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: 1.67). 09/2007; 26(4):441-446. DOI: 10.1097/pgp.0b013e31805152ab


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from women who were positive on either test were reviewed by two pathologists blinded to the histological diagnoses originally made by pathologists working at the Chittaranjan National Cancer Institute.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.
    Full-text · Article · Sep 2014 · International Journal of Gynecology & Obstetrics
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    • "Fifty percent of our study women were under 30 years of age, which may have contributed to the observed low specificity, as lesions in young women may be more prone to regress. The use of CIN2+ as an outcome has also been an area of discussion, since the reproducibility of the diagnosis is considered poor [30]. A re-evaluation of the evidence for HPV66 [31] has revealed it to be a relatively common type, though it is rarely found in cancer, which could decrease the specificity and PPV of an assay that includes this type [31]. "
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    ABSTRACT: Expression of the viral E6/E7 oncogenes of high-risk human papillomaviruses (HR-HPV) is necessary for malignant conversion and maintenance in cervical tissue. In order to determine whether HR-HPV E6/E7 mRNA testing more effectively predicts precancerous lesions and invasive cervical cancer than HR-HPV DNA testing, we aimed to compare triage using HR-HPV E6/E7 mRNA testing by APTIMA HPV Assay (APTIMA) to HPV16 DNA testing, HPV16/18 DNA testing, and repeat cytology. Liquid-based (PreservCyt) cell samples were obtained from HR-HPV-positive women diagnosed with atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesions (LSIL) within the framework of the population-based cervical cancer screening program in Stockholm, Sweden. Samples were tested for HR-HPV E6/E7 mRNA by APTIMA (Gene-Probe Inc., San Diego, CA, USA). Women were followed up for 4 years after the index cytology via medical and laboratory records, and the Stockholm Oncology Center. Nine of 25 (36%) women in the ASCUS group, and 64 of 180 (36%) women in the LSIL group developed cervical intraepithelial neoplasia (CIN) grade 2 or worse during 4 years of follow-up. 162 (74%) women were APTIMA-positive, and APTIMA had the highest sensitivity to predict CIN2 or worse and CIN3 or worse in the ASCUS (77.8% and 100%) and LSIL (78.1 and 75.8%) groups, although specificity was insufficient (<50%). HPV16 DNA testing and repeat cytology were more specific than APTIMA. The results of this population-based study with comprehensive follow-up support the use of APTIMA as a triage test for women with ASCUS. More focused investigation is required for women with LSIL.
    Full-text · Article · Feb 2014 · PLoS ONE
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    • "Although the risk of CIN2 progressing to invasive cancer is low, diagnosis of CIN2 has limited reproducibility and validity, and thus CIN2 is used as the treatment threshold for safety reasons [64]. Surgical treatment options for CIN2/3 include ablative methods that destroy the affected cervical tissue in vivo, such as cryotherapy, laser ablation, electrofulguration, and cold coagulation, as well as and excisional methods that remove the affected tissue and provide a specimen for pathological examination; these include cold-knife conization, laser conization, electrosurgical needle conization, and loop electrosurgical excision procedures (LEEPs), also known as large loop excision of the transformation zone (LLETZ). "
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    ABSTRACT: Cervical cancer is the second most common cause of death from cancer in women worldwide, and the development of new diagnostic, prognostic, and treatment strategies merits special attention. Many efforts have been made to design new drugs and develop immunotherapy and gene therapy strategies to treat cervical cancer. HPV genotyping has potentially valuable applications in triage of low-grade abnormal cervical cytology, assessment of prognosis and followup of cervical intraepithelial neoplasia, and in treatment strategies for invasive cervical cancer. It is known that during the development of cervical cancer associated with HPV infection, a cascade of abnormal events is induced, including disruption of cellular cycle control, alteration of gene expression, and deregulation of microRNA expression. Thus, the identification and subsequent functional evaluation of host proteins associated with HPV E6 and E7 oncoproteins may provide useful information in understanding cervical carcinogenesis, identifying cervical cancer molecular markers, and developing specific targeting strategies against tumor cells. Therefore, in this paper, we discuss the main diagnostic methods, management strategies, and followup of HPV-associated cervical lesions and review clinical trials applying gene therapy strategies against the development of cervical cancer.
    Full-text · Article · Apr 2013 · Obstetrics and Gynecology International
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