CIN2 Is a Much Less Reproducible and Less Valid Diagnosis than CIN3: Results from a Histological Review of Population-Based Cervical Samples

Division of Cancer Epidemiology and Genetics, The National Cancer Institute, National Institutes of Health, Department of Health and Human Services Rockville, Maryland 20852, USA.
International Journal of Gynecological Pathology (Impact Factor: 1.63). 09/2007; 26(4):441-446. DOI: 10.1097/pgp.0b013e31805152ab

ABSTRACT We wished to compare the relative reproducibility and validity of cervical intraepithelial neoplasia (CIN) 2 and CIN3 diagnoses. In a population-based cohort study (1993-2001) of human papillomavirus (HPV) and cervical neoplasia in Costa Rica, we compared community pathologists' diagnoses with those of the 2 independent reviewers from the United States (total, n = 357). As measures of validity, we correlated primary and review diagnoses with HPV positivity and cytological interpretations. Two review pathologists agreed with 84% and 81%, respectively, of initial diagnoses of CIN3 compared with 13% and 31% of CIN2. The CIN3 diagnoses made by review pathologists were 94% oncogenic HPV positive, compared with 72% of CIN2 diagnoses. Eighty-one percent of CIN3 diagnoses versus 61% of CIN2 were correlated with high-grade cytological interpretations. The CIN3 is a substantially more reproducible diagnosis that can be validated more frequently with HPV tests and cytological interpretations than CIN2.

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    • "The observer variability was much higher in the CIN 1 and CIN 2 categories compared with the CIN 3 category. These observations were similar to those of other studies evaluating the reproducibility of cervical cancer precursor diagnosis in cytology-based screening programs [2] [9]. "
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    ABSTRACT: Objective To assess the reproducibility of cervical intraepithelial neoplasia (CIN) diagnosis in a visual inspection with acetic acid (VIA) and HPV detection-based screening program, and to correlate CIN diagnosis with oncogenic HPV status. Methods A total of 9630 women were screened by VIA and high-risk HPV detection at community outreach clinics in India between June 2011 and June 2012. Biopsies obtained from women who were positive on either test were reviewed by two pathologists blinded to the histological diagnoses originally made by pathologists working at the Chittaranjan National Cancer Institute. Results The interobserver agreement between the pathologists’ diagnoses and the diagnoses made by the expert reviewers on 424 slides was fair (kappa = 0.26). There was a distinct difference in agreement in detecting CIN 2 (kappa = 0.21) and detecting CIN 3 (kappa = 0.74). The overall agreement in diagnosis improved when the slides obtained from the HPV-positive women were considered (kappa = 0.5). Almost half of the discordant CIN 2 cases were high-risk HPV negative. Conclusion Diagnosis of CIN 2 is poorly reproducible. The natural history of CIN 2 lesions is more similar to CIN 1 than CIN 3; it is therefore necessary to re-evaluate whether to consider CIN 2 lesions as high-grade squamous intraepithelial lesions with CIN 3, as in the Bethesda system of classification.
    International Journal of Gynecology & Obstetrics 09/2014; 126(3). DOI:10.1016/j.ijgo.2014.03.037 · 1.56 Impact Factor
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    • "Therefore, the performance of colposcopic impression and/or guided biopsies is only part of an overall quality assessment of colposcopy-based patient management. There is sufficient evidence that CIN3 is a true precursor of cervical cancer with a high risk of malignant progression [13] [14] [15]. Therefore, the most reliable endpoint for colposcopy failure is the CIN3+ rate during follow-up of women managed according to protocol. "
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    ABSTRACT: OBJECTIVE: Combining HPV and Pap screening achieves very good risk stratification and sensitive detection of CIN3 and cancer (CIN3+), but poorer specificity, and may result in an increased risk of glandular and new lesions during follow-up. We examined if this phenomenon may compromise the accuracy of colposcopy. METHODS: As part of a primary HPV screening pilot project comprising 19,624 participants aged over 30years, the failure rate to detect CIN3 at first visit was measured over a five-year period to assess the quality of colposcopy as an overall management concept. Management relied on excisional biopsies in all HSIL cytology or major findings on colposcopy, endocervical assessment in type 3 transformation zones (TZ) and guided biopsies in type 1 or 2 TZ. RESULTS: Of 667 women referred for colposcopy because of atypical Pap smears and/or HPV persistency, 171 were diagnosed with CIN3+. All 18 cancers and 140/153 CIN3 cases were diagnosed at the first visit. Of 13 CIN3 observed during follow-up, five were classified as new cases, five as definite and three as probably colposcopy failures, giving a failure rate of 4.7% (8/171). Only three failures were related to false-negative punch biopsies while five occurred because of false-negative endocervical assessment in type 3 TZ. CONCLUSIONS: Colposcopy management following defined pathways was safe in this HPV screening programme with an acceptable failure rate. Further improvements may depend on developing better methods for endocervical assessment rather than for ectocervical biopsies.
    Gynecologic Oncology 10/2012; 128(2). DOI:10.1016/j.ygyno.2012.10.017 · 3.69 Impact Factor
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    • "We focused our efforts to overcome these limitations by performing a complete analysis of reproducibility and determining the level of intra-and inter-variability in the number of cells counted by the pathologists. Carreon et al. 2007 found that CIN3 histological classification is more reproducible than CIN2 [29]. In agreement with previous reports, we found that inter-observer reproducibility is very good for the classification of invasive lesions, moderate for CIN3 and very poor for CIN1 and CIN2. "
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    ABSTRACT: Only a small proportion of women infected with Human Papillomavirus (HPV) develop cervical cancer. Host immune response seems to play a role eliminating the viral infection and preventing progression to cancer. Characterization of tumor infiltrating lymphocytes (TILs) in cervical pre-neoplastic lesions and cervical cancer may be helpful to understand the mechanisms that mediate this protection. The aim of this study was to determine if there are differences in the localization and density (cells/mm(2)) of CD8+ T-cells, CD4+ T-cells and Tregs (CD25 + Foxp3+) in cervical pre-neoplastic lesions and cervical cancer. Immunohistochemical analysis of sections of 96 (26 CIN1, 21 CIN2, 25 CIN3, and 24 SCC) samples revealed that regardless of CIN grades, CD8+ T-cells are more abundant than CD4+, CD25+ and Foxp3+ cells in both the stroma and epithelium. There was a higher density of CD8+ cells in the stroma of cervical cancer compared to CIN3 (OR = 4.20, 95% CI 1.2-15), CIN2 (OR = 7.86, 95% CI 1.7-36.4) and CIN1 (OR = 4.25, 95% CI 1.1-17). Studies evaluating whether these cells are recruited before or after cancer progression will be helpful to understand the role of these cells in the natural history of HPV-induced lesions.
    Cancer Microenvironment 01/2012; DOI:10.1007/s12307-012-0097-8
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