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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In Norway, repeat cytology and HPV testing comprise delayed triage of women with minor cytological lesions. The objective of this study was to evaluate HPV DNA and HPV mRNA testing in triage of women with an ASC-US/LSIL diagnosis. We used repeat cytology, HPV DNA testing (Cobas 4800) and HPV mRNA testing (PreTect HPV-Proofer) to follow up 311 women aged 25-69 years with ASC-US/LSIL index cytology. Of 311 women scheduled for secondary screening, 30 women (9.6%) had ASC-H/HSIL cytology at triage and 281 women (90.4%) had ASC-US/LSIL or normal cytology. The HPV DNA test was positive in 92 (32.7%) of 281 instances, and 37 (13.2%) were mRNA positive. Of the 132 women with repeated ASC-US/LSIL, we received biopsies from 97.0% (65/67) of the DNA-positive and 92.9% (26/28) of the mRNA-positive cases. The positive predictive values for CIN2+ were 21.5% (14/65) for DNA positive and 34.6% (9/26) for mRNA positive (ns). The odds ratio for being referred to colposcopy in DNA-positive cases were 2.8 times (95% CI: 1.8-4.6) higher that of mRNA-positive cases. Compared to the mRNA test, the DNA test detected four more cases of CIN2 and one case of CIN3. The higher positivity rate of the DNA test in triage leads to higher referral rate for colposcopy and biopsy, and subsequent additional follow-up of negative biopsies. By following mRNA-negative women who had ASC-US/LSIL at triage with cytology, the additional cases of CIN2+ gained in DNA screening can be discovered. Our study indicates that in triage of repeated ASC-US/LSIL, HPV mRNA testing is more specific and is more relevant in clinical use than an HPV DNA test.
    PLoS ONE 11/2014; 9(11):e112934. DOI:10.1371/journal.pone.0112934 · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cervical carcinoma (CC) is one of the most important health problems of adult women in developing countries. CC is the second most common carcinoma of the women worldwide. Efficient screening and early therapeutic programmes are vital because of the higher burden of the disease. The authors included a total of 53 cases in this study. Distribution of diagnoses among cases was as follows: cervical intraepithelial neoplasm (CIN) (n=44), squamous cell carcinoma (SCC) (n=7), adenocarcinoma in situ (n=1), and condyloma accuminatum (n=l). Presence, density, and nuclear identification form of human papilloma virus (HPV) DNA in relation with host cell DNA were evaluated by in situ hybridization (ISH) and p16 and survivin by immunohistochem- ical methods (IHC). The authors determined that the presence, density, and nuclear identification form of high risk HPV DNA had diagnostic and prognostic importance in CC and CIN (p < 0.05). p16 and survivin also had diagnostic significance. Since p16 and survivin expressions signalled progressive oncogenic events, p16 and survivin were persistent HPV markers (for p16, p < 0.001, for survivin p < 0.01). The authors determined that expressions, density, and prevalence of all three markers showed correlation with increasing CIN grade (for p 16, p < 0.001, for survivin, p < 0.01, for HPV, p = 0.002). The episomal pattern which is the independent visit of Hr HPV DNA to host cell DNA, signalled early HPV infection (p = 0.001). When it is integrated into host cell DNA, especially if HPV DNA signal intensity and prevalence increases, then this signal signifies persistent HPV infection (p = 0.001). With the aid of these findings, the authors determined that HPV is infectious in CIN I and proliferative (neoplastic) in CIN II-CIN III lesions.
    European journal of gynaecological oncology 01/2014; 35(6):708-17. · 0.60 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: There is growing evidence that human immunodeficiency virus (HIV)-infected women might have a different human papillomavirus (HPV) type distribution in cervical dysplasia specimens as compared to the general population. This has implications for primary prevention. Objective: We aimed to obtain preliminary data on the HPV genotypes prevalent in histological samples of HIV-infected women with cervical intraepithelial neoplasia (CIN) 3/CIS of the cervix in Miami, FL, USA. Methods: Retrospective data were collected on HIV-infected women referred to the University of Miami-Jackson Memorial Hospital colposcopy clinic between years 2000 and 2008. The histology slides of CIN 3/CIS biopsies underwent pathological review and sections were cut from these archived specimens for HPV DNA extraction. HPV genotyping was then performed using the GeneSquare™ HPV genotyping assay. We report on our first set of 23 samples. Results: Eight high-risk HPV types were detected. Types in decreasing order of frequency were 16, 35, 45, 52, 59, 31, 58, and 56. Most cases had multiple infections. HPV type 16 was the most common (45%) followed by HPV-35 and -45 with equal frequency (40%). No samples contained HPV-18. Conclusion: Our preliminary results suggest that cervical dysplasia specimens of HIV-infected women more likely (55%) contain non-16 and -18 high-risk HPV types. We show that this held true for histologically confirmed severe dysplasia and carcinoma-in situ. Epidemiological studies guide vaccine development, therefore HPV type prevalence in CIS and invasive cervical cancer among HIV-infected women should be more rigorously explored to ensure that this highly vulnerable population receives appropriate primary prevention.
    Frontiers in Oncology 08/2014; 4:179. DOI:10.3389/fonc.2014.00179