Change of Practice Patterns Following an Educational Comment on Reports of Benign-Appearing Endometrial Cells in Papanicolaou Tests.

OBJECTIVES: Since the publication of our study demonstrating high negative predictive values (>99% for women in their 40s) of benign-appearing endometrial cells (nEMCs), we have begun to include an educational comment in Papanicolaou (Pap) test reports with nEMCs that recommends routine periodic screening for asymptomatic premenopausal women (APW). The current study evaluated how the inclusion of this comment has affected clinical practice patterns at our institution. METHODS: The 2017 to 2019 database identified 175 reports containing the educational comment in women aged 45 to 54 years with a follow-up time of 11 to 37 months. Data, including age, menopause status, symptoms, imaging, and outcome, were collected. The procedure rate and the impact of clinical modifiers were assessed. RESULTS: Thirty-seven (20.6%) patients had biopsies within 6 months, which decreased from 48.1% as we previously reported. All nine (5%) APW with biopsies triggered only by nEMCs had benign histopathology. The remaining 28 biopsied patients had abnormal bleeding or a thickened endometrium, or they were postmenopausal, including a 53-year-old patient with complex atypical hyperplasia. None of the 138 patients with conservative follow-up developed atypical/malignant lesions. CONCLUSIONS: A qualifying educational note included in Pap reports significantly reduced follow-up biopsies in APW. Optimal follow-up of nEMCs should be based on relevant clinical modifiers.

Immunohistochemical Markers With Potential Diagnostic, Prognostic, and Therapeutic Significance in Uterine Carcinosarcoma: A Clinicopathologic Study of 43 Cases.

Uterine carcinosarcomas (UCS) are rare and highly aggressive tumors. Although it is currently accepted that the majority of UCS are metaplastic carcinomas, their aggressive behavior is unparalleled to that of any other high-grade endometrial neoplasms. Therefore, the search for the distinct immunohistochemical and molecular features that could help in the development of new treatment strategies continues. We evaluated the expression of PDL-1, growth hormone releasing hormone receptor, p53, WT1, PAX-8, estrogen receptor, HNF-1, and mismatch repair proteins in 43 UCS. Tumors were selected from the archives of the Magee-Womens Hospital University of Pittsburgh Medical Center Department of Pathology. Seventeen were stage I, 4 were stage II, 15 were stage III, and 7 were stage IV. The median age was 67 yr and median overall survival was 3.2 yr. Immunostaining for PAX8, HNF-1, and estrogen receptor showed statistically significant difference between epithelial and stromal components. Expression of p53 was significantly associated with clinical high stage, but other markers did not correlate with stage or survival. Immunostaining for programmed death ligand-1 was strongly positive in 30 UCS (70%), including 24 cases with tumor cell positivity, 12 cases with tumor cell and tumor-infiltrating immune cell positivity, and 6 cases with tumor-infiltrating immune cell positivity only. Of 27 tumors tested for mismatch repair expression, 12 (44%) showed loss of expression, 7 of which were PDL-1 positive. Growth hormone releasing hormone receptor was positive in 38 tumors (88%) and predominantly expressed in the epithelial component. The range of positivity for programmed death ligand-1 and growth hormone releasing hormone receptor suggests a possible potential adjuvant treatment that may be considered for UCS.

Personalized Medicine and Cervical Screening: Development of Individualized Quantitative Risk Assessments for Cervical Adenocarcinoma and Adenocarcinoma in situ.

INTRODUCTION: Cervical screening has decreased the incidence of cervical carcinoma around the world primarily by preventing cervical squamous carcinoma, with significantly less measurable protective benefits in prevention of cervical adenocarcinoma. In this study, we apply Bayesian modeling of cervical clinical, screening, and biopsy data from a large integrated health system to explore the feasibility of calculating personalized risk assessments on screened system patients for subsequent histopathologic diagnoses of invasive cervical adenocarcinoma (AdCa) or cervical adenocarcinoma in situ (AIS). MATERIALS AND METHODS: Diagnoses of cervical AIS or AdCa rendered between 2005 and 2018 were identified in our large health system database with 1,053,713 cytology results, 354,843 high-risk (hr) human papillomavirus (HPV) test results, and 99,012 cervical histopathologic results. Using our continuously updated Bayesian cervical cancer screening model which includes clinical data, cervical screening results, and cervical biopsy results, we projected quantitative estimates of patients' 5-year cumulative risk for cervical AIS or AdCa. RESULTS: 161 patients were identified with AIS (ages 17-75, mean 37 years), and 99 patients had diagnoses of cervical AdCa (ages 26-91, mean 48 years). Quantitative Bayesian 5-year cumulative risk projections for diagnoses of cervical AdCa or AIS in patients with different cervical screening test and biopsy histories were determined. The highest patient risk projections for subsequent cervical AdCa and/or AIS histopathologic diagnoses were associated with prior cervical screening test results of HPV-positive atypical glandular cells. Prior squamous cytologic abnormalities were associated with lower risk estimates. Prior histopathologic diagnoses of squamous abnormalities also influenced quantitative risk. A prior histopathologic diagnosis of AIS was associated with a very low risk of subsequent AdCa, consistent with effective excisional treatment. AdCa risk was greatest in women aged 30-65 years with prior CIN3 biopsy results, whereas AIS risk was greatest in women <30. CONCLUSION: Prevention of cervical AdCa in screened patients remains a major challenge for cervical screening. Individualized risk projections for cervical glandular neoplasia reflecting patient age, prior cervical screening test results, and prior cervical biopsy history are feasible using Bayesian modeling of health system data.

Contributions of Liquid-Based (Papanicolaou) Cytology and Human Papillomavirus Testing in Cotesting for Detection of Cervical Cancer and Precancer in the United States.

OBJECTIVES: Given the recent debate challenging the contribution of cytology in cervical screening, we evaluated results of liquid-based cytology (LBC) and human papillomavirus (HPV) testing in cotesting preceding cervical cancer (CxCa) and precancer diagnoses in a national, heterogeneous population. METHODS: We assessed the results of cotesting, performed by Quest Diagnostics, in 13,633,071 women 30 years and older, tested 2010 to 2018. Cotest results preceding CxCa or precancer diagnoses were analyzed and stratified by histopathology. RESULTS: Among all screening results, 1,615 cotests preceded 1,259 CxCa diagnoses, and 11,164 cotests preceded 8,048 cervical precancer diagnoses. More women who were subsequently diagnosed with CxCa within 1 year were identified by the LBC result than by the HPV result (85.1%, 1,015/1,193 vs 77.5%, 925/1,193). Among all women with CxCa, the overall rate of nondetection was 13.1% (212/1,615) for cotesting results (LBC negative/HPV negative) and this rate increased substantially when testing exceeded 12 months compared to within 1 year prediagnosis of either CxCa or precancer. CONCLUSIONS: Analysis of 9-year cotest results from a national reference laboratory confirms the value of LBC element in cotesting. This supports that LBC/HPV cotesting enhances screening for the identification of CxCa in women 30 years and older, more so than LBC or HPV alone within cotesting.

Individualized Bayesian Risk Assessment for Cervical Squamous Neoplasia.

BACKGROUND: Cervical screening could potentially be improved by better stratifying individual risk for the development of cervical cancer or precancer, possibly even allowing follow-up of individual patients differently than proposed under current guidelines that focus primarily on recent screening test results. We explore the use of a Bayesian decision science model to quantitatively stratify individual risk for the development of cervical squamous neoplasia. MATERIALS AND METHODS: We previously developed a dynamic multivariate Bayesian network model that uses cervical screening and histopathologic data collected over 13 years in our system to quantitatively estimate the risk of individuals for the development of cervical precancer or invasive cervical cancer. The database includes 1,126,048 liquid-based cytology test results belonging to 389,929 women. From-the-vial, high risk human papilloma virus (HPV) test results and follow-up gynecological surgical procedures were available on 33.6% and 12% of these results (378,896 and 134,727), respectively. RESULTS: Historical data impacted 5-year cumulative risk for both histopathologic cervical intraepithelial neoplasia 3 (CIN3) and squamous cell carcinoma (SCC) diagnoses. The risk was highest in patients with prior high grade squamous intraepithelial lesion cytology results. Persistent abnormal cervical screening test results, either cytologic or HPV results, were associated with variable increasing risk for squamous neoplasia. Risk also increased with prior histopathologic diagnoses of precancer, including CIN2, CIN3, and adenocarcinoma in situ. CONCLUSIONS: Bayesian modeling allows for individualized quantitative risk assessments of system patients for histopathologic diagnoses of significant cervical squamous neoplasia, including very rare outcomes such as SCC.

Effects of Hydrochloric Acid and Formic Acid Decalcification on Breast Tumor Biomarkers and HER2 Fluorescence In Situ Hybridization.

Biomarker analysis of metastatic breast carcinoma (MBC) is routinely recommended by ASCO/CAP guidelines, and establishing a diagnosis of MBC often requires immunohistochemistry (IHC). The reliability of breast tumor biomarkers and breast-specific markers on decalcified tissues has not been extensively studied. We performed IHC studies on breast tumors exposed to hydrochloric acid (HCl) and formic acid (FA) decalcification solutions, and HER2 fluorescence in situ hybridization on a subset of these tumors to establish a protocol for handling bone specimens with suspicion for MBC. Fifteen fresh cases of primary breast carcinoma and 8 HER2+ paraffin-embedded core biopsy cases were studied. Fresh tissue was divided into 5 fragments to approximate a bone core biopsy. One fragment (control) was fixed in 10% neutral buffered formalin. The remaining fragments were also exposed to FA or HCl decalcification for 1 or 5 hours. All fragments were embedded in 1 block and tested with an IHC panel. The known HER2+ cases were exposed to either 1 or 5 hours of FA, and HER2 fluorescence in situ hybridization was also performed. Results were interpreted as follows: H-scores for estrogen receptor, progesterone receptor, and GATA-3 were assigned from 0 to 300; HER2, cytokeratin 7, gross cystic disease fluid protein-15, Pax-8, TTF-1, cytokeratin 20, and mammaglobin were scored from 0 to 3+; and Ki67 from 0% to 100%. Mean scores were compared using the t test or Wilcoxon test for paired samples. No significant differences in mean score were seen between NF and 1 hour FA for any IHC immunoreactivity. After 5 hours of FA, only Ki67 average score was significantly less than NF. Mean scores for estrogen receptor, progesterone receptor, HER2, Ki67, and GATA-3 were significantly lower than NF in the tissue after either 1 or 5 hours of HCl. Mean scores for gross cystic disease fluid protein-15, mammaglobin, and cytokeratin 7 staining were not significantly lower than NF after 1 or 5 hours of HCl.

Application of Bayesian network modeling to pathology informatics.

BACKGROUND: In the era of extensive data collection, there is a growing need for a large scale data analysis with tools that can handle many variables in one modeling framework. In this article, we present our recent applications of Bayesian network modeling to pathology informatics. METHODS: Bayesian networks (BNs) are probabilistic graphical models that represent domain knowledge and allow investigators to process this knowledge following sound rules of probability theory. BNs can be built based on expert opinion as well as learned from accumulating data sets. BN modeling is now recognized as a suitable approach for knowledge representation and reasoning under uncertainty. Over the last two decades BN have been successfully applied to many studies on medical prognosis and diagnosis. RESULTS: Based on data and expert knowledge, we have constructed several BN models to assess patient risk for subsequent specific histopathologic diagnoses and their related prognosis in gynecological cytopathology and breast pathology. These models include the Pittsburgh Cervical Cancer Screening Model assessing risk for histopathologic diagnoses of cervical precancer and cervical cancer, modeling of the significance of benign-appearing endometrial cells in Pap tests, diagnostic modeling to determine whether adenocarcinoma in tissue specimens is of endometrial or endocervical origin, and models to assess risk for recurrence of invasive breast carcinoma and ductal carcinoma in situ. CONCLUSIONS: Bayesian network models can be used as powerful and flexible risk assessment tools on large clinical datasets and can quantitatively identify variables that are of greatest significance in predicting specific histopathologic diagnoses and their related prognosis. Resulting BN models are able to provide individualized quantitative risk assessments and prognostication for specific abnormal findings commonly reported in gynecological cytopathology and breast pathology.

Breast cancer global tumor biomarkers: a quality assurance study of intratumoral heterogeneity.

Biomarker analysis of invasive breast carcinoma is useful for prognosis, as surrogate for molecular subtypes of breast cancer, and prediction of response to adjuvant and neoadjuvant systemic therapies. Breast cancer intratumoral heterogeneity is incompletely studied. Comprehensive biomarker analysis of estrogen receptor (ER), progesterone receptor (PR), HER2, and Ki67 labeling index was performed on each tissue block of 100 entirely submitted breast tumors in 99 patients. Invasive carcinoma and in situ carcinoma was scored using semiquantitative histologic score (H-score) for ER and PR, HER2 expression from 0 to 3+, and percentage positive cells for Ki67. Core biopsy results were compared with surgical excision results, invasive carcinoma was compared with in situ carcinoma, and interblock tumoral heterogeneity was assessed using measures of dispersion (coefficient of variation and quartile coefficient of dispersion). Overall concordance between core biopsy and surgical excision was 99% for ER and 95% for PR. Mean histologic score of ER was significantly lower in invasive carcinoma between core biopsy and surgical excision (p = 0.000796). Intratumoral heterogeneity was higher for PR than for ER (mean coefficient of variation for ER 0.08 stdv 0.13 vs. PR 0.26 stdv 0.41). Ki67 labeling index was significantly higher in invasive carcinoma as compared with associated ductal carcinoma in situ on surgical resection specimen (p ≤ 0.0001). Ki67 hotspots were identified in 47% of cases. Of 52 HER2 negative cases on core biopsy, 10 were scored as equivocal on surgical resection. None (0/10) were amplified by Her-2/neu fluorescence in situ hybridization. Overall, biomarkers on core biopsy showed concordance with the surgical excision specimen in the vast majority of cases. Biomarker expression of in situ closely approximates associated invasive carcinoma. Intratumoral heterogeneity of PR is greater than ER. Biomarker expression on diagnostic core biopsy or single tumor block is representative of breast carcinoma as a whole in most cases and is appropriate for clinical decision-making.

Enhanced Detection of Cervical Cancer and Precancer Through Use of Imaged Liquid-Based Cytology in Routine Cytology and HPV Cotesting.

OBJECTIVES: Cervical screening strives to prevent cervical cancer (CxCa), minimizing morbidity and mortality. Most large US reports on cytology and human papillomavirus (HPV) cotesting of women aged 30 years and older are from one laboratory, which used conventional Papanicolaou (Pap) smears from 2003 to 2009. METHODS: We quantified detection of CxCa and precancer (cervical intraepithelial neoplasia 3/adenocarcinoma in situ [CIN3/AIS]) in 300,800 cotests at Magee Womens Hospital since 2005. Screening histories preceding CxCa and CIN3/AIS diagnoses were examined to assess the contribution of cytology and HPV testing. Cotesting utilized Food and Drug Administration-approved imaged liquid-based cytology (LBC) and from-the-vial HPV tests. RESULTS: LBC identified more women subsequently diagnosed with CxCa and CIN3/AIS than HPV testing. HPV-negative/cytology-positive results preceded 13.1% of CxCa and 7.2% of CIN3/AIS diagnoses. CONCLUSIONS: LBC enhanced cotesting detection of CxCa and CIN3/AIS to a greater extent than previously reported with conventional Pap smear and HPV cotesting.

Pathologist's health-care value in the triage of Oncotype DX® testing: a value-based pathology study of tumour biology with outcomes.

AIMS: Pathologists provide expert tissue assessment of breast cancer, yet their value to guide the appropriate use of breast cancer gene expression profile tests (GEPT) is underutilised. The specific aims of this study are to report morpho-immunohistological characteristics of breast tumours with Oncotype DX® (ODx) recurrence scores (RS) of 10 or fewer (ultra-low risk) and 25 or fewer (low risk) in order to determine if pathologists can identify prospectively patient tumours that do not require ODx testing. METHODS AND RESULTS: Oncotype DX® cases with RS < 10 from 2005 to 2010 comprised 441 of 2594 (17%) of clinical cases; this cohort had 5 years' follow-up and was treated with endocrine therapy alone. Tumours were analysed for tumour type, Nottingham grade, mitosis score (MS) semi-quantitative (H-score) hormone receptor content and Magee equation 3. Knowledge derived from this data set was used to develop algorithms in order to identify prospectively tumours with RS of 10 or fewer or 25 or fewer. Thirty-four per cent of tumours were low-grade special types, while the remainder were enriched with high hormone receptor content with MS of 1. These algorithmic selection criteria identified correctly all patient cases below the chemotherapy cut-point, i.e. RS < 25, indicating that these oncotype test orders were an unnecessary cost. CONCLUSIONS: This unique study demonstrates that (i) pathologists add great value to triage breast cancer for GEPT; and (ii) can identify prospectively low-grade tumour biology with high sensitivity and high specificity for those cases which do not require chemotherapy (RS < 25) using MS and hormone receptor content.

Negative Predictive Value and Significance of Benign-Appearing Endometrial Cells in Papanicolaou Tests.

OBJECTIVES: Reporting benign-appearing endometrial cells (nEMCs) in Papanicolaou (Pap) smears of women 40 years and older, introduced in The Bethesda System 2001, may be interpreted as an abnormal finding and lead to unnecessary endometrial biopsies. To our knowledge, this is the first study on the negative predictive value (NPV) of this cytology finding. METHODS: An 11-year database with 1,036,629 Pap test reports and 121,079 surgical pathology reports identified reports of nEMCs in women 40 years and older with follow-up endometrial histopathology within 6 months. Endometrial carcinoma and atypical endometrial hyperplasia were chosen as relevant outcomes. NPVs were calculated. Bayesian modeling assessed the impact of age, bleeding, and postmenopausal status on risk. RESULTS: NPVs for patients aged 40 to 44 years and 45 to 49 years (99.5% and 99.3%, respectively) were not significantly different. NPVs for patients aged 50 to 54 years, 55 to 59 years, and 60 years and older (97.1%, 95.3%, and 94.5%, respectively) were lower than the NPV for patients aged 40 to 49 years. Bayesian modeling indicated that asymptomatic patients in all age groups 40 years and older have very low risk. Bleeding history increased risk in all age groups, especially in women 50 years and older. CONCLUSIONS: nEMCs in Pap test reports of women 40 years and older are a normal cytology finding in premenopausal women, which may result in unnecessary endometrial biopsies. The NPV associated with this finding for women aged 40 to 49 years exceeded 99%.

How to interpret the results of medical time series data analysis: Classical statistical approaches versus dynamic Bayesian network modeling.

BACKGROUND: Classical statistics is a well-established approach in the analysis of medical data. While the medical community seems to be familiar with the concept of a statistical analysis and its interpretation, the Bayesian approach, argued by many of its proponents to be superior to the classical frequentist approach, is still not well-recognized in the analysis of medical data. AIM: The goal of this study is to encourage data analysts to use the Bayesian approach, such as modeling with graphical probabilistic networks, as an insightful alternative to classical statistical analysis of medical data. MATERIALS AND METHODS: This paper offers a comparison of two approaches to analysis of medical time series data: (1) classical statistical approach, such as the Kaplan-Meier estimator and the Cox proportional hazards regression model, and (2) dynamic Bayesian network modeling. Our comparison is based on time series cervical cancer screening data collected at Magee-Womens Hospital, University of Pittsburgh Medical Center over 10 years. RESULTS: The main outcomes of our comparison are cervical cancer risk assessments produced by the three approaches. However, our analysis discusses also several aspects of the comparison, such as modeling assumptions, model building, dealing with incomplete data, individualized risk assessment, results interpretation, and model validation. CONCLUSION: Our study shows that the Bayesian approach is (1) much more flexible in terms of modeling effort, and (2) it offers an individualized risk assessment, which is more cumbersome for classical statistical approaches.

Increased cervical cancer risk associated with extended screening intervals after negative human papillomavirus test results: Bayesian risk estimates using the Pittsburgh Cervical Cancer Screening Model.

INTRODUCTION: Questions have recently been raised about the acceptability of increased cervical cancer risk projected with the new guideline-recommended rescreening interval of 5 years after negative cytology and human papillomavirus (HPV) cotest results. Additional data sources capable of evaluating cervical cancer risk over time are being sought. We employed the continuously updated Bayesian Pittsburgh Cervical Cancer Screening Model (PCCSM) to estimate invasive cancer risks for patients screened at extended screening intervals after negative HPV test results. MATERIALS AND METHODS: The analyzed database included cervical screening data collected over 10 years (2005-2014) at Magee Womens Hospital with 976,624 liquid-based cytology (LBC) results, 285,351 companion high-risk US Food and Drug Administration-approved HPV test results from LBC vials, and 112,435 follow-up histopathologic results from surgical procedures with cervical tissue sampling. Histopathologic cervical cancer risk estimates for patients with prior double negative results with cervical LBC and from-the-vial HPV cotesting were computed using the PCCSM for women rescreened at intervals ranging from 1 to 9 years. Similar risks were computed for women with any negative HPV test result, not considering cytology results. RESULTS: Histopathologic invasive cervical cancer risk computed following LBC and HPV cotesting double negative results progressively increased with rescreening intervals of 1 to 9 years. Cervical cancer risks computed following any HPV-negative result, not considering cytology results, were consistently even higher at each comparable extended rescreening interval. CONCLUSIONS: The PCCSM is a new data source that allows evaluation of cervical cancer risk over time. Cervical cancer risk is minimized with more frequent cytology and HPV cotesting.

Impact of precision of Bayesian network parameters on accuracy of medical diagnostic systems.

OBJECTIVE: One of the hardest technical tasks in employing Bayesian network models in practice is obtaining their numerical parameters. In the light of this difficulty, a pressing question, one that has immediate implications on the knowledge engineering effort, is whether precision of these parameters is important. In this paper, we address experimentally the question whether medical diagnostic systems based on Bayesian networks are sensitive to precision of their parameters. METHODS AND MATERIALS: The test networks include Hepar II, a sizeable Bayesian network model for diagnosis of liver disorders and six other medical diagnostic networks constructed from medical data sets available through the Irvine Machine Learning Repository. Assuming that the original model parameters are perfectly accurate, we lower systematically their precision by rounding them to progressively courser scales and check the impact of this rounding on the models' accuracy. RESULTS: Our main result, consistent across all tested networks, is that imprecision in numerical parameters has minimal impact on the diagnostic accuracy of models, as long as we avoid zeroes among parameters. CONCLUSION: The experiments' results provide evidence that as long as we avoid zeroes among model parameters, diagnostic accuracy of Bayesian network models does not suffer from decreased precision of their parameters.

Immunohistochemistry and HPV in situ hybridization in pathologic distinction between endocervical and endometrial adenocarcinoma: a comparative tissue microarray study of 76 tumors.

OBJECTIVES: It is clinically important to determine whether adenocarcinoma present in a biopsy or curettage is of endometrial or endocervical origin. When tumors are difficult to distinguish based on routine histologic sections, immunohistochemistry and human papillomavirus (HPV) in situ hybridization may be used. MATERIALS AND METHODS: We compare immunohistochemical profile and HPV expression in 76 tumors, including various types of endocervical adenocarcinoma and the most common endometrioid type of endometrial adenocarcinoma using tumor tissue microarray. Immunostaining for p16, mammaglobin, vimentin, monoclonal carcinoembryonic antigen, estrogen receptor, progesterone receptor, and PAX-8 as well as HPV in situ hybridization was performed in 37 endocervical adenocarcinomas and 39 endometrioid-type endometrial adenocarcinomas. The staining patterns were analyzed with Bayesian network model. RESULTS: The markers with the highest discriminatory values were p16, HPV, vimentin, estrogen receptor, and monoclonal carcinoembryonic antigen. The various histologic types of endocervical adenocarcinoma showed similar immunohistochemical profile, and most were positive for p16 (86%) and HPV (65%). Most (90%) of the endometrial adenocarcinomas were positive for vimentin and estrogen receptor, all were negative for HPV, and 97% were negative for carcinoembryonic antigen. CONCLUSIONS: Immunohistochemical testing with multiple markers and HPV testing aids in diagnostic evaluation of adenocarcinomas of endocervix and endometrium and is recommended in tumors of uncertain origin.

A validation study of quantum dot multispectral imaging to evaluate hormone receptor status in ductal carcinoma in situ of the breast.

The assessment of hormone receptors, including estrogen receptor and progesterone receptor, has become a standard practice in breast cancer management. However, the need for multiple sections to evaluate each receptor individually by conventional immunohistochemistry may preclude the analysis on some core biopsies with a limited amount of tumors. The aim of the study was to validate the quantitative analysis of nuclear markers estrogen receptor and progesterone receptor by quantum dot-based immunohistochemistry using a multispectral imaging system in ductal carcinoma in situ of the breast. Consecutive sections from a total of 17 cases of ductal carcinoma in situ with excisional biopsies or mastectomies were stained with conventional immunohistochemistry and quantum dot-based, single- and double-labeled immunohistochemistry for estrogen receptor and progesterone receptor. The semiquantitative results from double-labeled, quantum dot-based immunohistochemistry were compared with those from single-labeled, quantum dot-based immunohistochemistry as well as from conventional immunohistochemistry. There was good concordance between double- and single-labeled quantum dot-based immunohistochemistry, and quantum dot-based immunohistochemistry correlated well with conventional immunohistochemistry (Spearman correlation coefficient range from 0.884 to 0.958, P < .001). The findings proved the validity and accuracy of quantum dot-based multiplex, multispectral technique in detecting 2 tumor markers in the same cellular compartment simultaneously on a single slide. This technique may enhance our ability to assess multiple breast tumor markers in specimens with limited available tissue. However, several technical and logistic issues await significant improvement before this novel technique can be justified for routine clinical application.

Follow-up outcomes for a large cohort of US women with negative imaged liquid-based cytology findings and positive high risk human papillomavirus test results.

OBJECTIVE: This study aimed to follow a large group of US women with negative computer-imaged liquid-based cytology (LBC) and positive high risk (hr) HPV DNA results. METHODS: Negative LBC and positive hrHPV cases were identified between July 1, 2005 and December 31, 2009. Cytologic and histopathologic follow-up results, repeat HPV results, and prior history were analyzed. RESULTS: 1099 Patients with negative LBC and positive hrHPV results were identified. Eight hundred sixty-nine had repeat Pap or histopathologic follow-up results. Average age was 41.2 years. Average follow-up was 23.2 months. Two hundred ninety of 869 had colposcopic examination and biopsies, including 33 diagnostic excisional procedures and 10 hysterectomies. Cervical intraepithelial neoplasia (CIN) 1 and low-grade squamous intraepithelial lesions (CIN1/LSIL) and more severe lesions (CIN1/LSIL+) were detected in 211 of 689 (24.3%). CIN2+ was diagnosed in 21 (2.4%) (1 VAIN3, 2 adenocarcinoma in situ, 1 invasive cervical adenocarcinoma). Six hundred six had repeat HPV tests and 200 had multiple repeat HPV tests. More LSIL/CIN1+ was identified with repeat positive HPV results than with repeat negative HPV results (P<0.001). LSIL/CIN1+ was detected more often with a history of LSIL/CIN1+ than with a history of negative Paps (P<0.001). Eight of 105 (7.6%) cytology-negative HPV-positive patients tested positive for HPV 16 and/or HPV 18. CONCLUSION: This is the largest study documenting follow-up on US cytology-negative hrHPV-positive patients screened with now widely utilized FDA-cleared methods of ciLBC and hrHPV testing. Of 869 patients followed for an average of almost 2 years, 20 cases of high grade intraepithelial neoplasia (2.3%) and one case of endocervical adenocarcinoma were detected. 90.5%(190/210) of intraepithelial neoplasias detected during follow-up were CIN1.

The Pittsburgh Cervical Cancer Screening Model: a risk assessment tool.

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.