Detection Of Cervical Cancer Precursors Research Articles

Human Papillomavirus E6/E7 oncogene transcripts as biomarkers for the early detection of cervical cancer.

Cancer of the cervix uteri is the fourth most common cancer worldwide with a high mortality rate. Due to limitations of the existing methods, alternative methods for triage are needed for early detection of cervical cancer precursors before progression to high-grade disease. The aim of this study was to evaluate human papillomavirus (HPV) E6/E7 oncogene expression as markers for early identification of cervical cancer risk in women with minor cytological abnormalities and in those with negative cytology. The detection of HPV was done using PCR and confirmed by southern hybridization. The high-risk (HR) and low-risk HPV types were identified by HPV typing. HPV DNA-positivepatients were further tested for markers of oncogene expression by real-time PCR. Out of the women screened, 54/512 (10.54%) women tested positive for HPV infection. HR HPV DNA was found in 32/485 (6.60%) women with normal cytology (Pap negative) and 22/27 (81.5%) atypical squamous cells of undetermined significance/low-grade intraepithelial lesion cases. HR HPV E6/E7 oncogene transcripts were detected in 36/512 (7.03%) patients. The positivity rate of E6/E7 messenger RNA (mRNA) was 2.48% (12/485) in normal cervical cytology group and 88.9% (24/27) in abnormal cervical cytology group. The HPV E6/E7 mRNA test sensitivity was found to be 88.89% and specificity was 97.53%. In comparison, the sensitivity of the HPV DNA test was found to be 81.48% and specificity was 93.40%. In conclusion, E6 and E7 transcripts could provide a sensitive, early predictor of cervical cancer risk in women with normal cytology and minor cytological alterations.

Previous Papanicolaou and Hybrid Capture 2 human papillomavirus testing results of 5699 women with histologically diagnosed cervical intraepithelial neoplasia 2/3

Cervical cancer remains an important public health problem in Chinese women owing to the lack of a national screening program. The aim of the present study was to evaluate human papillomavirus (HPV) and Papanicolaou (Pap) test results preceding the histologic diagnosis of cervical intraepithelial neoplasia 2/3 (CIN2/3) in China's largest College of American Pathologists-certified clinical laboratory. All cases of CIN2/3 histologically diagnosed from January 2011 to August 2016 were retrieved from the pathology department records. The Pap cytology and HPV test results from the 6 months before the CIN2/3 diagnoses were analyzed. A total of 5699 patients with histologically diagnosed CIN2/3 had previous Pap and/or HPV Hybrid Capture 2 testing results within the previous 6 months. The average age was 39.5 years (range, 16-82 years). Of these patients, 4288 had Pap test findings (average, 1.5 months) available. The results were high-grade squamous intraepithelial lesion in 44.1%, low-grade squamous intraepithelial lesion in 20.0%, atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion, in 16.0%, atypical squamous cells of undetermined significance, in 12.3%, atypical glandular cells in 0.7%, and negative in 6.9%. Of the 5699 patients, 2546 had HPV Hybrid Capture 2 test results (average, 1.4 months) available. Of these, 91.7% had positive results and 8.3% had negative results. Of 1135 patients with both previous Pap and HPV results, 7.1% had negative HPV results and 8.0% had negative Pap results (P = 0.38). Only 21 patients (1.9%) had double negative results. The present study has reported the previous results of HPV testing and Pap cytology for patients with high-grade cervical squamous precursor lesions in a population of women in China who had not undergone intensive previous screening. Both high-risk HPV and Pap cytology had similar negative testing rates for these women, although double negative results were less common. These results support the value of combined testing in the detection of cervical cancer precursors.

Role of p16/Ki-67 Dual Immunostaining in Detection of Cervical Cancer Precursors.

Background:Pap-smears-based cytology and human papilloma virus testing have their own limitations in detecting cervical precancerous lesions, and still need further standardization. Co-expression of p16ink4a and Ki-67 can be used as additional biomarker.Aims:To study the role of liquid-based cytology and the dual immunostaining for p16/Ki-67 in predicting the presence of significant lesion in cases of mild cytological atypia.Materials and Methods:A prospective, cross-sectional study was performed in the Department of Pathology, in collaboration with Department of Obstetrics and Gynecology over 15 months including 545 patients. Immunocytochemistry followed by colposcopy-guided biopsy were performed in 52 cases with epithelial abnormalities.Results:Thirty-five cases (67%) were dual-stain positive among the cases with epithelial abnormalities. In the ASC-US and LSIL group, the sensitivity and specificity of the immunostaining in diagnosing CIN2+ lesions were 100 and 70% and 87.5 and 100%, respectively. p16/Ki-67 positivity also increased with cytological severity which in turn corresponded with histological findings: it reached from 33% in ASC-US to 100% in both HSIL and SCC categories.Conclusion:This dual immunostaining may potentially be a useful tool in the triage of the ASC-US and the LSIL group, considering the high sensitivity and specificity values.

A Review on Advancement Perspectives in Cervical Cancer

Cervical cancer is the second most common cancer among women and remains one among the major worldwide health concern. It is estimated that more than 500,000 and 300000 women’s develop and die annually from cervical cancer. Human papillomaviruses (HPVs) are the main cause for the origin of >99% of cervical cancers and are considered to be the major etiologic factor besides environmental and hormonal. Since the number of women reporting with cervical cancer is increasing annually better screening as well as diagnostic methods are to be initiated. Pap smears, as of now considered, to be a successful means for early detection of cervical cancer precursors but is limited in its use in countries with developed health care systems. Current approaches for treating cancer have limited success. In this line, as of studies reported so far on treatment for cervical cancer, is chemotherapy, radiation therapy along with surgical treatments.

Cancer of the cervix: Early detection and cost-effective solutions.

Cervical cancer is known to be a preventable disease through the detection of cervical cancer precursors, historically using cytology of the cervix as the primary screening test. Over 85% of cervical cancer cases and deaths occur in low-resource countries. Alternatives to cytology have been investigated with the strongest possibilities being visual inspection with acetic acid (VIA) and HPV DNA testing. HPV DNA testing has been shown in randomized trials to be significantly more sensitive for the detection of cervical cancer precursors than either cytology or VIA. In this paper we argue that prevention really does cost less than cure, or that prevention and treatment of cancer costs less than no prevention, in effect just treatment, of cancer. The true cost savings of prevention will include a more difficult assessment of the socioeconomic savings associated with longer, healthier lives for women in their prime who have a major role in supporting their families.

Multiple biopsies and detection of cervical cancer precursors at colposcopy.

Women with abnormal cervical cancer screening results are referred to colposcopy and biopsy for diagnosis of cervical cancer precursors (high-grade squamous intraepithelial lesions [HSILs]). Colposcopy with a single biopsy can miss identification of HSILs. No systematic study has quantified the improved detection of HSIL by taking multiple lesion-directed biopsies. The Biopsy Study was an observational study of 690 women referred to colposcopy after abnormal cervical cancer screening results. Up to four directed biopsies were taken from distinct acetowhite lesions and ranked by colposcopic impression. A nondirected biopsy of a normal-appearing area was added if fewer than four directed biopsies were taken. HSIL identified by any biopsy was the reference standard of disease used to evaluate the incremental yield and sensitivity of multiple biopsies. In the overall population, sensitivities for detecting HSIL increased from 60.6% (95% CI, 54.8% to 66.6%) from a single biopsy to 85.6% (95% CI, 80.3% to 90.2%) after two biopsies and to 95.6% (95% CI, 91.3% to 99.2%) after three biopsies. A significant increase in sensitivity of multiple biopsies was observed in all subgroups. The highest increase in yield of HSIL was observed for women with a high-grade colposcopic impression, HSIL cytology, and human papillomavirus (HPV) type 16 positivity. Only 2% of all HSILs diagnosed in the participants were detected by biopsies of normal-appearing transformation zone. Collection of additional lesion-directed biopsies during colposcopy increased detection of histologic HSIL, regardless of patient characteristics. Taking additional biopsies when multiple lesions are present should become the standard practice of colposcopic biopsy.

O1-S02.06 Detection of cervical cancer precursors and associated HPV types in the USA: HPV-IMPACT preliminary results

BackgroundCervical intraepithelial neoplasia (CIN) grade 2 or 3 and adenocarcinoma in situ (AIS) (CIN2+) can be used to monitor HPV vaccine impact. This spectrum of preinvasive cervical lesions are commonly...

Comparison of Liquid-Based Cytology With Conventional Cytology for Detection of Cervical Cancer Precursors: A Randomized Controlled Trial

The Papanicolaou (Pap) test—the conventional screening method for cervical intraepithelial neoplasia (CIN)—is suboptimal due to high false-negative and false-positive test results due to the poor quality of sampling, preparation problems and errors in detection and interpretation. In a large number of studies, the diagnostic accuracy of an alternative procedure, liquid-based cytology, has been compared with the Pap test with conflicting results. Few of these studies, however, were randomized and none of the randomized trials were well designed. This cluster randomized controlled trial compared liquid-based cytology and the Pap test with respect to testing positivity rates, histologically confirmed detection rates, and positive predictive values (PPVs). The study subjects were women aged 30 to 60 years who were participants in the Dutch cervical screening program. Between 2004 and 2006, 49,222 patients at 122 practices were screened with liquid-based cytology and 40,562 patients at 124 practices were screened with the Pap test. Screen-positive women were followed prospectively for 18 months after initial screening. All medical personnel and others involved with follow-up of screen-positive women were blinded to the cytology screening system used and initial results. Both the intention-to-treat and per-protocol analysis were used. Multivariate logistic regression analysis was used to adjust for possible confounding factors (age, urbanization level, study site, and period). Detection rate ratios of verified cervical abnormalities were calculated for the liquid-based test relative to the Pap test for the primary histological outcome of CIN grades 1+, 2+, and 3+ and carcinoma. The adjusted positive predictive value (PPV) ratios were also calculated. PPV ratios were evaluated at different levels of test positivity and outcome thresholds. The adjusted detection rate ratio for CIN grade 1+ was 1.01, with a 95% confidence interval [CI] of 0.85–1.19); for CIN grade 2+, the rate ratio was 1.00 (95% CI, 0.84–1.20); for CIN grade 3+, the rate ratio was 1.05 (95% CI, 0.86–1.29); and for carcinoma, the rate was 1.69 (95% CI, 0.96–2.99). Comparable results were found for the PPV ratios. Both the detection rate and PPV ratios were close to one and none of the ratios significantly differed from unity. These findings demonstrate that liquid-based cytology is neither more sensitive nor more specific than the Pap test in detecting CIN or cancer.

Comparison of Liquid-Based Cytology With Conventional Cytology for Detection of Cervical Cancer Precursors: A Randomized Controlled Trial

Comparison of Liquid-Based Cytology With Conventional Cytology for Detection of Cervical Cancer Precursors: A Randomized Controlled Trial

Incorrect Funding Source in: Comparison of Liquid-Based Cytology With Conventional Cytology for Detection of Cervical Cancer Precursors: A Randomized Controlled Trial

Incorrect Funding Source in: Comparison of Liquid-Based Cytology With Conventional Cytology for Detection of Cervical Cancer Precursors: A Randomized Controlled Trial

Comparison of Liquid-Based Cytology With Conventional Cytology for Detection of Cervical Cancer Precursors

Liquid-based cytology has been developed as an alternative for conventional cervical cytology. Despite numerous studies and systematic reviews, controversy remains about its diagnostic accuracy. To assess the performance of liquid-based cytology compared with conventional cytology in terms of detection of histologically confirmed cervical intraepithelial neoplasia (CIN). Cluster randomized controlled trial involving 89,784 women aged 30 to 60 years participating in the Dutch cervical screening program at 246 family practices. One hundred twenty-two practices were assigned to use liquid-based cytology and screened 49,222 patients and 124 practices were assigned to use the conventional Papanicolaou (Pap) test and screened 40,562 patients between April 2004 and July 1, 2006. Patients were followed up for 18 months through January 31, 2008. Screening for CIN using liquid-based cytology or conventional papanicolaou (Pap) test and the blinded review of all follow-up of screen-positive women (blinded to the type of cytology and the initial result). Intention-to-treat and per-protocol analysis of the detection rates of and positive predictive values for histologically verified CIN in both cytology systems. Outcomes are presented as crude and adjusted rate ratios (adjustment for age, urbanization, study site, and period). The adjusted detection rate ratios for CIN grade 1+ was 1.01 (95% confidence interval [CI], 0.85-1.19); for CIN grade 2+, 1.00 (95% CI, 0.84-1.20); for CIN grade 3+, 1.05 (95% CI, 0.86-1.29); and for carcinoma, 1.69 (95% CI, 0.96-2.99). The adjusted positive predictive value (PPV) ratios, considered at several cytological cutoffs and for various outcomes of CIN did not differ significantly from unity. This study indicates that liquid-based cytology does not perform better than conventional Pap tests in terms of relative sensitivity and PPV for detection of cervical cancer precursors. trialregister.nl Identifier: NTR1032.

Molecular methods for the detection of human papillomavirus infection: new insights into their role in diagnostics and epidemiological surveillance

Human papillomaviruses (HPVs) comprise more than 180 genotypes. HPV infection is mainly diagnosed by molecular methods. The aim of our study was to review the main molecular methods used to diagnose HPV infection, underscoring their characteristics. Several methods have been developed for molecular diagnosis of Papilloma infection, such as those based on PCR technique. Another commercial non-PCR based diagnostic method is Hybrid Capture test; it is the only commercially available HPV DNA detection test approved by the FDA. Several Authors have suggested that viral load and E6/E7 transcripts could be used as surrogate markers of persistent HPV infection, being more specific predictors of progressive disease than the simple presence of HPV DNA. Validating clinical sensitivity and specificity of each technique and improving the interpretation of the results are essential; consequently, there is a clear need for well characterized international quality control panels to compare the various diagnostic methods. HPV DNA testing could be useful both as a primary screening test, alone or in combination with a Pap smear, for the early detection of cervical cancer precursors, and as triage test to select women with minor cytological abnormalities who will need further follow-up and to predict possible treatment failure in women with diagnosed high-grade intraepithelial lesions who have undergone excisional therapy. In the next future surveillance for HPV infections, based on these molecular methods, could represent an important step for the development of primary and secondary prophylactic interventions, such as new vaccines targeted to genotypes who might replace those previously prevalent.

Screening and management of women and girls with human papillomavirus infection

In the US, reductions in cervical cancer-related mortality over the past five decades can be attributed to the implementation of screening programs. US-based guidelines recommend that screening should be initiated approximately 3 years after initiation of sexual intercourse, but no later than age 21 years and be continued at least until age 65 or 70. Annual screening is recommended by the American Cancer Society and the American College of Obstetricians and Gynecologists, although in women aged ≥ 30 years with ≥ 3 negative Pap tests, screening may be conducted every 2 to 3 years. Human papillomavirus (HPV) testing has been approved by the US Food and Drug Administration and most US guidelines say that it is reasonable to consider HPV testing, in combination with triennial cytology screening. Pharmacoeconomic analyses indicate that combined cytology and HPV testing every three years in women aged ≥ 30 years is comparable in sensitivity to annual liquid-based cytology for the detection of cervical cancer precursors and is more cost-effective. Both surgical and nonsurgical therapies are commonly employed in patients with HPV lesions although papilloma recurrence is not uncommon. Treatment should be individualized based on the extent of disease and the needs of the patient. Current treatment of cervical cancer reflects the stage of the disease and should take into account patient- and tumor-related factors to ensure optimal patient outcomes.

PL8 The causal role of genital human papillomavirus (hpv) infections in cervical carcinogenesis

Well over 150 different human papillomavirus (HPV) types are currently recognised, divided according to their preferential targets into (i) cutaneous and (ii) mucosal HPV types. The latter are further classified as low‐risk (HPV 6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81, and CP6108), intermediate risk (HPV 26, 53, and 66) and high‐risk (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82) types, according to their association with malignant lesions at genital‐ and extra‐genital mucosal sites. Since the recognition of their close association with cervical cancer precursor (CIN) lesions in 1976, HPVs have emerged as the most important human tumour viruses. Beyond any doubt, oncogenic HPV types are the single most important etiological agents of cervical cancer (CC) and CIN lesions, whereas low‐risk HPV types are associated with benign mucosal squamous cell lesions (papillomas and condylomas). Apart from extensive epidemiological documentation, the link between HPV and CC has been confirmed by molecular biological research and prospective cohort studies disclosing the natural history of HPV infections and the true precancer nature of high‐grade CIN lesions. The latter develop as a result of persistent oncogenic HPV infections, known to predispose the women to significantly increased risk of CC. Factors predicting both the disease outcome (persistence, progression, regression) and the viral events (incident infections, HPV persistence, virus clearance) are emerging only recently. In addition to testing the feasibility of various optional screening tools in early detection of CC precursors, as well as to ongoing clinical trials with prophylactic HPV vaccines, another major focus of current HPV research includes the intense screening of new biomarkers as potential predictors of disease progression and outcome of oncogenic HPV infections.

Efficacy of a liquid-based thin layer method for cervical cancer screening in a population with a low incidence of cervical cancer

The performance of the ThinPrep(R) Pap Testtrade mark (TP) (Cytyc Corp., Boxborough, MA) for detection of cervical cancer precursors in a population with a low incidence of disease was evaluated. This prospective trial compared results obtained with TP to those obtained with the standard cytologic smear in women from the general community who were being screened for cervical cancer from January 1, 1995-December 31, 1997 by physicians in private practice (n x 130, 381 conventional examinations and 39,864 TP examinations). In the TP series there was a significant increase in the proportion of "satisfactory" examinations (91.9% TP vs. 72.2% conventional) and positive diagnoses (5.5% TP vs 2.4% conventional, odds ratio x 2.21; 95% confidence interval (CI), 2.08-2.34). The likelihood of detecting a high-grade squamous intraepithelial lesion (HSIL) by TP was significantly greater than in controls (odds ratio x 1.86; 95% CI, 1.68-2.06). Detection of low-grade squamous intraepithelial lesions (LSIL), or atypical squamous cells of undetermined significance (ASCUS), was significantly greater in the TP series than in controls (LSIL odds ratio x 3.41; 95% CI, 3.07-3.79; ASCUS odds ratio x 1.68; 95% CI, 1.56-1.82). A histologic lesion was confirmed in 141 (93%) of the biopsies for HSIL (130 HSIL or greater, 10 LSIL, 1 SIL not otherwise specified). In conclusion, both diagnostic sensitivity and sample adequacy were significantly improved using the ThinPrep(R) Pap test under routine conditions in an outpatient population with a low incidence of cervical cancer.

Efficacy of a liquid‐based thin layer method for cervical cancer screening in a population with a low incidence of cervical cancer

The performance of the ThinPrep® Pap Test™ (TP) (Cytyc Corp., Boxborough, MA) for detection of cervical cancer precursors in a population with a low incidence of disease was evaluated. This prospective trial compared results obtained with TP to those obtained with the standard cytologic smear in women from the general community who were being screened for cervical cancer from January 1, 1995–December 31, 1997 by physicians in private practice (n × 130,381 conventional examinations and 39,864 TP examinations). In the TP series there was a significant increase in the proportion of “satisfactory” examinations (91.9% TP vs. 72.2% conventional) and positive diagnoses (5.5% TP vs 2.4% conventional, odds ratio × 2.21; 95% confidence interval (CI), 2.08–2.34). The likelihood of detecting a high-grade squamous intraepithelial lesion (HSIL) by TP was significantly greater than in controls (odds ratio × 1.86; 95% CI, 1.68–2.06). Detection of low-grade squamous intraepithelial lesions (LSIL), or atypical squamous cells of undetermined significance (ASCUS), was significantly greater in the TP series than in controls (LSIL odds ratio × 3.41; 95% CI, 3.07–3.79; ASCUS odds ratio × 1.68; 95% CI, 1.56–1.82). A histologic lesion was confirmed in 141 (93%) of the biopsies for HSIL (130 HSIL or greater, 10 LSIL, 1 SIL not otherwise specified). In conclusion, both diagnostic sensitivity and sample adequacy were significantly improved using the ThinPrep® Pap test under routine conditions in an outpatient population with a low incidence of cervical cancer. Diagn. Cytopathol. 2000;22:52–59. © 2000 Wiley-Liss, Inc.