R. Marshall Austin

Histologic follow-up results in 662 patients with Pap test findings of atypical glandular cells: Results from a large academic womens hospital laboratory employing sensitive screening methods

OBJECTIVE Atypical glandular cell (AGC) Pap interpretations and screening for glandular neoplasias remain major challenges. We document the largest reported AGC histopathologic follow-up experience and include verification bias-adjusted data on laboratory screening sensitivity. METHODS AGC Pap tests of endocervical origin (AGC-EC), endometrial origin (AGC-EM), and not otherwise specified (AGC-NOS) were documented at a center serving an older low risk population. 98% of Pap tests were liquid-based cytology (LBC) specimens screened using computer-assisted screening. Follow-up diagnoses were correlated with cytology and stratified into age groups. Screening sensitivity was assessed by examining Pap results during 1 year preceding neoplastic diagnoses. Verification bias was adjusted with findings in over 2000 patients with hysterectomies. RESULTS Of 247,131 Pap tests, 1021 (0.41%) reported AGC results and 662 cases had tissue follow-up. Precancerous or malignant neoplastic histologic outcomes were documented in 101 patients (15.3%), including 8.3% cervical, 6.3% endometrial, and 0.6% ovarian. AGC results were most often associated with neoplastic cervical outcomes in women younger than 40 and with neoplastic endometrial outcomes in women 50 or older. AGC-NOS with a squamous cell abnormality and AGC-EC results suggested cervical neoplasia, while AGC-EM results suggested endometrial neoplasia. CONCLUSIONS AGC Pap results detected significant numbers of cervical and non-cervical neoplasias. Since 38 of 44 (86%) of AGC-detected carcinomas were endometrial or ovarian, HPV co-testing would not have aided screening in detecting the majority of malignancies diagnosed after AGC Pap results. Verification bias-adjusted Pap screening sensitivity in the laboratory for detection of significant neoplastic cervical disease was 93%.

Comparison of cervical cancer screening results among 256,648 women in multiple clinical practices

In the United States, human papillomavirus (HPV) and Papanicolaou (Pap) testing (cotesting) for cervical screening in women ages 30 to 65 years is the preferred strategy, and cytology alone is acceptable. Recently, a proprietary automated test for identifying high‐risk HPV types for primary cervical screening was approved by the US Food and Drug Administration. The objective of the current study was to document extensive cervical screening among these screening options.

Adjunctive Human Papillomavirus DNA Testing Is a Useful Option in Some Clinical Settings for Disease Risk Assessment and Triage of Females With ASC-H Papanicolaou Test Results

CONTEXT Recent guidelines recommend colposcopy for women with atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H). objective: To determine whether adjunctive high-risk human papillomavirus (hrHPV) testing is useful for disease risk assessment in females with ASC-H Papanicolaou (Pap) test results. DESIGN High-risk HPV prevalence and histopathologic follow-up data on 1187 females with ASC-H ThinPrep Pap test (TPPT) and hrHPV test results were analyzed. RESULTS ASC-H was reported in 1646 (0.59%) [corrected] of 277 400 (270 338 TPPT and 7062 conventional) Pap test results. The difference in ASC-H detection rates between TPPTs and conventional Pap smears was statistically significant (0.60% vs 0.38%; P = .02). High-risk HPV was detected in 589 (49.6%) of 1187 females with ASC-H TPPT and hrHPV testing. The hrHPV DNA-positive rate in females younger than 40 years was 54.7%, significantly higher than the 36.5% in women 40 years and older. Among 505 females with histopathologic follow-up, cervical intraepithelial neoplasia 2/3 was identified in 32.7% of hrHPV-positive females compared with 1.2% in hrHPV-negative females. The sensitivity, specificity, positive predictive value, and negative predictive value of ASC-H cytology in conjunction with hrHPV DNA testing results for detection of cervical intraepithelial neoplasia 2/3 were 96.1% versus 100.0%, 54.0% versus 68.4%, 35.8% versus 20.8%, and 98.1% versus 100.0% in females younger than 40 years and women 40 years and older, respectively. CONCLUSIONS Our data suggest that reflex hrHPV testing is a highly useful option for women with ASC-H Pap tests. Females with ASC-H and negative hrHPV testing may be more efficiently managed by follow-up with regular Pap and hrHPV testing rather than universal colposcopy, especially for women 40 years and older.

Cervical cytology specimen adequacy: Patient management guidelines and optimizing specimen collection

Objective. To provide updated management guidelines according to cervical cytology specimen adequacy and techniques to optimize adequacy based on literature review and expert opinion. Materials and Methods. Selected members of the American Society for Colposcopy and Cervical Pathology committee and invited experts conducted a literature review and discussed appropriate management and areas for future research emphasis. Results. The guidelines recommend a repeat Pap test in a short interval of 2 to 4 months for most women when the cytology result is unsatisfactory. The preferred follow-up for women with a negative cytology result lacking an endocervical/transformation zone component or showing other quality indicators is a repeat Pap test in 12 months. Indications for an early repeat Pap test in 6 months are provided, and the influence of human papillomavirus testing results on management is discussed. Techniques for optimizing specimen adequacy are provided in detail. Conclusion. The specimen adequacy management guidelines will help promote uniform and optimal follow-up of patients receiving cervical cytology screening. The topics for future research emphasis will be helpful in promoting studies in needed areas.

Very low human papillomavirus DNA prevalence in mature women with negative computer-imaged liquid-based Pap tests

The prevalence of high‐risk Human Papillomavirus DNA (hrHPV DNA) in women with negative Papanicolaou (Pap) test results provides a measure of residual risk for cervical neoplasia after cytology screening. The purpose of this study was to document the prevalence of hrHPV DNA in several thousand women ages ≥30 years with negative ThinPrep Imaging System (TIS)‐imaged Pap test results in a large academic hospital cytology laboratory.

Clinical utility of adjunctive high-risk human papillomavirus DNA testing in women with Papanicolaou test findings of atypical glandular cells.

CONTEXT Atypical glandular cell (AGC) Papanicolaou (Pap) test interpretations are challenging. Most biopsy findings are benign, but AGC results may also reflect highly significant noninvasive neoplastic and malignant histologic outcomes. High-risk human papillomavirus (hrHPV) test use with AGC Pap test results is evolving. OBJECTIVE To further evaluate the utility and limitations of hrHPV testing with AGC Pap tests. DESIGN Hospital records were searched for AGC Pap tests results from June 1, 2005, to August 31, 2007. Cases of AGC with hrHPV tests and histopathologic follow-up were included. RESULTS Of the 662 women with AGC Pap test results and follow-up analyzed, hrHPV results were available for 309 (46.7%) and were positive in 75 cases (24.3%). Among the 75 cases with hrHPV+ AGC results, 13 (17.3%) had cervical intraepithelial neoplasia grades 2/3, 10 (13.3%) had adenocarcinoma in situ, and 3 (4.0%) had cervical invasive adenocarcinoma, whereas for 234 women with hrHPV(-) results, 1 (0.4%) had cervical intraepithelial neoplasia grades 2/3, 1 (0.4%) had adenocarcinoma in situ, 1 each (0.4%) had cervical adenocarcinoma and ovarian carcinoma, and 8 (3.4%) had endometrial carcinoma. CONCLUSIONS Positive hrHPV AGC results were most strongly associated with cervical intraepithelial neoplasia grades 2/3 and adenocarcinoma in situ in women younger than 50 years. Positive hrHPV AGC results were also present in all 3 cases of invasive cervical adenocarcinoma in women younger than 50 years. Of note, hrHPV(-) AGC results were present in 10 of 13 carcinomas (76.9%) detected after AGC Pap tests, all in women 40 years or older with endometrial adenocarcinomas (n = 8), ovarian carcinoma (n = 1), and cervical adenosquamous carcinoma in a woman (n = 1) in her 50s. Testing for hrHPV after AGC Pap testing was most helpful in the detection of cervical intraepithelial neoplasia grades 2/3, adenocarcinoma in situ, and invasive cervical adenocarcinomas in women younger than 50 years.

High-risk HPV DNA detected in less than 2% of over 25,000 cytology negative imaged liquid-based Pap test samples from women 30 and older

OBJECTIVE The purpose of this study was to document the prevalence of high-risk HPV DNA (HPV) in the largest cohort of woman studied to date with negative ThinPrep Imaging system (TIS)-imaged Pap tests. METHODS Women with negative (TIS)-imaged ThinPrep Pap Tests (TPPT) who also were tested for HPV were identified between July 1, 2005 and December 31, 2007 from a large womens hospital practice. HPV detection rates were compared for women with either presence or absence of a transformation zone/endocervical cell sample (EC/TZS). RESULTS 26,558 negative TPPT also underwent HPV testing. HPV detection was higher in women younger than 30 and sharply declined in women 30-39 (P<0.001). Declining HPV detection rates continued in the 40-49 age group (age 30-39 vs. 40-49; 2.8% vs. 1.7%, P<0.001) and then levelled off. No statistically significant difference for HPV prevalence was identified comparing women with and without a TZ/ECS. CONCLUSION This is the largest study to date documenting very low HPV detection rates in women screened cytology negative with computer-imaged liquid-based Pap methods now representing a major portion of the U.S. cervical cytology market. Findings of very low rates of HPV detection in 490 (1.9%) of 25,259 cytology negative women 30 and older extend and confirm previously reported findings in smaller study populations. Because HPV testing provides an objective measure of relative residual risk for cervical neoplasia after screening, these data are relevant to discussions on how best to combine cytology and HPV testing in screening low risk populations.

Screening Test Results Associated With Cancer Diagnoses in 287 Women With Cervical Squamous Cell Carcinoma

CONTEXT The limitations of newer cervical screening tests are still being studied. OBJECTIVE To investigate those limitations, we conducted a retrospective review of 287 cases of cervical squamous cell carcinoma (SCC). DESIGN A search through 5 years of records identified 287 women with cervical SCC diagnoses. Clinical history, histopathology, and liquid-based cytology (ThinPrep) and Hybrid Capture 2 (HC2) high-risk human papillomavirus (HPV) results were documented. Polymerase chain reaction HPV tests were performed on SCC tissues with prior negative HC2 results. RESULTS Of 287 women, 156 (54.4%) had abnormal cytology results, and 75 (26.1%) had abnormal clinical findings triggering tissue diagnoses of SCC. Among 156 patients with abnormal Papanicolaou (Pap) test results, more-seriously abnormal Pap test results were reported in 142 women (91.1%). Among 31 women with Pap and HC2 HPV cotesting within 1 year of SCC diagnoses, 28 (90%) were Pap⁺/HPV⁺, 2 (15.5%) were Pap⁺/HPV⁻, and 1 (3%) was Pap⁻/HPV⁻. Two of 3 women with negative HC2 results before SCC diagnosis had abnormal Pap results; 1 had negative Pap reports with questionable lesional cells mimicking atrophy. In all 3 cases of SCC with negative HC2 results, HPV-18 was detected; in 2 cases (66%), HPV-16 was also detected. CONCLUSIONS Although abnormal cytology preceded most SCC diagnoses, about one-third of patients were referred for diagnostic testing because of clinical suspicion alone. Among 31 SCC cases with liquid-based cytology and high-risk HPV cotest results less than 1 year before SCC diagnoses, 2 patients (6.5%) had Pap⁺/HPV⁻ results, and 1 patient (3.2%) had Pap⁻/HPV⁻ results. Polymerase chain reaction detected high-risk HPV DNA in tumor tissues of 3 SCC cases with recent HC2⁻ results.

HPV Test Results Stratify Risk for Histopathologic Follow-Up Findings of High-Grade Cervical Intra-Epithelial Neoplasia in Women with Low-Grade Squamous Intra-Epithelial Lesion Pap Results

Objective: Age-adjusted evaluations have explored the possible utility of human papillomavirus (HPV) test results in women with low-grade squamous intra-epithelial lesion (LSIL) Paps. We document LSIL correlation data with HPV test results and histopathologic follow-up from a large academic women’s hospital practice. Study Design: LSIL Pap tests with intermediate-/high-risk HPV DNA testing between July 1, 2005 and April 30, 2008 were studied along with follow-up histopathologic diagnoses. Patients were divided into age groups, and tissue diagnoses were correlated with HPV test results. Results: 1,083 (80.2%) of a total of 1,351 LSIL Pap samples tested HPV positive. HPV prevalence declined in older age groups. 719 women with LSIL Pap and HPV test results had at least 1 follow-up cervical biopsy result. 89 of 612 patients with HPV-positive LSIL (14.5%) had a follow-up histopathological diagnosis of cervical intra-epithelial neoplasia (CIN) 2/3. Only 4 of 107 patients with HPV-negative LSIL (3.7%) had CIN 2/3. Conclusions: In the largest study to date to document histopathological follow-up of older women with LSIL and HPV test results, no histopathological CIN 2/3 diagnoses were identified in women 50 years and older with HPV-negative LSIL. HPV test results stratified women with LSIL cytology findings into lower- and higher-risk groups for follow-up histopathologic CIN 2/3 outcomes.

Adjunctive high‐risk human papillomavirus DNA testing is a useful option for disease risk assessment in patients with negative Papanicolaou tests without an endocervical/transformation zone sample

Current guidelines recommend that women with negative Papanicolaou (Pap) test results and no endocervical/transformation zone (EC/TZ) sample return for screening within 12 months. For some women, this represents earlier follow‐up than advocated in several routine screening guidelines. Controversy remains with regard to the correlation between sampling of the EC/TZ, Pap test quality, and disease risk assessment.