Atypical glandular cells in Pap tests: cytology-histology correlation and risk assessment with human papillopmavirus (HPV) testing.

INTRODUCTION: Atypical glandular cells (AGC) represent less than 1% of Pap test cases and include a variety of lesions in both the cervix and endometrium. The study aimed to investigate the cytology-histology correlation in AGC patients and to evaluate the clinical utility of hrHPV testing in this diagnostic context. MATERIALS AND METHODS: We identified 491 atypical glandular cells (AGC) cases in our quality analysis (QA) database of 336,064 Pap tests interpreted between March 1, 2013 and July 12, 2016. Of these, 251 cases had follow-up biopsies with hrHPV tests in 148 cases. RESULTS: The most common histologic diagnosis associated with AGC was normal/benign or low-grade lesions, comprising 55% of cervical biopsies and 24% of endometrial biopsies. High-grade lesions were identified in 21% of follow-up biopsies. In patients with AGC cytology, a positive hrHPV test significantly increased the likelihood of cervical HSIL or above lesions on biopsy by 26.4 times (OR = 26.4, 95% CI: 5.8-119.4, P < 0.0001). A positive genotyping result for HPV 16 dramatically increased the likelihood of cervical HSIL or above lesions on biopsy (OR = 84, 95% CI: 12.0-590.5, P < 0.0001). The HPV test had a negative predictive value of 97% (CI: 85%-100%). CONCLUSIONS: Our study confirms that AGC is a significant diagnosis with an overall risk for high-grade cervical or endometrial lesions as high as 21%. hrHPV testing with genotyping is an effective tool for identifying high-risk individuals within the AGC population, with excellent positive and negative predictive values. This approach is valuable for clinical risk stratification and differential diagnosis in patients with AGC cytology.

Role of HPV genotyping in risk assessment among cytology diagnosis categories: analysis of 4562 cases with cytology-HPV cotesting and follow-up biopsies.

OBJECTIVE: Human papilloma virus (HPV) detection and genotyping are increasingly used in clinical risk assessment. We aimed to analyze HPV genotyping performance in risk stratification among cytology diagnosis categories. METHODS: Between January 1, 2015 and December 31, 2016, 4562 cases with cytology-HPV co-testing and biopsy follow-up were identified. HPV tests were performed on Cobas (n=3959) or Aptima (n=603) platforms. Of the biopsies, 669 demonstrated high-grade squamous intraepithelial lesions or worse. RESULTS: Pooled high-risk HPV testing had high overall sensitivity (97%) but low specificity (20%) and positive predictive value (20%) for biopsy-confirmed high-grade squamous intraepithelial lesions or worse. HPV16/18 genotyping had considerably improved specificity (81%) and positive predictve value (35%) in predicting high-grade squamous intraepithelial lesions or worse, especially in atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesion categories. Significantly more biopsy-confirmed high-grade squamous intraepithelial lesions or worse were detected by Aptima than Cobas testing, as measured by HPV16/18 (48% vs 33%, p<0.001), non-16/18 high-risk HPV (18% vs 13%, p=0.029), or all high-risk HPV genotypes (27% vs 19%, p<0.001). Aptima genotyping showed a significantly higher positive predictive value than Cobas genotyping for biopsy-confirmed high-grade squamous intraepithelial lesions or worse in the atypical squamous cells of undetermined significance category (47% vs 23%, p<0.05). CONCLUSIONS: HPV genotyping was sensitive for biopsy-confirmed high-grade squamous intraepithelial lesions or worse in all cytologic categories, and is particularly valuable in risk evaluation for women with atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesions. The triaging role was greatly diminished in high-risk lesions (atypical glandular cells, atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesions and high-grade squamous intraepithelial lesions) due to low specificity and positive predictive value. Aptima performance in risk management was superior to Cobas, with significantly higher positive predictive value for biopsy-confirmed high-grade squamous intraepithelial lesions or worse. Our results highlight the importance of careful data interpretation from studies using different HPV testing methods and the need to incorporate HPV E6/E7-mRNA testing into management guidelines.