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Context: Cervical cancer affects 12 000 women in the United States annually. However, despite its prevalence, there remains no good methodology to detect its recurrence., Objective: To identify the role of cervicovaginal high-risk human papilloma virus (hr-HPV) testing in predicting cervical cancer recurrence., Design: This is a retrospective study of patients who underwent hr-HPV testing as part of their routine surveillance for cervical cancer. Standard statistical analyses, including χ² test and multivariable logistic regression, were performed with IBM SPSS 19.0., Results: A total of 133 patients were identified, of whom 107 (80%) had squamous cell carcinoma. Ninety patients (68%) had bulky disease and were treated primarily with chemoradiation and brachytherapy. Of patients whose disease recurred, 5 patients (42%) had tested positive for hr-HPV during their surveillance period, compared to 13 patients (11%) for whom disease did not recur (relative risk: 3.88, P = .002). On multivariate logistic regression, hr-HPV status remained significantly predictive of disease recurrence (odds ratio: 12.3, P = .02, 95% confidence interval: 1.5-99.6). Using 2 × 2 table analysis, we found that while cervicovaginal cytology has limited specificity (5.7%) in predicting recurrence, the combination of cytology with hr-HPV testing increases the specificity of testing to 89.3%., Conclusions: Persistence of hr-HPV is a risk factor for disease recurrence. High-risk-HPV testing is not routinely used during surveillance for cervical cancer, but this study suggests that large, prospective trials investigating the role of hr-HPV testing in cervical cancer surveillance are needed.

Context: Reports that use the Bethesda System categories for Chinese Papanicolaou test results are rare., Objective: To document and analyze rates reported in the Bethesda System for conventional Papanicolaou tests and liquid-based cytology between 2007 and 2012 in China's largest College of American Pathologists-accredited laboratory., Design: Results from 1,394,389 Papanicolaou tests, rendered between 2007 and 2012 by the Guangzhou Kingmed Diagnostics Cytology Laboratory, were documented by the Bethesda System report categories and Papanicolaou test methodology, which included both conventional Papanicolaou tests and 4 different liquid-based cytology preparations., Results: Results were documented for 326,297 conventional Papanicolaou tests and 1,068,092 liquid-based cytology specimens, which included 928,884 ThinPrep (Hologic, Bedford, Massachusetts), 63,465 SurePath (BD Diagnostics, Franklin Lakes, New Jersey), 50,422 Liqui-Prep (LGM International, Melbourne, Florida), and 25,321 Lituo liquid-cytology (Lituo Biotechnology Co, Hunan, China) specimens. Abnormality rates reported were significantly higher with liquid-based cytology than they were with conventional Papanicolaou tests in all the Bethesda System categories (P < .001). Reporting rates were within the 2006 benchmark ranges from the College of American Pathologists, except for atypical glandular cells (low) and unsatisfactory rates for conventional Papanicolaou tests (low)., Conclusion: Participation in the international College of American Pathologists Laboratory Accreditation Program provides laboratory quality standards not otherwise available in many international settings.

Context: Cervical screening in the United States increasingly involves newer US Food and Drug Administration-approved cytologic methods and adjunctive high-risk human papillomavirus (hrHPV) DNA testing., Objective: To document cervical screening test performance preceding histopathologic cervical intraepithelial neoplasia (CIN) 2/3 diagnoses., Design: Preceding screening test results with computer-imaged, liquid-based cytology (LBC) and hrHPV results were analyzed for 2827 patients with histopathologic CIN 2/3 diagnoses., Results: Of 2827 patients with CIN 2/3 diagnoses, 2074 (73.4%) had system LBC findings within 4 months of CIN 2/3 diagnoses: high-grade squamous intraepithelial lesion (n = 862; 41.6%), low-grade squamous intraepithelial lesion (n = 464; 22.4%), atypical squamous cells of undetermined significance (n = 445; 21.5%), atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (n = 288; 13.9%), and atypical glandular cells/adenocarcinoma in situ (n = 15; 0.7%). Of the 2827 patients, 1488 (52.6%) also had earlier system LBC results at more than 4 months to 3 years before CIN 2/3 diagnoses: one or more abnormal LBC results (n = 978; 65.7%), one or more negative LBC results (n = 911; 61.2%), both abnormal and negative LBC (n = 401; 26.9%). Of 807 patients with hrHPV cotest results within 4 months of CIN 2/3 diagnoses, 786 (97.4%) had hrHPV(+) results. Of 454 patients who also had earlier hrHPV results at more than 4 months to 3 years before CIN 2/3 diagnoses: 377 (83.0%) had one or more hrHPV(+) result, 110 (24.2%) had one or more hrHPV(-) result, and 33 (7.3%) had both positive and negative HPV results., Conclusion: Patients with histopathologic CIN 2/3 had recent abnormal LBC results, most often, high-grade squamous intraepithelial lesions. Among cotested patients, 97.4% (786 of 807) tested hrHPV(+). However, a significant number of patients tested during an extended period of several years had earlier negative Papanicolaou or negative HPV test results, suggesting the recent development of some CIN 2/3 lesions and supporting the value of cotesting for enhanced detection of other developing, small, inaccessible, or nondiagnostic precursor lesions.

Context: The College of American Pathologists (CAP) conducted a national survey of gynecologic cytology quality assurance (QA) practices. Experts in gynecologic cytology were asked to join 5 working groups that studied the survey data on different aspects of QA. Evaluating the survey data and follow-up questions online, together with a review of pertinent literature, the working groups developed a series of preliminary statements on good laboratory practices in cytology QA. These were presented at a consensus conference and electronic voting occurred., Objective: To evaluate a set of QA monitors in gynecologic cytology. Working group 1 evaluated (1) monitoring interpretive rate categories for Papanicolaou tests (Pap tests), (2) concordance of cytotechnologist and pathologist interpretations before sign-out, and (3) turnaround time for Pap tests., Data Sources: The statements are based on a survey of gynecologic cytology QA practice patterns and of opinions from working group members and consensus conference attendees., Conclusions: The outcomes of this process demonstrate the current state of practice patterns in gynecologic cytology QA. Monitoring interpretive rates for all Bethesda System categories is potentially useful, and it is most useful to monitor interpretive rates for cytotechnologists individually and in comparison to the entire laboratory. Laboratories need to determine what level of discrepancy between cytotechnologist and pathologist interpretations of Pap tests is important to track. Laboratories should consider formalizing procedures and policies to adjudicate such discrepant interpretations. Turnaround time should be monitored in gynecologic cytology, but individual laboratories should determine how to measure and use turnaround time internally.

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.

Context: Data on high-risk human papillomavirus (hrHPV) DNA test results in vaginal, liquid-based cytology (LBC) specimens and corresponding cytologic and histopathologic correlation data are limited., Objective: To analyze follow-up correlation data associated with vaginal (after hysterectomy) low-grade squamous intraepithelial lesion (LSIL) LBC and hrHPV test results., Design: Hospital records were searched for vaginal LSIL LBC and hrHPV results between July 1, 2005, and July 30, 2009. Histopathologic and Papanicolaou test follow-up correlation data were analyzed., Results: During the study period, 2892 patients with test results from both posthysterectomy vaginal LBC and hrHPV were identified: 148 (5.1%) of the patients had vaginal Papanicolaou test results reported as LSIL, with hrHPV detected in 113 of the 148 patients (76.4%). Of 148 patients, 59 of those with vaginal LSIL including 48 (81.4%) with positive HPV testing and 11 (18.6%) with negative HPV testing results had a follow-up vaginal biopsy. Histopathologic vaginal intraepithelial neoplasia (VAIN) 2/3 was diagnosed in 7 of 59 patients (11.9%) with biopsies. In all 7 patients who were diagnosed with VAIN 2/3, hrHPV was detected in the LBC vial. No VAIN 2/3 diagnoses were documented in the biopsy specimens from the 11 patients with hrHPV(-) LSIL Papanicolaou test results. Histopathologic VAIN 2/3 was diagnosed from vaginal biopsies in 7 of the 48 patients (14.6%) with vaginal hrHPV(+) LSIL test results., Conclusions: Sensitivity and specificity of hrHPV test results associated with histopathologic follow-up diagnoses of VAIN 2/3 in patients with vaginal LSIL results were 100% and 21.2%, respectively. The positive predictive value of a vaginal hrHPV(+) LSIL result for a subsequent histopathologic VAIN 2/3 diagnosis was 14.6%. No cases of VAIN 2/3 were diagnosed in the 11 patients with vaginal hrHPV(-) LSIL results. Correlations of vaginal cytologic, histopathologic, and human papillomavirus findings were quite similar to correlation findings previously reported in older women with cervical LSIL test results.

Context: New guidelines discourage cervical screening and procedures in young females, given available human papillomavirus vaccines, concerns regarding procedure-associated harms, and the rarity of cervical cancers., Objective: To analyze histopathologic follow-up data on a large number of young females with high-grade squamous intraepithelial lesion (HSIL) Papanicolaou (Pap) test results., Design: Hospital records were searched for HSIL Pap test results in females 20 years or younger between January 2002 and December 2007. Histopathologic and Pap test follow-up, age group variations, and impact of Pap test transformation zone/endocervical sampling were analyzed., Results: Four hundred seventy-four females aged 20 years or younger had HSIL Pap test results during the study period. Three hundred thirty-five young females with at least one cervical biopsy were included. The average age was 18.6 years (range, 13-20 years). The average follow-up period was 24 months (range, 0.1-75 months), with a median of 22 months. Histopathologic detection rates were 44.2% for cervical intraepithelial neoplasia (CIN) 2/3 and 47.8% for CIN 1. The average period between the HSIL Pap test result and an initial diagnosis of CIN 2/3 was 5 months (range, 0.1-62 months), with a median of 2 months. Neither invasive carcinoma nor adenocarcinoma in situ was identified. Presence or absence of a transformation zone/endocervical sample did not significantly impact CIN 2/3 risk (44.5% versus 38.9%, P = .64)., Conclusions: Histopathologic CIN 2/3 was documented in 148 of 335 (44%) of biopsied young females with HSIL Pap results, likely reflecting both the reported high likelihood of HSIL regression in younger females and the challenge of colposcopic sampling of relatively short-lived smaller CIN 2/3 lesions. Although no cases of invasive carcinoma were identified in this study, updated guidelines pose new risks for maturing females with undetected cervical precancer.

Context: Data on cytologic screening and follow-up disproportionately reflect findings from frequently screened younger women, and data from screened women 50 years and older using newer screening technologies remain limited., Objective: To better understand the utility of adjunctive high-risk human papillomavirus (hrHPV) testing for disease risk stratification in women 50 years and older with a range of liquid-based cytology, abnormal, squamous cell Papanicolaou test results., Design: Liquid-based cytology cases interpreted as high-grade squamous intraepithelial lesion (HSIL); low-grade squamous intraepithelial lesion (LSIL); atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H); and atypical squamous cells of undetermined significance (ASC-US) at Magee-Womens Hospital (Pittsburgh, Pennsylvania) were retrospectively identified for a 36-month period between July 1, 2005, and June 30, 2008, from women 50 years and older who also had hrHPV DNA test results. Histopathologic follow-up diagnoses were analyzed., Results: During the study period, 4855 women 50 years and older had HSIL, LSIL, ASC-H, or ASC-US Papanicolaou test results and hrHPV testing. In 89.3% of HSIL cases, 71.0% of LSIL cases, 38.9% of ASC-H cases, and 14.2% of ASC-US cases, hrHPV test results were positive. The positive predictive value of a positive hrHPV test for histopathologic cervical intraepithelial neoplasia 2/3(+) detection was 90.5% with HSIL, 15% with ASC-H, 9.8% with LSIL, and 3.2% with ASC-US. A negative hrHPV test result had a 100% negative predictive value for histopathologic cervical intraepithelial neoplasia 2/3(+) in both LSIL and ASC-H cases., Conclusions: In women 50 years and older, a positive hrHPV test result significantly increased the likelihood of follow-up histopathologic diagnoses of cervical intraepithelial neoplasia 2 /3(+) in patients with HSIL, LSIL, and ASC-H Papanicolaou test results compared with women with negative hrHPV test results. No cervical intraepithelial neoplasia 2/3(+) diagnoses were documented in women 50 years and older with LSIL or ASC-H Papanicolaou test results and negative hrHPV test results.

Context: Evaluation of cervical cancer screening has grown increasingly complex with the introduction of human papillomavirus (HPV) vaccination and newer screening technologies approved by the US Food and Drug Administration., Objective: To create a unique Pittsburgh Cervical Cancer Screening Model (PCCSM) that quantifies risk for histopathologic cervical precancer (cervical intraepithelial neoplasia [CIN] 2, CIN3, and adenocarcinoma in situ) and cervical cancer in an environment predominantly using newer screening technologies., Design: The PCCSM is a dynamic Bayesian network consisting of 19 variables available in the laboratory information system, including patient history data (most recent HPV vaccination data), Papanicolaou test results, high-risk HPV results, procedure data, and histopathologic results. The model's graphic structure was based on the published literature. Results from 375 441 patient records from 2005 through 2008 were used to build and train the model. Additional data from 45 930 patients were used to test the model., Results: The PCCSM compares risk quantitatively over time for histopathologically verifiable CIN2, CIN3, adenocarcinoma in situ, and cervical cancer in screened patients for each current cytology result category and for each HPV result. For each current cytology result, HPV test results affect risk; however, the degree of cytologic abnormality remains the largest positive predictor of risk. Prior history also alters the CIN2, CIN3, adenocarcinoma in situ, and cervical cancer risk for patients with common current cytology and HPV test results. The PCCSM can also generate negative risk projections, estimating the likelihood of the absence of histopathologic CIN2, CIN3, adenocarcinoma in situ, and cervical cancer in screened patients., Conclusions: The PCCSM is a dynamic Bayesian network that computes quantitative cervical disease risk estimates for patients undergoing cervical screening. Continuously updatable with current system data, the PCCSM provides a new tool to monitor cervical disease risk in the evolving postvaccination era.

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.

Context: Reflex human papillomavirus (HPV) testing has been designated in consensus guidelines as "preferred" for women with atypical squamous cells of undetermined significance (ASC-US) liquid-based cytology (LBC) results, and colposcopy is currently recommended for patients with HPV-positive ASC-US results. Data from large clinical practices using newer screening methods and current cytology terminology are limited., Objectives: We analyzed data from patients with ASC-US LBC and positive HPV test results. We also assessed the impact of the presence or absence of an endocervical cell/ transformation zone sample (EC/TZS) on biopsy diagnoses., Design: The information system of a large women's hospital serving an older-than-average population was searched over a 21-month period between July 1, 2005, and March 31, 2007, for HPV-positive cases interpreted as ASC-US (Bethesda System 2001) using computer-imaged LBC. Histologic diagnoses, patient ages, and presence or absence of an EC/TZS were analyzed. The average follow-up period was 7.5 months., Results: Among 4273 women with HPV-positive ASC-US results, the cumulative cervical intraepithelial neoplasia 2 or 3 (CIN 2/3) and CIN 1 rates for 2192 women with available biopsies were 5.1% and 43.6%, respectively. Cervical intraepithelial neoplasia 2/3 and CIN 1 rates for women with HPV-positive ASC-US results were not significantly different for women with and without an EC/TZS., Conclusions: The risk of CIN 2/3 in the study population was significantly lower than reported in widely cited trial data. Neither presence nor absence of an EC/TZS, nor the age of the patient, had a statistically significant impact on the likelihood of biopsy diagnoses of CIN 2/3 and CIN 1 for patients with HPV-positive ASC-US 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.

Risk management efforts in the cytology laboratory must address the gap between what can be achieved with medical history's most effective cancer screening test, the Papanicolaou (Pap) test, and even higher entrenched public expectations. Data from the Atypical Squamous Cells of Undetermined Significance (ASCUS)/Low-Grade Squamous Intraepithelial Lesion Triage Study (ALTS) now provide level I clinical evidence from a large, randomized, controlled, multicenter clinical trial that reflex human papillomavirus (HPV) DNA testing of ASCUS cases is generally the preferred method for initial assessment of the most prevalent category of abnormal Pap interpretation. The proposed combination of HPV DNA testing with cytologic Pap testing, the DNA Pap test, further shows the potential to nearly eliminate false-negative screening results, based on sensitivity and negative predictive values reported in available studies. Human papillomavirus DNA testing also appears to represent a significant enhancement for detection of endocervical adenocarcinomas, which are difficult to detect and prevent. Human papillomavirus DNA testing, when used in conjunction with cervical cytology, can significantly reduce risk to both the patient and the laboratory.

Review of Papanicolaou smear cases that are the focus of litigation typically takes place in a biased setting with foreknowledge of an adverse patient outcome (outcome bias) or litigation and with more time allotted for slide review than is available in normal screening situations. Factors that normally mitigate against overly aggressive slide interpretation, such as concern about false-positive diagnoses and possible unnecessary surgical procedures and expense, are absent. This results in a tendency toward overly aggressive interpretation of questionable or uncertain cytologic abnormalities. These factors can be minimized by a variety of blinded slide review formats with the goal of simulating normal, on-the-job, prospective screening as in actual practice. Despite some limitations, blinded rescreening can provide valuable insight into the relative degree of difficulty involved in interpreting specific slides. The difficulty of a case in question is arguably the second most important factor, after assessment of overall laboratory performance, in determining whether a reasonable standard of practice has been followed.