High-risk human papillomavirus DNA testing: a marker for atypical glandular cells.

Cervical/endocervical cytology screening has decreased morbidity and mortality, and implementing adjunctive human papilloma virus (HPV) DNA testing for atypical squamous cells of undetermined significance has improved the specificity for detecting premalignant squamous lesions. Currently, there are no guidelines to perform HPV DNA testing on cervical/endocervical ThinPreps with atypical glandular cells (AGC). To assess the potential role of HPV DNA testing on AGC cases, Hybrid Capture 2 (Digene Corp.) testing was performed on 144 cervical/endocervical AGC specimens. One hundred three of 144 cases had follow-up; 60/103 (58.3%) were high-risk HPV negative and 43/103 (42.3%) were high-risk HPV positive. Of 43 HPV-positive patients, 37 had adenocarcinoma in situ (AIS), atypical squamous cells of undetermined significance (ASCUS), or cervical squamous intraepithelial neoplasia, while only one patient without high-risk HPV had a squamous intraepithelial neoplasia. Furthermore, most high-risk HPV positive AGC cases harbored high-grade squamous intraepithelial lesion (HSIL) rather than AIS. Our data support HPV DNA testing of all AGC specimens to detect cervical, especially squamous, neoplasia.

Atypical glandular cells (AGC): ThinPrep Imaging System (TIS), manual screening (MS), and correlation with Hybrid Capture 2 (HC2) HPV DNA testing.

OBJECTIVE: The aim of the study was to determine if the ThinPrep Imaging System (T1S) improves the positive predictive value (PPV) of atypical glandular cell (AGC) diagnosis for identifying HPV-related squamous and/or glandular lesions over manual screening (MS), and if human papilloma virus (HPV)-DNA testing improves the diagnostic yield. MATERIALS AND METHODS: 85 ThinPrep cervical cytology specimens with a diagnosis of AGC by TIS (n = 51) and MS (n = 34) were retrieved. The diagnoses were correlated with corresponding histologic follow-up and high risk (HR)-HPV testing results. RESULTS: The PPV of AGC by TIS and MS for HPV-related squamous lesions were similar. In the MS group, more cases of glandular pathology were identified, however only three represented adenocarcinoma in-situ (AIS), and the remaining ten were endometrial carcinomas (EMCA). CONCLUSIONS: TIS and MS are comparable in the detection of AGC representing squamous histology and the addition of HPV DNA testing does not differentially improve performance. Although the MS group harbored more glandular pathology, the differences in the detection of AIS were not statistically significant.

The Bethesda System 2001 recommendation for reporting of benign appearing endometrial cells in Pap tests of women age 40 years and older leads to unwarranted surveillance when followed without clinical qualifiers.

OBJECTIVES: The purpose of this study is to determine the impact of the Bethesda System 2001 recommendation of reporting cytologically benign appearing endometrial cells (BEC) seen in Papanicolaou (Pap) tests of all women age 40 years and older, and to determine the significance of such finding. METHODS: Pap tests of women age 40 years and older containing BEC outside of the first half of menstrual cycle reported before and after the Bethesda System 2001 implementation were included. 300 postmenopausal women without BEC were included as control group. Clinical follow-up was reviewed and significant endometrial pathology was defined as simple hyperplasia or a higher diagnosis. RESULTS: BEC reporting rate increased from 0.17% to 0.49% before and after the Bethesda System 2001 (P=0.0001), due to reporting in women with premenopausal status. Significant endometrial pathology was detected in 14 of 121 (11.6%) postmenopausal patients compared to 7 of 300 (2.3%) in the control group (P=0.0002, relative risk=4.96, 95% confidence interval 2.05-11.98), and in none of premenopausal patients. 12 of 14 women with significant endometrial pathology had either postmenopausal bleeding or hormone replacement therapy use. CONCLUSIONS: The Bethesda System 2001 led to increased reporting of BEC only in premenopausal women, leading to biopsies performed solely for BEC in these women with no pathology detected. Presence of BEC in Pap tests of postmenopausal women warrants a thorough clinical review, and immediate biopsy is a valid consideration. Presence of hormone therapy or postmenopausal bleeding may be modifiers of risk.

Comparison of human papillomavirus DNA prevalence in atypical squamous cells of undetermined significance subcategories as defined by the original Bethesda 1991 and the new Bethesda 2001 Systems.

CONTEXT: The new Bethesda System 2001 (TBS 2001) minimized the subclassification of atypical squamous cells of undetermined significance (ASCUS). OBJECTIVE: The primary goal of this study was to determine the impact of the new subclassification on the accuracy of Papanicolaou (Pap) test diagnosis by examining the prevalence of human papillomavirus (HPV) DNA in different ASCUS subcategories, as defined by the new TBS 2001 versus the original TBS 1991. The second goal was to identify specific morphologic features of atypical squamous cells that are more frequently associated with HPV detection. DESIGN: Consecutive cases of ThinPrep Pap tests were retrospectively reviewed by a panel of pathologists to obtain consensus diagnoses. The study group consisted of ASCUS cases; the positive control group consisted of low- and high-grade squamous intraepithelial lesions (LSILs and HSILs, respectively); and the negative control group consisted of cases "negative for intraepithelial lesion or malignancy." All ASCUS cases were subclassified according to TBS 1991 into the following categories: favor reactive (ASCUS-R), favor LSIL (ASCUS-L), favor HSIL (ASCUS-H), and not otherwise specified (ASCUS-NOS). In a separate review, ASCUS cases were subclassified according to TBS 2001 into the following categories: atypical squamous cells of undetermined significance (ASC-US) and atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H). Furthermore, morphologic ASCUS subtypes were recorded (atypical mature, immature, parakeratotic, and atrophic cells); in addition, individual morphologic features of atypical cells were recorded. Broad- spectrum HPV DNA amplification and genotyping was performed using short PCR fragment (SPF 10) polymerase chain reaction/Line Probe assays. RESULTS: In cases classified according to TBS 1991, HPV was detected in 32% of negative, 49% of ASCUS, and 93% of LSIL/HSIL cases. On the second review, using the diagnostic categories of TBS 2001, which eliminated the ASCUS-;R category, the number of ASCUS cases decreased by 45%. The prevalence of HPV DNA in ASCUS cases downgraded to the negative category was 38%, which was not significantly different from HPV prevalence in negative cases as diagnosed under TBS 1991. Furthermore, HPV was detected in 56% of ASC-US and 71% of ASC-H cases. The prevalence of HPV in different morphologic subtypes of ASCUS was not significantly different, and none of the 8 individual morphologic features of atypical cells were more frequently associated with HPV detection. CONCLUSION: Elimination of the ASCUS-R category in TBS 2001 resulted in a significant decrease in the number of ASCUS diagnoses. Downgraded cases had a relatively low prevalence of HPV DNA. It is expected that TBS 2001 will increase specificity of the Pap test without compromising its sensitivity.