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Context Human papillomavirus (HPV) is a major cause of oropharyngeal squamous cell carcinomas, and HPV (and/or surrogate marker p16) status has emerged as a prognostic marker that significantly impacts clinical management. There is no current consensus on when to test oropharyngeal squamous cell carcinomas for HPV/p16 or on which tests to choose. Objective To develop evidence-based recommendations for the testing, application, interpretation, and reporting of HPV and surrogate marker tests in head and neck carcinomas. Design The College of American Pathologists convened a panel of experts in head and neck and molecular pathology, as well as surgical, medical, and radiation oncology, to develop recommendations. A systematic review of the literature was conducted to address 6 key questions. Final recommendations were derived from strength of evidence, open comment period feedback, and expert panel consensus. Results The major recommendations include (1) testing newly diagnosed oropharyngeal squamous cell carcinoma patients for high-risk HPV, either from the primary tumor or from cervical nodal metastases, using p16 immunohistochemistry with a 70% nuclear and cytoplasmic staining cutoff, and (2) not routinely testing nonsquamous oropharyngeal carcinomas or nonoropharyngeal carcinomas for HPV. Pathologists are to report tumors as HPV positive or p16 positive. Guidelines are provided for testing cytologic samples and handling of locoregional and distant recurrence specimens. Conclusions Based on the systematic review and on expert panel consensus, high-risk HPV testing is recommended for all new oropharyngeal squamous cell carcinoma patients, but not routinely recommended for other head and neck carcinomas.

As the human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma epidemic has developed in the past several decades, it has become clear that these tumors have a wide variety of morphologic tumor types and features. For the practicing pathologist, it is critical to have a working knowledge about these in order to make the correct diagnosis, not to confuse them with other lesions, and to counsel clinicians and patients on their significance (or lack of significance) for treatment and outcomes. In particular, there are a number of pitfalls and peculiarities regarding HPV-related tumors and their nodal metastases that can easily result in misclassification and confusion. This article will discuss the various morphologic types and features of HPV-related oropharyngeal carcinomas, specific differential diagnoses when challenging, and, if established, the clinical significance of each finding.

In 2018, an evidence-based guideline was published by the College of American Pathologists to develop recommendations for the testing, application, interpretation, and reporting of high-risk human papillomavirus and surrogate marker tests in head and neck carcinomas. Substantial new evidence has prompted a review, including data on human papillomavirus (HPV) in nonoropharyngeal anatomic sites, HPV global rates, p16 immunohistochemistry, and HPV testing performance in cytology specimens, and performance of p16 immunohistochemistry as a surrogate marker. To assess research published since the release of the original 2018 guideline and to update evidence-based recommendations for HPV testing in head and neck carcinomas. The College of American Pathologists convened a panel of experts to update the guideline following the standards established by the National Academy of Medicine for developing trustworthy clinical practice guidelines. The expert panel defined the key questions and performed a systematic review of the literature. Using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, recommendations were updated on the basis of available evidence, certainty of that evidence, and key judgments. Seven strong recommendations, 4 conditional recommendations, and 5 good practice statements are offered in the guideline update. The updated guideline statements provide direction on the nature of HPV testing in various head and neck specimens (including key updates based on new research on sinonasal squamous cell carcinoma) and expanded guidance on specific scenarios and practice settings. The goal is to improve and standardize, where possible, HPV testing across diverse pathology practice settings and different countries.

Coccidioidomycosis is a rare fungal infection that can closely mimic squamous cell carcinoma (SCC) clinically and radiologically when presenting in the larynx, leading to potential misdiagnosis. This case highlights the importance of considering fungal infections in the differential diagnosis of laryngeal lesions, particularly in endemic regions.

Abstract Objectives In this feasibility study, we explored the combined use of circulating tumor human papillomavirus (HPV) DNA (ctHPVDNA) and HPV serology as diagnostic tests for HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). Methods Among patients with research-banked serum or plasma at diagnosis, IgG antibodies to oncoproteins from HPV types 16, 18, 31, 33, 35, 45, 52, and 58 were detected with multiplex serology. Positivity for HPV 16 was defined based on detection of combinations of anti-E6, E1, E2, and E7 and for other high-risk types on detection of anti-E6 and anti-E7. Circulating tumor HPV DNA was detected by custom digital droplet polymerase chain reaction (ddPCR) assays for HPV types 16, 18, 33, 35, and 45. p16 immunohistochemistry and high-risk HPV RNA in situ hybridization (ISH) using a cocktail of 18 high-risk HPV types were performed on tissue. Results Of 75 patients, 67 (89.3%) were HPV-associated (p16 and HPV RNA ISH positive) and 8 (10.7%) were HPV-independent. All 8 HPV-independent patients were seronegative and negative for ctHPVDNA (100% specificity). Serology was positive in 53 (79.1%) of 67 HPV-associated patients, while ddPCR was positive for ctHPVDNA in 59 (88.6%) of 67 HPV-associated patients. Requiring both tests to be positive resulted in a sensitivity of 50 (74.6%) of 67 while combining assays (either positive) improved sensitivity to 62 (92.6%) of 67. Conclusions Compared to HPV RNA ISH, HPV serology and ctHPVDNA are sensitive and highly specific biomarkers for HPV-associated OPSCC at the time of presentation.

Background The use of antibiotics is the single most important driver in antibiotic resistance. Nevertheless, antibiotic overuse remains common. Decline in antibiotic prescribing in the United States coincided with the launch of national educational campaigns in the 1990s and other interventions, including the introduction of routine infant immunizations with the pneumococcal conjugate vaccine (PCV-7); however, it is unknown if these trends have been sustained through recent measurements. Methods We performed an analysis of nationally representative data from the Medical Expenditure Panel Surveys from 2000 to 2010. Trends in population-based prescribing were examined for overall antibiotics, broad-spectrum antibiotics, antibiotics for acute respiratory tract infections (ARTIs) and antibiotics prescribed during ARTI visits. Rates were reported for three age groups: children and adolescents (<18 years), adults (18 to 64 years), and older adults (≥65 years). Results An estimated 1.4 billion antibiotics were dispensed over the study period. Overall antibiotic prescribing decreased 18% (risk ratio (RR) 0.82, 95% confidence interval (95% CI) 0.72 to 0.94) among children and adolescents, remained unchanged for adults, and increased 30% (1.30, 1.14 to 1.49) among older adults. Rates of broad-spectrum antibiotic prescriptions doubled from 2000 to 2010 (2.11, 1.81 to 2.47). Proportions of broad-spectrum antibiotic prescribing increased across all age groups: 79% (1.79, 1.52 to 2.11) for children and adolescents, 143% (2.43, 2.07 to 2.86) for adults and 68% (1.68, 1.45 to 1.94) for older adults. ARTI antibiotic prescribing decreased 57% (0.43, 0.35 to 0.52) among children and adolescents and 38% (0.62, 0.48 to 0.80) among adults; however, it remained unchanged among older adults. While the number of ARTI visits declined by 19%, patients with ARTI visits were more likely to receive an antibiotic (73% versus 64%; P <0.001) in 2010 than in 2000. Conclusions Antibiotic use has decreased among children and adolescents, but has increased for older adults. Broad-spectrum antibiotic prescribing continues to be on the rise. Public policy initiatives to promote the judicious use of antibiotics should continue and programs targeting older adults should be developed.

Our goal for medicine is to make zero mistakes, yet the reality is that mistakes are an unfortunate part of medical practice. And when it comes to surgical pathology, it is a special case where the diagnostic “bottom line” is provided starkly and directly for all to see in the final diagnosis of the pathology report. When this diagnosis is wrong, particularly when it has serious adverse consequences for the patient, the resulting physical, mental, and emotional effects on patient, provider, pathologist, and health care system can be extremely serious. Head and neck surgical pathology, based on large second review-type studies, is a subspecialty area with average rates of major diagnostic error, but with potential for severely negative impacts on patients. Studies have shown between 1% and 7% major error rates for head and neck practice. How then, as the pathologist, can we react to and manage things when we have made a serious diagnostic mistake? Through personal experience over more than two decades, the hard-won answer is through extreme ownership and a focus on the needs of the patients, who, in the words of William J. Mayo, should have their “needs come first”. The emotional impact on us as pathologists and on the clinicians we work with should also be acknowledged and managed. This article will serve as a thorough and open examination of these mistake scenarios and, focusing specifically on diagnostic errors, serve as a practical guide for what you can do, moving forward, to “make things right” to the best of your ability.

Abstract Objectives To establish baseline error rates due to misinterpretation and to identify scenarios in which major errors were most common and potentially preventable. Methods Our database was queried over a 3-year period for major discrepancies due to misinterpretation. These were stratified by histomorphologic setting, service, availability/type of prior material, and years of experience and subspecialization of the interpreting pathologist. Results The overall discordance rate between frozen section (FS) and final diagnoses was 2.9% (199/6,910). Seventy-two errors were due to interpretation, of which 34 (47.2%) were major. Major error rates were highest on the gastrointestinal and thoracic services. Of major discrepancies, 82.4% were rendered in subdisciplines outside those of the FS pathologist. Pathologists with fewer than 10 years’ experience made more errors than those with more experience (55.9% vs 23.5%, P = .006). Major error rates were greater for cases without previous material compared to those with a prior glass slide (47.1% vs 17.6%, P = .009). Common histomorphologic scenarios in which disagreements were made involved discriminating mesothelial cells from carcinoma (20.6%) and accurately recognizing squamous carcinoma/severe dysplasia (17.6%). Conclusions To improve performance and decrease future misdiagnoses, monitoring discordances should be a continuous component of surgical pathology quality assurance programs.

DEK::AFF2 carcinoma of the sinonasal tract is an emerging entity. The tumor is typically characterized by papillary proliferation of non-keratinizing squamous epithelial cells with monotonous cytologic features, which may mimic other sinonasal tumors. The confirmation of this gene fusion has thus far relied solely on next-generation sequencing, fluorescence in situ hybridization (FISH), or reverse transcription polymerase chain reaction (RT-PCR). This current study aimed to validate an immunohistochemical assay for AFF2 C-terminus as an ancillary marker. We first analyzed publicly available RNA sequencing data of sinonasal tumors from the national center for biotechnology information (NCBI) sequence read archive and identified 3 DEK::AFF2 carcinomas out of 28 sinonasal tumors. The gene expression of AFF2 was significantly higher in the fusion-positive cases compared to the wild-type tumors (p < 0.001), while DEK was not. We then optimized an immunohistochemical assay with an anti-AFF2 C-terminus antibody for ancillary diagnosis. Seventeen DEK::AFF2 carcinomas, including 11 cases with predominantly low-grade morphology and one showing glandular differentiation, as well as 78 DEK FISH-negative sinonasal tumors were evaluated by AFF2 immunohistochemistry (IHC). Sixteen of the 17 DEK::AFF2 carcinomas showed nuclear AFF2 expression in ≥30% of tumor cells, including one decalcified case that failed FISH and RT-PCR confirmation. The one case that was negative for AFF2 IHC in the tumor cells also lacked expression in the internal positive control. It was thus considered a failure of the IHC rather than a truly negative case and was excluded from the statistical analysis. All DEK FISH-negative sinonasal tumors were negative for nuclear AFF2 expression. The nuclear expression of AFF2 IHC showed 100% sensitivity and specificity for DEK::AFF2 carcinoma. Accordingly, AFF2 IHC is a highly sensitive and specific ancillary marker that distinguishes DEK-AFF2 carcinoma from the other sinonasal tumors with overlapping morphological features and may be an especially useful alternative for decalcified specimens.

Detection of high-risk human papillomavirus (HR-HPV) in squamous cell carcinoma is important for classification and prognostication. In situ hybridization (ISH) is a commonly used HR-HPV-specific test that targets viral RNA or DNA. The College of American Pathologists (CAP) provides proficiency testing for laboratories performing HR-HPV ISH. To compare the analytical performance of RNA- and DNA-based ISH methods on CAP HR-HPV proficiency tests. Data from the 2016-2018 CAP HPV ISH proficiency testing surveys were reviewed. These surveys consist of well-characterized samples with known status for HR-HPV, including 1 to 2 copies, 50 to 100 copies, 300 to 500 copies, and no copies of HR-HPV per cell. Ninety-five participants submitted 1268 survey results from 20 cores. Overall, RNA ISH had a significantly higher percentage of correct responses than DNA ISH: 97.4% (450 of 462) versus 80.6% (650 of 806) ( < .001). This disparity appears to be the consequence of a superior sensitivity of RNA ISH compared to DNA ISH for samples with 1 to 2 and with 50 to 100 copies of HR-HPV per cell: 95.2% (120 of 126) versus 53.8% (129 of 240), < .001, respectively, and 100% (89 of 89) versus 76.3% (119 of 156), < .001, respectively. An assessment of CAP HR-HPV proficiency test performance indicates that RNA ISH shows significantly higher accuracy than DNA ISH owing to higher analytical sensitivity of RNA ISH in tumors with low (1-2 copies per cell) to intermediate (50-100 copies per cell) HR-HPV viral copy numbers. These data support the use of RNA over DNA ISH in clinical laboratories that perform HR-HPV testing as part of their testing algorithms.