2019 ASCCP Risk-Based Management Consensus Guidelines: Updates Through 2023.

ABSTRACT: This Research Letter summarizes all updates to the 2019 Guidelines through September 2023, including: endorsement of the 2021 Opportunistic Infections guidelines for HIV+ or immunosuppressed patients; clarification of use of human papillomavirus testing alone for patients undergoing observation for cervical intraepithelial neoplasia 2; revision of unsatisfactory cytology management; clarification that 2012 guidelines should be followed for patients aged 25 years and older screened with cytology only; management of patients for whom colposcopy was recommended but not completed; clarification that after treatment for cervical intraepithelial neoplasia 2+, 3 negative human papillomavirus tests or cotests at 6, 18, and 30 months are recommended before the patient can return to a 3-year testing interval; and clarification of postcolposcopy management of minimally abnormal results.

Recommendations for Use of p16/Ki67 Dual Stain for Management of Individuals Testing Positive for Human Papillomavirus.

OBJECTIVES: The Enduring Consensus Cervical Cancer Screening and Management Guidelines Committee developed recommendations for dual stain (DS) testing with CINtec PLUS Cytology for use of DS to triage high-risk human papillomavirus (HPV)-positive results. METHODS: Risks of cervical intraepithelial neoplasia grade 3 or worse were calculated according to DS results among individuals testing HPV-positive using data from the Kaiser Permanente Northern California cohort and the STudying Risk to Improve DisparitiES study in Mississippi. Management recommendations were based on clinical action thresholds developed for the 2019 American Society for Colposcopy and Cervical Pathology Risk-Based Management Consensus Guidelines. Resource usage metrics were calculated to support decision-making. Risk estimates in relation to clinical action thresholds were reviewed and used as the basis for draft recommendations. After an open comment period, recommendations were finalized and ratified through a vote by the Consensus Stakeholder Group. RESULTS: For triage of positive HPV results from screening with primary HPV testing (with or without genotyping) or with cytology cotesting, colposcopy is recommended for individuals testing DS-positive. One-year follow-up with HPV-based testing is recommended for individuals testing DS-negative, except for HPV16- and HPV18-positive results, or high-grade cytology in cotesting, where immediate colposcopy referral is recommended. Risk estimates were similar between the Kaiser Permanente Northern California and STudying Risk to Improve DisparitiES populations. In general, resource usage metrics suggest that compared with cytology, DS requires fewer colposcopies and detects cervical intraepithelial neoplasia grade 3 or worse earlier. CONCLUSIONS: Dual stain testing with CINtec PLUS Cytology is acceptable for triage of HPV-positive test results. Risk estimates are portable across different populations.

The combined finding of HPV 16, 18, or 45 and cytologic Atypical Glandular Cells (AGC) indicates a greatly elevated risk of in situ and invasive cervical adenocarcinoma.

BACKGROUND: Cervical screening has not effectively controlled cervical adenocarcinoma (AC). Human papillomavirus (HPV) testing is recommended for cervical screening but the optimal management of HPV-positive individuals to prevent AC remains a question. Cytology and HPV typing are two triage options to predict the risk of AC. We combined two potential biomarkers (atypical glandular cell, AGC, cytology and HPV-types 16, 18, or 45) to assess their joint effect on detecting AC. METHODS: Kaiser Permanente Northern California (KPNC) used triennial co-testing with cytology and HPV testing (positive/negative) for routine cervical screening between 2003 and 2020. HPV typing of a sample of residual HPV test specimens was performed on a separate cohort selected from KPNC (Persistence and Progression, PaP, cohort). We compared risk of prevalent and incident histologic AC/AIS (adenocarcinoma in situ) associated with preceding combinations of cytologic results and HPV typing. Risk of squamous cell cancer (SCC)/cervical intraepithelial neoplasia grade 3 (CIN3) (SCC/CIN3) was also included for comparison. RESULTS: Among HPV-positive individuals in PaP cohort, 99% of prevalent AC and 96% of AIS were linked to HPV-types 16, 18, or 45 (denoted HPV 16/18/45). Although rare (0.09% of screening population), the concurrent detection of HPV 16/18/45 with AGC cytology predicted a highly elevated relative risk of underlying histologic AC/AIS; the absolute risk of diagnosing AC/AIS was 12% and odds ratio (OR) was 1341 (95%CI:495-3630) compared to patients with other high-risk HPV types and normal cytology. Cumulatively (allowing non-concurrent results), approximately one-third of the AC/AIS cases ever had HPV 16/18/45 and AGC cytology (OR = 1785; 95%CI:872-3656). AGC was not as strongly associated with SCC/CIN3. CONCLUSION: Detection of HPV 16/18/45 positivity elevates risk of adenocarcinoma, particularly if AGC cytology is also found.

Incorporating Stakeholder Feedback in Guidelines Development for the Management of Abnormal Cervical Cancer Screening Tests.

OBJECTIVE: The 2019 ASCCP Risk-Based Management Consensus Guidelines present a paradigm shift from results- to risk-based management. Patient and provider factors can affect guideline adoption. We sought feedback from stakeholders to inform guideline development. MATERIALS AND METHODS: To solicit provider feedback, we surveyed attendees at the 2019 ASCCP annual meeting regarding readiness to adopt proposed changes and used a web-based public comment period to gauge agreement/disagreement with preliminary guidelines. We elicited patient feedback via a brief survey on preferences around proposed recommendations for treatment without biopsy. Surveys and public comment included both closed-ended and free-text items. Quantitative results were analyzed using descriptive statistics; qualitative results were analyzed using content analysis. Results were incorporated into guideline development in real time. RESULTS: Surveys indicated that 98% of providers currently evaluate their patients' past results to determine management; 88% felt formally incorporating history into management would represent an improvement in care. Most providers supported expedited treatment without biopsy: 22% currently perform expedited treatment and 60% were willing to do so. Among patients, 41% preferred expedited treatment, 32% preferred biopsy before treatment, and the remainder were undecided. Responses from the public comment period included agreement/disagreement with preliminary guidelines, reasons for disagreement, and suggestions for improvement. CONCLUSIONS: Stakeholder feedback was incorporated into the development of the 2019 ASCCP Risk-Based Management Consensus Guidelines. Proposed recommendations with less than two-thirds agreement in the public comment period were considered for revision. Findings underscore the importance of stakeholder feedback in developing guidelines that meet the needs of patients and providers.

Improving Cancer Diagnosis and Care: Patient Access to High-Quality Oncologic Pathology.

Drawing on discussions at a workshop hosted by the National Cancer Policy Forum, current challenges in pathology are reviewed and practical steps to facilitate high­quality cancer diagnosis and care through improved patient access to expertise in oncologic pathology are highlighted.

Suboptimal Agreement Among Cytopathologists in Diagnosis of Malignancy Based on Endoscopic Ultrasound Needle Aspirates of Solid Pancreatic Lesions: A Validation Study.

BACKGROUND & AIMS: Despite the widespread use of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) to sample pancreatic lesions and the standardization of pancreaticobiliary cytopathologic nomenclature, there are few data on inter-observer agreement among cytopathologists evaluating pancreatic cytologic specimens obtained by EUS-FNA. We developed a scoring system to assess agreement among cytopathologists in overall diagnosis and quantitative and qualitative parameters, and evaluated factors associated with agreement. METHODS: We performed a prospective study to validate results from our pilot study that demonstrated moderate to substantial inter-observer agreement among cytopathologists for the final cytologic diagnosis. In the first phase, 3 cytopathologists refined criteria for assessment of quantity and quality measures. During phase 2, EUS-FNA specimens of solid pancreatic lesions from 46 patients were evaluated by 11 cytopathologists at 5 tertiary care centers using a standardized scoring tool. Individual quantitative and qualitative measures were scored and an overall cytologic diagnosis was determined. Clinical and EUS parameters were assessed as predictors of unanimous agreement. Inter-observer agreement (IOA) was calculated using multi-rater kappa (κ) statistics and a logistic regression model was created to identify factors associated with unanimous agreement. RESULTS: The IOA for final diagnoses, based on cytologic analysis, was moderate (κ = 0.56; 95% CI, 0.43-0.70). Kappa values did not increase when categories of suspicious for malignancy, malignant, and neoplasm were combined. IOA was slight to moderate for individual quantitative (κ = 0.007; 95% CI, -0.03 to -0.04) and qualitative parameters (κ = 0.5; 95% CI, 0.47-0.53). Jaundice was the only factor associated with agreement among all cytopathologists on multivariate analysis (odds ratio for unanimous agreement, 5.3; 95% CI, 1.1-26.89). CONCLUSIONS: There is a suboptimal level of agreement among cytopathologists in the diagnosis of malignancy based on analysis of EUS-FNA specimens obtained from solid pancreatic masses. Strategies are needed to refine the cytologic criteria for diagnosis of malignancy and enhance tissue acquisition techniques to improve diagnostic reproducibility among cytopathologists.

The Paris System for Reporting Urinary Cytology: The Quest to Develop a Standardized Terminology.

The main purpose of urine cytology is to detect high-grade urothelial carcinoma. With this principle in mind, The Paris System (TPS) Working Group, composed of cytopathologists, surgical pathologists, and urologists, has proposed and published a standardized reporting system that includes specific diagnostic categories and cytomorphologic criteria for the reliable diagnosis of high-grade urothelial carcinoma. This paper outlines the essential elements of TPS and the process that led to the formation and rationale of the reporting system. TPS Working Group, organized at the 2013 International Congress of Cytology, conceived a standardized platform on which to base cytologic interpretation of urine samples. The widespread dissemination of this approach to cytologic examination and reporting of urologic samples and the scheme's universal acceptance by pathologists and urologists is critical for its success. For urologists, understanding the diagnostic criteria, their clinical implications, and limitations of TPS is essential if they are to utilize urine cytology and noninvasive ancillary tests in a thoughtful and practical manner. This is the first international/inclusive attempt at standardizing urinary cytology. The success of TPS will depend on the pathology and urology communities working collectively to improve this seminal paradigm shift, and optimize the impact on patient care.

The Pap Test and Bethesda 2014. "The reports of my demise have been greatly exaggerated." (after a quotation from Mark Twain).

The history of 'The Bethesda System' for reporting cervical cytology goes back almost 3 decades. This terminology and the process that created it have had a profound impact on the practice of cervical cytology for laboratorians and clinicians alike. The Bethesda conferences and their ensuing output have also set the stage for standardization of terminology across multiple organ systems, including both cytology and histology, have initiated significant research in the biology and cost-effective management for human papillomavirus-associated anogenital lesions, and, finally, have fostered worldwide unification of clinical management for these lesions. Herein, we summarize the process and rationale by which updates were made to the terminology in 2014 and outline the contents of the new, third edition of the Bethesda atlas and corresponding website.

The Pap Test and Bethesda 2014: "The reports of my demise have been greatly exaggerated. (after a quotation from Mark Twain)".

The Bethesda System for gynecologic cytopathology has standardized reporting terminology over the past quarter of a century. In doing so, it has allowed for improved communication among practitioners around the world, facilitated large research projects and clinical trials, and has provided the basis from which uniformly accepted risk-based management strategies have been developed. Over time, changes in terminology and the underlying science require revisions, and the third edition of the Bethesda "Atlas" is the result of a yearlong effort to provide such an update. New material was developed and proposed via an Internet bulletin board, allowing for wide commentary that was compiled and incorporated. New images were collected, which comprised many new examples of equivocal presentations and mimics. New background material on the scientific basis supporting the terminology categories, the most current management algorithms, and comprehensive references were included. The effort completely refurbishes this standard reference that forms an inexpensive and, therefore, widely available resource for the world's cytology community.

Radiological-pathological analysis of WHO, RECIST, EASL, mRECIST and DWI: Imaging analysis from a prospective randomized trial of Y90 ± sorafenib.

UNLABELLED: The aim of this study was to compare radiological and pathological changes and test the adjunct efficacy of Sorafenib to Y90 as a bridge to transplantation in hepatocellular carcinoma (HCC). 15 patients with 16 HCC lesions were randomized to Y90 without (Group A, n = 9) or with Sorafenib (Group B, n = 7). Size (WHO, RECIST), enhancement (EASL, mRECIST) and diffusion-weighted imaging criteria (apparent diffusion coefficient, ADC) measurements were obtained at baseline, then at 1 and every 3 months after treatment until transplantation. Percentage necrosis in explanted tumors was correlated with imaging findings. 100%, 50%-99% and <50% pathological necrosis was observed in 6 (67%), 1 (11%), and 2 (22%) tumors in Group A and 3 (42%), 2 (28%), and 2 (28%) in Group B, respectively (P = 0.81). While ADC (P = 0.46) did not change after treatment, WHO (P = 0.06) and RECIST (P = 0.08) response at 1 month failed to reach significance, but significant responses by EASL (P < 0.01/0.03) and mRECIST (P < 0.01/0.03) at 1 and 3 months were observed. Response was equivalent by EASL or mRECIST. No difference in response rates was observed between groups A and B at 1 and 3 months by WHO, RECIST, EASL, mRECIST or ADC measurements. Despite failing to reach significance, smaller baseline size was associated with complete pathological necrosis (CPN) (RECIST: P = 0.07; WHO: P = 0.05). However, a cut-off size of 35 mm was predictive of CPN (P = 0.005). CPN could not be predicted by WHO (P = 0.25 and 0.62), RECIST (P = 0.35 and 0.54), EASL (P = 0.49 and 0.46), mRECIST (P = 0.49 and 0.60) or ADC (P = 0.86 and 0.93). CONCLUSION: The adjunct of Sorafenib did not augment radiological or pathological response to Y90 therapy for HCC. Equivalent significant reduction in enhancement at 1 and 3 months by EASL/mRECIST was noted. Neither EASL nor mRECIST could reliably predict CPN.

HPV-related squamous neoplasia of the lower anogenital tract: an update and review of recent guidelines.

Squamous cell carcinomas of the lower anogenital tract that are related to human papillomavirus (HPV) infection represent a significant disease burden worldwide. The diagnosis and management of their noninvasive precursors has been the subject of extensive study and debate over several decades, accompanied by an evolving understanding of HPV biology. Recent new consensus recommendations for the pathologic diagnosis of these precursor lesions were published in 2012, the result of the Lower Anogenital Squamous Terminology project cosponsored by the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. Most salient among the new guidelines are the recommendation to switch to a 2-tiered nomenclature (high-grade squamous intraepithelial lesion and low-grade squamous intraepithelial lesion) rather than the traditional 3-tiered "intraepithelial neoplasia" terminology, and the recommendation to expand use of the immunohistochemical marker p16 to distinguish between low-grade squamous intraepithelial lesion and high-grade squamous intraepithelial lesion/intraepithelial neoplasia 2. The goals of the project were to align diagnostic terminology with our knowledge of HPV biology, increase reproducibility, consolidate diverse systems of nomenclature, and ultimately better determine a patient's true cancer risk. The clinical guidelines for screening and management of cervical intraepithelial neoplasia have also been recently updated, most notably with a lengthening of screening intervals. In this review, we focus on the new guidelines put forth for pathologic diagnosis of HPV-related anogenital neoplasia, with discussion of the evidence behind them and their potential implications. We also provide an update on relevant biomarkers, clinical recommendations, and the newest developments relating to cervical neoplasia.

2013 statement on human papillomavirus [corrected] test utilization.

This statement from the Cytopathology Education and Technology Consortium summarizes appropriate and inappropriate uses of human papillomavirus testing in cervical cancer screening based on guidelines from the American Society for Colposcopy and Cervical Pathology and the American Cancer Society. © 2014 S. Karger AG, Basel.

Supernatant fluid from endobronchial ultrasound-guided transbronchial needle aspiration for rapid next-generation sequencing.

INTRODUCTION: There is an increasing demand to optimize the workflow and maximize tissue available for next-generation sequencing (NGS) for non-small cell carcinoma. We looked at transbronchial needle endobronchial ultrasound-guided bronchoscopy with transbronchial needle aspiration samples and evaluated the performance of supernatant (SN) fluid processed from a dedicated aspirate collected for NGS testing. MATERIALS AND METHODS: Nineteen samples were collected and processed using a new workflow. Five aspirates were collected in formalin. One additional dedicated pass was collected fresh and centrifuged. The resulting cell pellet was added to formalin for cell block (CB) processing. DNA and RNA were extracted from concentrated SN for targeted testing using the Oncomine Precision Assay (Thermo Scientific, Waltham, MA). NGS results from the corresponding CB samples were used as "controls" for comparison. RESULTS: Thirty-one mutations were detected in SN (Table 1). The most frequently mutated genes were TP53 (35%), EGFR (23%), KRAS (13%), CTNNB1 (6%), and ERBB2 (6%). There was 100% concordance between the mutations detected in SN and corresponding CBs with comparable variant allele frequencies. Turnaround time of NGS results was 1 day for SN compared to 4-10 days for CB. CONCLUSIONS: We were able to demonstrate the usefulness of SN for reliable rapid molecular results. We successfully incorporated the workflow for tissue handling and processing among our clinical, cytopathology, and molecular teams. Molecular results were available at the same time as the cytologic diagnosis, allowing for timely reporting of a comprehensive diagnosis. This approach is particularly useful in patients with advanced disease requiring urgent management.

Routine on-site evaluation of specimen adequacy during initial ultrasound-guided fine needle aspiration of thyroid nodules: a cost-effectiveness analysis.

BACKGROUND: On-site evaluation (OSE) of specimen adequacy during fine needle aspiration (FNA) of thyroid nodules reduces unsatisfactory results but adds cost. We hypothesized that the addition of routine OSE to initial ultrasound-guided FNA of thyroid nodules is not cost-effective. METHODS: Formal cost-effectiveness analysis was performed using a decision model to compare strategies of routine initial OSE versus restriction of OSE to cases of prior inadequate FNA. Adequacy rates for FNA without OSE and detriment to quality-adjusted life expectancy (QALE) for undergoing repeat FNA were estimated on the basis of literature review and institutional experience. Costs were estimated using Medicare limiting charges and Bureau of Labor Statistics wage rates. Sensitivity analysis was used to examine the uncertainty of the model variable estimates. RESULTS: The routine OSE strategy produced a gain of 0.00007 quality-adjusted life-years (QALYs) at an additional cost of $43.75 for an incremental cost-effectiveness ratio of $639,143/QALY when compared to restriction of OSE to cases with prior inadequate results. During sensitivity analysis, routine OSE became cost-effective if FNA adequacy rate without OSE decreased from 90 to 85 %, cost of OSE decreased from $116 to $75, cost of FNA increased from $366 to $735, hourly wage increased from $23 to $123, or QALE detriment for repeat FNA increased from 0.25 to 1.6 days. CONCLUSIONS: OSE for initial ultrasound-guided FNA of thyroid nodules is not cost-effective unless the adequacy rate without OSE is less than 85 %. When operator performance exceeds this rate, OSE should be reserved for cases with previous inadequate results.

The Lower Anogenital Squamous Terminology Standardization project for HPV-associated lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology.

The terminology for human papillomavirus (HPV)-associated squamous lesions of the lower anogenital tract has a long history marked by disparate diagnostic terms derived from multiple specialties. It often does not reflect current knowledge of HPV biology and pathogenesis. A consensus process was convened to recommend terminology unified across lower anogenital sites. The goal was to create a histopathologic nomenclature system that reflects current knowledge of HPV biology, optimally uses available biomarkers, and facilitates clear communication across different medical specialties. The Lower Anogenital Squamous Terminology (LAST) project was co-sponsored by the College of American Pathologists (CAP) and the American Society for Colposcopy and Cervical Pathology (ASCCP) and included 5 working groups; three work groups performed comprehensive literature reviews and developed draft recommendations. Another work group provided the historical background and the fifth will continue to foster implementation of the LAST recommendations. After an open comment period, the draft recommendations were presented at a consensus conference attended by LAST work group members, advisors and representatives from 35 stakeholder organizations including professional societies and government agencies. Recommendations were finalized and voted upon at the consensus meeting. The final approved recommendations standardize biologically-relevant histopathologic terminology for HPV-associated squamous intraepithelial lesions and superficially invasive squamous carcinomas across all lower anogenital tract sites and detail appropriate use of specific biomarkers to clarify histologic interpretations and enhance diagnostic accuracy. A plan for disseminating and monitoring recommendation implementation in the practicing community was also developed. The implemented recommendations will facilitate communication between pathologists and their clinical colleagues and improve accuracy of histologic diagnosis with the ultimate goal of providing optimal patient care.

Rapid on-site evaluation of endoscopic ultrasound core biopsy specimens has excellent specificity and positive predictive value for gastrointestinal lesions.

BACKGROUND: Endoscopic ultrasound (EUS) with fine needle aspiration (FNA) is a safe and effective way to sample lesions in the gastrointestinal tract. Rapid on-site specimen evaluation (ROSE) improves the accuracy of EUS-FNA. While data suggests that EUS with fine-needle biopsy (EUS-FNB) is effective, it remains unclear if ROSE is predictive of a final diagnosis when obtaining core specimens. AIM: The aim of this study was to investigate the utility of ROSE in achieving a final diagnosis for EUS-FNB core specimens. METHODS: We evaluated 60 consecutive patients referred for EUS guided sampling of lesions within or adjacent to the gastrointestinal tract. All patients underwent EUS-FNB to evaluate the additive value of ROSE to the diagnostic accuracy of specimens obtained using a core biopsy needle. EUS-FNA was also performed in a majority of cases. RESULTS: EUS-FNB was feasible in all 60 cases; on-site specimen adequacy and final diagnostic accuracy was 58 % [95 % confidence intervals (CI) 45.1-71.2] and 83 % (95 % CI 71.9-91.5), respectively. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value of ROSE for core biopsies were 65, 100, 100, and 39 %, respectively. On-site adequacy and diagnostic accuracy for EUS-FNA was 38 % (95 % CI 22.2-53.5) and 63 % (95 % CI 50.1-75.8), respectively. There were no significant complications. CONCLUSIONS: EUS-FNB is safe, feasible, and effective. ROSE of the core biopsy provides excellent PPV; however, an inadequate ROSE appears to be of limited value. Further prospective studies are needed to assess the optimal handling and onsite processing of core specimens to determine whether ROSE is beneficial for EUS-FNB.