [72.7%].
The HPV type distribution and proportion of cases testing positive for any HPV type were observed to vary among U.S. cervical, vulvar and vaginal neoplasias and by grade of disease. Adjustment for the presence of multi-type HPV infections can have an important impact on the estimated attribution of HPV types to disease, particularly for types other than HPV 16.
human papillomavirus; prevalence; attribution; cervical; vulvar
Background: Infection with human papillomavirus (HPV) is the main cause of cervical cancer and its precursor lesion, cervical intraepithelial neoplasia (CIN). Variability in host immunogenetic background is important in determining the overall cellular immune response to HPV infections.
Objective: To determine whether the HLA-DQ or HLA-DR genes, or others in their vicinity, are associated with cervical cancer.
Methods: Markers covering the entire HLA region were genotyped in a large sample of CIN and cervical cancer patients and in controls (311 CIN, 695 cervical cancer, 115 family controls, and 586 unrelated controls).
Results: Two markers were associated with susceptibility to cervical neoplasia, G511525 and MICA. G511525, close to the region containing the HLA-DQ and HLA-DR genes, was most strongly associated, showing a decrease in frequency of allele 221 from 6.7% to 3.3% in patients with squamous cell cancer (SCC). An association was found for MICA (allele 184) with SCC (odds ratio (OR) = 1.31 (95% confidence interval, 1.13 to 1.53); homozygotes, OR = 1.48 (1.06 to 2.06)). No associations were observed with adenocarcinoma or CIN.
Conclusions: There is an association of the region containing the HLA-DQ and HLA-DR genes with the risk of developing squamous cell carcinoma. An increased risk was observed for carriers of allele 184 at the MICA locus, in particular for homozygotes, suggesting a recessive effect.