Diagnosis Of Cervical Neoplasia Research Articles

Doctors in Denial: The Forgotten Women in the "Unfortunate Experiment".

The "unfortunate experiment" that took place for a period of more than 20 years at the New Zealand Woman's Hospital in Auckland, New Zealand, had tragic results for numerous unsuspecting women and ultimately caused a 20-year setback in cervical cancer screening in New Zealand. The story of Herbert Green's evolving beliefs about cervical cancer, his pursuit of proof for his unfounded theory, based on "no more that a whim and misbelief" according to author Ron Jones, as well as the history of the active as well as passive complicity of superiors and colleagues for years in the rarified realm of academic medicine, is recounted in this engrossing and well-documented book.A historical account of an unfortunate experiment in cervical neoplasia diagnosis and management is presented.

Risk of persistent or recurrent neoplasia in conservatively treated women with cervical adenocarcinoma in situ with negative histological margins.

Conservative treatments including cold knife cone biopsy (CKC) or loop electrosurgical excision procedure (LEEP) are fertility-preserving alternatives to hysterectomy. The risks of persistent cervical neoplasia in women with negative surgical margins following conservative treatment of adenocarcinoma-in-situ (AIS) are uncertain. This study aims to investigate the risk of persistent or recurrent cervical neoplasia [AIS, adenocarcinoma and/or high-grade cervical squamous intraepithelial neoplasia (CIN)] and compliance with follow-up recommendations in conservatively treated women with AIS and negative histopathological margins. A retrospective, population-based study of Western Australian women treated by CKC or LEEP for AIS between 2001 and 2012. Histopathology reports were reviewed for demographic information, treatment procedures and clinicopathological factors. Primary outcomes were the diagnosis of cervical neoplasia during follow-up (defined as <12 months) and surveillance (≥12 months) periods. The cohort comprised 360 women, with 175 (48.6%) initially treated by CKC and 185 (51.4%) treated by LEEP. The median patient age at time of excisional treatment was 30.0 years (range 18-64 years) and the median follow-up time was 3.9 years (range six months to 12.2 years). During the follow-up and surveillance periods, seven (1.9%) women were diagnosed with CIN 2/3, 10 (2.8%) with AIS, and one (0.3%) with cervical adenocarcinoma, despite their initial excision specimens having negative histological margins. In this study, there was a low but significant risk of persistent or recurrent cervical neoplasia in women who had initial conservative management of AIS with negative histopathological margins.

Cost-effectiveness analysis of anal cancer screening in women with cervical neoplasia in British Columbia, Canada.

BackgroundPrecursors to anal squamous cell carcinoma may be detectable through screening; however, the literature suggests that population-level testing is not cost-effective. Given that high-grade cervical neoplasia (CIN) is associated with an increased risk of developing anal cancer, and in light of changing guidelines for the follow-up and management of cervical neoplasia, it is worthwhile to examine the costs and effectiveness of an anal cancer screening program delivered to women with previously-detected CIN.MethodsA model of anal cancer screening and treatment was constructed, to estimate the cost-effectiveness of a population of CIN II/III+ women who were screened using anal cytology vs. one that received no anal cancer screening. Costs were based on Canadian estimates, and survival was based on estimates taken from the scientific literature. Effectiveness was measured in terms of life years gained (LYG) and quality-adjusted life years (QALYs). The model was run for 50 cycles, with each cycle representing one year.ResultsIncremental cost (screened vs. unscreened) was $82.17 per woman in the model. Incremental effectiveness was 0.004 LYG, and was equivalent to zero in terms of QALY. An ICER of $20,561/LYG was calculated, while no meaningful incremental cost-effectiveness ratio (ICER) could be calculated for quality-adjusted survival.ConclusionOur analysis suggests that anal cancer screening is cost-effective in terms of overall survival in women with a previous diagnosis of CIN II or CIN III as part of regular follow-up, but may not contribute meaningfully-different quality-adjusted survival due to the adverse effects of screening-related interventions.Electronic supplementary materialThe online version of this article (doi:10.1186/s12913-016-1442-2) contains supplementary material, which is available to authorized users.

HPV infection and cervical neoplasia: associated risk factors.

BackgroundBehavioral risks such as age at first sexual intercourse, number of sexual partners and partner’s sexual behavior are associated with an increased risk of HPV infection, persistence of the infection and the development of neoplastic precursor lesions. The objective of this study was to evaluate the risk factors associated with HPV positivity and with a diagnosis of cervical neoplasia in women referred with an abnormal cervical smear.MethodsThis study evaluated a series of 198 women referred with an abnormal cervical smear. Risk factors for HPV infection were investigated using a questionnaire. All cervical specimens were tested for 27 HPV genotypes using the Roche polymerase chain reaction reverse line blot assay.ResultsThe overall prevalence of HPV was 87 %. First sexual intercourse before 16 years of age was significantly associated with a positive HPV test (OR 4.41; 95 %CI: 1.20 − 19.33; p = 0.01). A significant association was also found between this risk factor and CIN 1 lesions or worse (OR 2.2; 95 %CI 0.94 − 5.08; p = 0.03).ConclusionsThe age at which a woman begins to be sexually active is associated with HPV infection and with a diagnosis of cervical neoplasia.

Inflammatory Bowel Disease and Cervical Neoplasia: A Population-Based Nationwide Cohort Study

We examined the risk of cervical neoplasia (dysplasia or cancer) in women with ulcerative colitis (UC) or Crohn's disease (CD). We also calculated the reverse, the risk for diagnosis with cervical neoplasia before development of inflammatory bowel disease (IBD). We established a national cohort of women diagnosed with UC (n = 18,691) or CD (n = 8717) between 1979 and 2011 and a control cohort of individually matched women from the general population (controls, n = 1,508,334). Incidence rate ratios (IRRs) of screening activity and diagnosis of cervical neoplasia in women with IBD were assessed by Cox proportional hazards regression analysis. Odds ratios (ORs) of cervical neoplasia before diagnosis of IBD were calculated by using conditional logistic regression. Women with CD underwent cervical cancer screening as often as women in the general population (IRR, 0.99; 95% confidence interval [CI], 0.96-1.02), whereas screening frequency was slightly increased in women with UC (IRR, 1.06; 95% CI, 1.04-1.08). A total of 561 patients with UC were diagnosed with dysplasia during a median follow-up time of 7.8 years, and 28 patients with UC developed cervical cancer, compared with 1918 controls. A total of 407 patients with CD were diagnosed with dysplasia during a median follow-up time of 8.3 years, and 26 patients with CD developed cervical cancer, compared with 940 controls. Patients with UC had increased risk of low-grade (IRR, 1.15; 95% CI, 1.00-1.32) and high-grade (IRR, 1.12; 95% CI, 1.01-1.25) squamous intraepithelial lesions (SILs), whereas patients with CD had increased risks of low-grade SIL (IRR, 1.26; 95% CI, 1.07-1.48), high-grade SIL (IRR, 1.28; 95% CI, 1.13-1.45), and cervical cancer compared with controls (IRR, 1.53; 95% CI, 1.04-2.27). ORs for cervical cancer were also increased 1-9 years before diagnosis of UC, compared with women without UC (OR, 2.78; 95% CI, 2.12-3.64) or CD (OR, 1.85; 95% CI, 1.08-3.15). In a population-based nationwide cohort study, we found a 2-way association between IBD, notably CD, and neoplastic lesions of the uterine cervix. This observation is not explained by differences in screening activity.

The Efficacy of Using the Tissue Fragments Present in Cervical Scrapes for the Histologic Diagnosis of Cervical Neoplasia

Cervical scrapes to diagnose cervical neoplasia, collected by the clinician with brushes, are sent to the Leiden Cytology and Pathology Laboratory (LCPL) in vials containing BoonFix, a noncross-linking coagulant fixative. Because the residual material left in the vials contains tissue fragments with important diagnostic information, we stored the residual material in our archives. The tissue fragments can be mummified and archived in commercially available histology cassettes. We can produce paraffin sections thereof. Immunostaining is beautiful on serial paraffin sections cut from these blocks. We experienced that it is important to leave the brush in the vial such that all tissue fragments can be used for histologic diagnosis. In order to optimize the system, tissue fragments left in the endocervical part of the brush are removed in a paint shaker. We illustrate this principle of recovering mummified tissue fragments in a false negative case with cytology containing many undiagnosable collapsed tissue fragments. This case shows clearly the efficacy of using the tissue fragments present in cervical scrapes for the histologic diagnosis of cervical neoplasia.

Abstract 5011: Genome-wide methylation profiling identifies hypermethylated biomarkers in high-grade cervical intraepithelial neoplasia

Abstract Introduction: Cervical cancer is the second most common cancer in women worldwide and development of cervical cancer goes through different well-defined premalignant stages. Epigenetic modifications, such as aberrant DNA promoter methylation is frequently observed in cervical cancer. Identification of hypermethylated regions that allow discrimination between normal cervical epithelium and high-grade cervical intraepithelial neoplasia or worse (CIN2+) by DNA methylation state may improve current population-based screening programs for cervical cancer. In this study, the DNA methylome of CIN3 lesions were characterized using genome-wide methylation screening to identify potential biomarkers for early diagnosis of cervical neoplasia. Methods and results: Methyl-DNA ImmunoPrecipitation (MeDIP) assay combined with DNA microarray hybridization was used to compare DNA methylation patterns of epithelial cells derived from CIN3 lesions with normal cervical epithelium. In total, 80 hypermethylated differentially methylated regions (DMRs) were identified that significantly distinguished CIN3 lesions from normal cervice. Selected DMRs (n=9) were evaluated by methylation-specific PCR (MSP) on additional tissue specimens including normal cervix, CIN2/3 and cervical cancer samples and showed hypermethylation in up to 94.7% in CIN2/3 and 100% in cervical cancers. Quantitative MSP (QMSP) for two candidate biomarkers was applied to explore the test performance in a large series of cervical scrapings. Frequency and relative level of DNA methylation were significantly different between normal and cancer samples (p&amp;lt;0.05). In cervical scrapings from patients referred with an abnormal Pap smear, frequency and relative level of DNA methylation were also related with increasing severity of the underlying CIN lesion (p&amp;lt;0.01) In addition, ROC analysis showed that the methylation level was discriminative between low-grade CIN lesions and CIN2+ (p&amp;lt;0.05). Conclusion: Our study demonstrates specific DNA methylation patterns in high-grade CIN lesions through the newly identified discriminative hypermethylated DMRs and represents candidate biomarkers for early detection of high-grade CIN. This study was supported by the Dutch Cancer Society (NKB) (project-number RUG 2004-3161) and by OncoMethylome Sciences S.A., Liège, Belgium. CG was funded by the German Ministry of Education and Research (BMBF) within the NGFN-PLUS project PKT-01GS08111. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5011. doi:1538-7445.AM2012-5011

Immunohistochemical study of p16 INK4A and survivin expressions in cervical squamous neoplasm

Cervical cancer is the second most common cancer affecting Malaysian women. Despite the implementation of pap smear screening, many women are still diagnosed only in the advanced stage of cervical cancer. This could partly be due to failure of detection of its precursor lesions; hence the need to search for novel biomarkers to assist in the screening and diagnosis of cervical neoplasia. This study aims to determine the expression of p16INK4A and survivin as possible predictive biomarkers in cervical squamous neoplasm. This is a retrospective study on 201 cases of cervical neoplasm comprising of 129 cervical intraepithelial neoplasia (CIN) and 72 squamous cell carcinoma (SCC). All samples were evaluated by two independent observers using p16INK4A and survivin monoclonal antibodies. The p16 INK4A expression was graded as negative, focal and diffuse positivity. The intensity for survivin expression was graded as weak, moderate and intense. It is seen that p16 INK4A expression in CIN 1, CIN 2 and CIN 3 were 25.4%, 42.9% and 95.9% respectively. Majority of SCC (98.6%) showed p16 INK4A expression. Survivin expressions in CIN 1, CIN 2, CIN 3 and SCC were 56.7%, 33.4%, 87.5% and 98.6%. There was a linear relationship between increasing grade of CIN and p16 INK4A expressions. Our study showed that p16 INK4A expressions correlate well with the increasing grade of CIN. Although survivin does not correlate well to the increasing grade of CIN, it could be useful in differentiating CIN 3 from SCC.

Multiple biomarkers in molecular oncology. I. Molecular diagnostics applications in cervical cancer detection

The screening for cervical carcinoma and its malignant precursors (cervical neoplasia) currently employs morphology-based detection methods (Papanicolaou [Pap] smear) in addition to the detection of high-risk human papillomavirus. The combination of the Pap smear with human papillomavirus testing has achieved significant improvements in sensitivity for the detection of cervical disease. Diagnosis of cervical neoplasia is dependent upon histology assessment of cervical biopsy specimens. Attempts to improve the specificity of cervical disease screening have focused on the investigation of molecular biomarkers for adjunctive use in combination with the Pap smear. Active research into the genomic and proteomic alterations that occur during human papillomavirus-induced neoplastic transformation have begun to characterize some of the basic mechanisms inherent to the disease process of cervical cancer development. This research continues to demonstrate the complexity of multiple genomic and proteomic alterations that accumulate during the tumorigenesis process. Despite this diversity, basic patterns of uncontrolled signal transduction, cell cycle deregulation, activation of DNA replication and altered extracellular matrix interactions are beginning to emerge as common features inherent to cervical cancer development. Some of these gene or protein expression alterations have been investigated as potential biomarkers for screening and diagnostics applications. The contribution of multiple gene alterations in the development of cervical cancer suggests that the application of multiple biomarker panels has the potential to develop clinically useful molecular diagnostics. In this review, the application of biomarkers for the improvement of sensitivity and specificity of the detection of cervical neoplasia within cytology specimens will be discussed.

Human papillomavirus genotyping using HPV DNA chip analysis in Korean women

This study was designed to investigate the genotypes of human papillomavirus (HPV) in Korean women who had abnormal cervical cytology and to evaluate the clinical accuracy of HPV DNA chip analysis for the diagnosis of cervical neoplasia. Liquid-based cytology preparations, HPV DNA chip analysis, and cervical biopsy were performed in 2358 women. High-risk HPV was identified in 23.5% of 1650 histologically confirmed normal samples (including cervicitis and squamous metaplasia) and in 81.8% of 708 samples with cervical intraepithelial neoplasia (CIN) and carcinoma (P<0.01). The major prevalent high-risk HPV genotypes in 381 samples of CIN II/III were HPV-16, -58, -33, and -31, in order of prevalence rate (average overall, 78.0%), and HPV-16, -18, -58, and -33 (average overall, 81.2%) in 133 samples of squamous cell carcinoma (SCC). The infection rate of HPV-16 was significantly higher than that of other high-risk HPV genotypes in all normal, CIN, and SCC cases (P < 0.01) and increased with more advanced squamous cervical lesions (P<0.01). The detection accuracy of high-risk HPV using HPV DNA chip analysis for CIN II or worse was as follows: sensitivity 84% (81-87%), specificity 72% (70-74%), positive predictive value 47% (44-50%), and negative predictive value 94% (92-95%). These results suggest that HPV DNA chip analysis may be a reliable diagnostic tool for the detection of cervical neoplasia and that there are geographic differences in the distribution of high-risk HPV genotypes.

Age and FSH effects in fluorescence spectra from the cervix: An exploratory analysis

Introduction. Real-time optical technologies that could diagnose cervical cancer could improve the detection of cervical cancer. Our group is studying the technology assessment of optical devices in the screening and diagnosis of cervical neoplasias. Methods. We have conducted a diagnostic trial in 850 patients with referral Papanicolaou smears showing ASCUS or greater. Each colposcopically abnormal site and two normal sites were measured with fluorescence and reflectance spectroscopy and then biopsied. Each site generates a fluorescence excitation emission matrix that has a 3-dimensional map with peaks and valleys. Results. The early exploration of these data is presented and shows an effect of age, Follicle Stimulating Hormone or FSH, and, curiously, of their interaction. We have examined other biographical variables like smoking, HPV positivity, grade of CIN, device used, probe used, race, ethnicity, gravidity, parity, previous treatments, and others. None are significant predictors of this finding of increased intensity, except age and FSH. Conclusions. The effect of age supports the work done on fresh tissue slices in trying to better understand the biology of fluorescence. The effect of FSH is not a surrogate for age, but an independently significant effect, for which we currently do not have an explanation. We are exploring if FSH is a surrogate for estrogenization by measuring estradiol levels and calculating the BMI.

Diagnosis of Cervical Neoplasia Using Immunohistochemical Staining of p16(INK4A)

Objective : There is need for more objective diagnostic parameters to identify cervical dysplastic or neoplastic cells. So, we examined the expression in the cervical tissues to evaluate the value of as a diagnostic parameter. Methods : We examined the expression by mmunohistochemical staining in normal cervical tissues (n=3), preneoplastic lesions (n=6), carcinoma in situ (CIS, n=5), and invasive carcinomas (n=5) of the cervix, which were selected randomly by H&E staining from the archives of formalin-fixed and paraffin-embedded tissues and we also examined the status of human papillomavirus (HPV) infection in the same tissues. Results : The positive rates of expression was significantly higher in all abnormal cervical tissues including subclinical papillomavirus infection (SPI), dysplasia, CIS, and invasive carcinoma than in normal cervical epithelium (p=0.001). Despite the strong expression of in the area of CIS, no expression of was observed in the area of normal epithelium in the vicinity of CIS. 11 cases among 19 cases of examined tissue samples were tested for HPV infection. Seven of them showed positivity for HPV DNA. Conclusion : We herein demonstrated that would be a sensitive and specific marker for the abnormal cervical cells in tissue sections. This approach will help to reduce interobserver variations in the histopathologic interpretation of cervical biopsy specimens.

Tipificación del papilomavirus como método de cribado de la patología cervical en mujeres con el virus de la inmunodeficiencia humana

ObjectiveWe performed a cross-sectional study to compare human papilloma virus (HPV) typing and cytology in the prevention of cervical neoplasia in women with HIV infection and to determine the relationship between the degree of immunosuppression and HPV infection. Material and methodsThree tests (cytology, HPV typing and colposcopy-biopsy) were performed in 67 women with HIV infection who fulfilled the inclusion criteria. Risk factors for cervical lesions were evaluated according to HPV status, HPV subtype, type of cytology and biopsy lesions, CD4/mm3 count and viral load. ResultsA total of 35.8% of the sample were HPV-positive. The most common HPV subtype was HPV 18 (9 patients). The risk factors most strongly associated with HPV infection were a history of drug abuse, prostitution and infrequent condom use. There were 22 positive biopsies. HPV typing was more sensitive than cytology (63.6% vs 45.5%) but was less specific. The mean CD4/mm3 count was 255.75 in HPV-positive women and was 529.58 in HPV-negative women (P=0.000). ConclusionsHPV typing with cytology increased the sensitivity in the diagnosis of cervical neoplasia in HIV-infected women. A low CD4 count was significantly associated with HPV infection and cervical lesions.

Multimodal Hyperspectral Imaging for the Noninvasive Diagnosis of Cervical Neoplasia

Multimodal Hyperspectral Imaging for the Noninvasive Diagnosis of Cervical Neoplasia

Vulvar Intraepithelial Neoplasia III: A Viral Disease of Undetermined Progressive Potential

Seventy-three patients with vulvar intraepithelial neoplasia (VIN) grade III were followed for a median of 5 years after primary treatment. Thirty women also had a diagnosis of cervical neoplasia. During the follow-up 26 patients (36%) had one or more vulvar recurrences. Recurrences were seen significantly more often in the patients who also had cervical neoplasia, indicating a common etiology. Microinvasive carcinoma developed in 12 patients, 3 of whom later developed frankly invasive vulvar cancer. The original, paraffin-embedded vulvar specimens were examined by the polymerase chain reaction for human papillomavirus DNA of the types HPV 6, 11, 16, 18, and 33. HPV types 16 and 33 were found in 90% of the VIN lesions. It is concluded that VIN III is an HPV-related disease in all or almost all cases, and that a generalized genital HPV infection may be a factor in the development of multicentric genital neoplasia. No association was observed between the specific HPV type and the risk of recurrent vulvar disease, cervical neoplasia, or malignant progression.

Lack of serum antibodies to the major HSV‐2 specified DNA‐binding protein before diagnosis of cervical neoplasia

We report results based on a prospective case-control study within a cohort obtained by linking the Finnish Social Insurance Institutions Mobile Clinic Survey Registry and the Finnish Cancer Registry. The overall prevalence of herpes virus early antigen (ICSP 11/12) antibodies was similar in controls and in cervical neoplasia cases (consisting of invasive cervical carcinoma, ICC, and cervical intraepithelial neoplasia group III, CIN III cases). However, those CIN III cases, who after a long lag period (average 7 years after the blood sample was drawn) developed cervical neoplasia, had significantly lower antibody levels than did matched controls. Their ICSP 11/12 antibody levels became higher the shorter the lag period. The negative correlation between the ICSP 11/12 antibody levels and the lag period was most pronounced in the HSV-2 seropositive CIN III cases. In an analysis of cross-sectional case-control material from the Clinic of Obstetrics and Gynaecology, Tampere University Central Hospital, the patients with ICC had the highest ICSP 11/12 antibody levels. Statistically significant differences between cases and controls were not found. We conclude that in cervical neoplasia the kinetics of ICSP 11/12 antibody levels are determined by the malignant process itself. The cervical disease may selectively induce early viral antigens, thus giving rise to the antibody response described in this paper.

Hospital-based strategy for early diagnosis of cervical neoplasia in the northtern part of Italy

Hospital-based strategy for early diagnosis of cervical neoplasia in the northtern part of Italy

A monoclonal antibody against basal cells of human epidermis. Potential use in the diagnosis of cervical neoplasia.

A murine monoclonal antibody was generated against human skin cells obtained from psoriatic plaques. The antibody, called VM-2, recognizes an epitope expressed on the basal cell layer of human skin and other epithelia. VM-2 also binds to cultured cells from a variety of human carcinomas including HeLa cervical carcinoma, A-431 vulvar carcinoma, A-549 lung alveolar carcinoma, and SCL-1 skin squamous cell carcinoma cells. In several primary human cell lines, including fibroblasts, endothelial cells, and cells from the hematopoietic lineage, the antigenic site recognized by VM-2 could not be detected. The cellular antigen when immunoprecipitated by VM-2 from both normal and transformed cells appears to be proteins of approximately 100,000 and 120,000 mol weight. In frozen sections from human tumor-containing tissues, VM-2 labels skin, cervical, and lung squamous carcinoma cells, as well as skin basal carcinoma cells. Malignant cells present in exfoliative smears from epidermoid invasive neoplasias of the cervix are also selectively recognized by VM-2 in distinction to normal squamous cervical cells. VM-2 is thus directed against an antigen associated with neoplastic cells when applied in selected sites of exfoliative cytology. This monoclonal antibody represents a new reagent that should prove useful in the diagnosis of cervical neoplasia.

The value of immunohistochemical markers in the diagnosis of cervical neoplasia

This study was designed to determine whether immunohistochemical stains for tumour-associated markers may be useful in the detection and differential diagnosis of premalignant and malignant lesions of the cervix. The expression of four markers detected by monoclonal antibodies, human milk fat globule 1 and 2 (HMFG-1 and 2), Ca1 and anti-carcinoembryonic antigen (anti-CEA) on conventional histological sections of various cervical lesions has been investigated. None of these markers was specific for neoplastic lesions of the cervix and all four markers were expressed by metaplastic as well as neoplastic cells, and it was concluded that their application in the histopathological examination of the cervix is limited.

Monoclonal antibodies for the histopathological diagnosis of cervical neoplasia

Five monoclonal antibodies (Ca1, HMFG 1 and 2, 8.30.3 and 77.1) were used to study the distribution of antibody binding sites in cervical tissue with a view to identifying a marker which would distinguish between benign and malignant cervical epithelium. Both benign tissue (mature and immature metaplastic squamous epithelium, congenital transformation zone and glandular epithelium) and neoplastic tissue (cervical intraepithelial neoplasia, 1, 2 and 3 and invasive squamous cell carcinoma) were stained by these antibodies. Although immature metaplastic epithelium stained strongly with all the antibodies, the intensity and distribution of staining in general did not distinguish between benign and neoplastic conditions. All five antibodies, raised against three different antigens, stained cervical tissue in a similar way and thus were unsuitable for use as specific tumour markers in equivocal cases. Further studies on other tumour markers are indicated in view of the potential value of this approach.