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Objective: To evaluate head and neck squamous cell carcinomas (SCCAs) for the expression of nerve cell adhesion molecule (N-CAM). We propose that expression of N-CAM by tumor cells may be associated with perineural invasion in SCCA of the head and neck.Methods: Seventy-six archived specimens of histologically proven SCCA were analyzed by immunohistochemistry for the expression of N-CAM. Positive and negative controls were used to assess staining. Two sections of each specimen were reviewed for the presence of perineural invasion. A retrospective chart review was performed for each patient that corresponded to the above specimens.Results: Perineural invasion was present in 28 (37%) of the 76 patients evaluated for the expression of N-CAM. N-CAM expression was demonstrated in 38 (50%) of the 76 specimens. The incidence of N-CAM expression was significantly associated with perineural invasion (P = .002). There was no significant association between the presence of staining or the presence of perineural invasion and the incidence of locoregional recurrence, distant metastasis, or survival status; however, the mean follow-up was only 13.6 months (range, 1-49 mo).Conclusion: There is a positive correlation between the presence of N-CAM expression and perineural invasion in SCCA of the head and neck. The expression of this adhesion molecule by tumor cells may facilitate both homophilic cell-to-cell and heterophilic cell-to-substrate adhesion, thereby enabling the tumor cells to use the perineural tissues or neural cells, or both as a conduit for perineural spread. [ABSTRACT FROM AUTHOR]

Context.—: Sinonasal tract malignancies are rare cancers with frequent morphologic overlap. Given the similar histologic profiles seen in many of these entities, they often present a diagnostic challenge to the practicing pathologist., Objective.—: To provide a streamlined algorithm using histologic clues, immunohistochemical profiles, and molecular assays to aid in diagnosis of these lesions., Data Sources.—: Sources were the World Health Organization Tumor Classification, literature review, and institutional experience., Conclusions.—: Although many sinonasal tract malignancies show similar histology, distinct immunohistochemical and molecular profiles can help parse out differences, thereby facilitating diagnosis for the pathologist., Competing Interests: The authors have no relevant financial interest in the products or companies described in this article., (© 2024 College of American Pathologists.)

Competing Interests: The author has no relevant financial interest in the products or companies described in this article.

Background: Chromosomal rearrangements involving one of the NTRK genes result in oncogenic driver mutations in thyroid carcinoma (TC) and serve as a target for therapy. We compared the clinicopathologic features of thyroid carcinomas with NTRK fusions vs. thyroid neoplasms with other malignancy associated gene fusions within our institution., Materials and Methods: Our pathology archives were searched from 2013 to 2023 for thyroid neoplasms with gene fusions, excluding THADA fusions and medullary thyroid carcinomas., Results: 55 thyroid lesions were identified: 22 with NTRK fusions (NTRK cohort) and 33 with other fusions (non-NTRK cohort). On fine needle aspiration (FNA), 54% of the NTRK cohort were classified as Category V as per Bethesda System for Reporting Thyroid Cytology (TBSRTC) and 51.5% of non-NTRK cohort as TBSRTC Category III. In the NTRK cohort, the most common reported fusion was ETV6::NTRK3 and the most common reported fusion in the non-NTRK cohort was PAX8::PPAR-gamma. On histologic examination both cohorts were most commonly diagnosed as PTC follicular variant. Invasive features were more common in the NTRK cohort in comparison to the non-NTRK cohort. Locoregional recurrence occurred in 2/22 NTRK cases and 2/33 non-NTRK cases, with average time from surgery to recurrence being 5.5 months and 21 months, respectively. The majority of patients in both groups are alive with no evidence of disease., Conclusions: Thyroid neoplasms with a malignancy associated gene fusion are likely to be diagnosed as subtype/variant of PTC. Patients whose thyroid lesions harbor NTRK fusions present with a PTC-FV that on presentation has more aggressive clinicopathologic findings and are likely to have earlier disease recurrence., Competing Interests: Declaration of competing interest The authors of this manuscript have no conflicts of interest to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Recent research suggests that endothelial activation plays a role in coronavirus disease 2019 (COVID-19) pathogenesis by promoting a pro-inflammatory state. However, the mechanism by which the endothelium is activated in COVID-19 remains unclear., Objective: To investigate the mechanism by which COVID-19 activates the pulmonary endothelium and drives pro-inflammatory phenotypes., Hypothesis: The "inflammatory load or burden" (cytokine storm) of the systemic circulation activates endothelial NADPH oxidase 2 (NOX2) which leads to the production of reactive oxygen species (ROS) by the pulmonary endothelium. Endothelial ROS subsequently activates pro-inflammatory pathways., Methods: The inflammatory burden of COVID-19 on the endothelial network, was recreated in vitro, by exposing human pulmonary microvascular endothelial cells (HPMVEC) to media supplemented with serum from COVID-19 affected individuals (sera were acquired from patients with COVID-19 infection that eventually died. Sera was isolated from blood collected at admission to the Intensive Care Unit of the Hospital of the University of Pennsylvania). Endothelial activation, inflammation and cell death were assessed in HPMVEC treated with serum either from patients with COVID-19 or from healthy individuals. Activation was monitored by measuring NOX2 activation (Rac1 translocation) and ROS production; inflammation (or appearance of a pro-inflammatory phenotype) was monitored by measuring the induction of moieties such as intercellular adhesion molecule (ICAM-1), P-selectin and the NLRP3 inflammasome; cell death was measured via SYTOX™ Green assays., Results: Endothelial activation (i.e., NOX2 activation and subsequent ROS production) and cell death were significantly higher in the COVID-19 model than in healthy samples. When HPMVEC were pre-treated with the novel peptide PIP-2, which blocks NOX2 activation (via inhibition of Ca2+-independent phospholipase A2, aiPLA2), significant abrogation of ROS was observed. Endothelial inflammation and cell death were also significantly blunted., Conclusions: The endothelium is activated during COVID-19 via cytokine storm-driven NOX2-ROS activation, which causes a pro-inflammatory phenotype. The concept of endothelial NOX2-ROS production as a unifying pathophysiological axis in COVID-19 raises the possibility of using PIP-2 to maintain vascular health., Competing Interests: A.B.F. is a shareholder in Peroxitech LLC, a company that is developing PIP-2 as a therapeutic agent. O.P., S.C. and A.B.F. have filed a U.S. Provisional Patent Application titled “Protective Agent Against Endothelial Dysfunction”, application No. No. 63/469,255 filed May 26, 2023. No related or modified products are applicable or filed. This patent application does not affect our adherence to PLOS ONE policies on sharing data, data acquisition parameters, and materials., (Copyright: © 2024 Paul et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

An "induced PARP inhibitor (PARPi) sensitivity by epigenetic modulation" strategy is being evaluated in the clinic to sensitize homologous recombination (HR)-proficient tumors to PARPi treatments. To expand its clinical applications and identify more efficient combinations, we performed a drug screen by combining PARPi with 74 well-characterized epigenetic modulators that target five major classes of epigenetic enzymes. Both type I PRMT inhibitor and PRMT5 inhibitor exhibit high combination and clinical priority scores in our screen. PRMT inhibition significantly enhances PARPi treatment-induced DNA damage in HR-proficient ovarian and breast cancer cells. Mechanistically, PRMTs maintain the expression of genes associated with DNA damage repair and BRCAness and regulate intrinsic innate immune pathways in cancer cells. Analyzing large-scale genomic and functional profiles from TCGA and DepMap further confirms that PRMT1, PRMT4, and PRMT5 are potential therapeutic targets in oncology. Finally, PRMT1 and PRMT5 inhibition act synergistically to enhance PARPi sensitivity. Our studies provide a strong rationale for the clinical application of a combination of PRMT and PARP inhibitors in patients with HR-proficient ovarian or breast cancer., Competing Interests: Declaration of interests L.Z. and X.H. report having received research funding from AstraZeneca, Bristol-Myers Squibb/Celgene, and Prelude Therapeutics. Y.Z. is employees of GlaxoSmithKline. O.T. and H.M.C. are employees of AstraZeneca.

There is currently interest regarding CRSsNP patients with refractory symptomatology following functional endoscopic sinus surgery, and which of these patients can derive benefit from low-dose macrolide therapy. In the present study, we analyze a cohort of over fifty CRSsNP patients on macrolide therapy; structured histopathological findings at the time of surgery were analyzed against the success of macrolide treatment. Independently, fibrosis, absence of squamous metaplasia, absence of eosinophilia, presence of neutrophilic infiltrate, and lymphoplasmocytic predominance were all associated with objective success of macrolide treatment; these findings may allow clinicians to more appropriately select patients for this therapy., (© 2024 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Differentiated high-grade thyroid carcinomas (DHGTCs) are a new diagnostic entity most recently defined in the 2022 World Health Organization's (WHO) Classification of Endocrine and Neuroendocrine Tumors. This new entity has been minimally described in the literature, and additional cases classified as such are missing., Materials and Methods: Cases of DHGTCs diagnosed at our institution from 2012 to 2022 were identified, and the following were reviewed: cytologic and histologic diagnoses, ancillary testing, immunohistochemical staining, treatments, and patient outcomes. Immunohistochemical staining for Ki67 was performed on selected cases lacking this immunostain. A systematic literature review of the English literature on DHGTCs from 2013 to 2023 was performed using PubMed and Embase., Results: Case cohort included 32 cases of DHGTCs, with an average age of 52.6 years (range 17-84 years) and a male:female ratio of 1.3:1. All cases underwent fine needle aspiration (FNA) and were categorized by The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) as follows: 14 cases as malignant (43.8 %), 10 as follicular neoplasm (31.3 %), 5 as atypia of undetermined significance (15.6 %), 2 as suspicious for malignancy (6.2 %), and 1 as non-diagnostic (3.1 %). The average tumor size was 5.15 cm, and most were papillary thyroid carcinoma (28, 87.5 %), with classic subtype being the most common. Twenty-one cases revealed tumor necrosis and the mitotic activity in lesions without necrosis averaged to 5.5 mitoses per 2 mm 2 (range 0-7). The average Ki67 proliferative index was 5.6 %. Extrathyroidal extension was seen in 17, angioinvasion in 21, lymphatic invasion in 7, and perineural invasion in 1 case. Foci of solid or trabecular growth were identified in five cases. Lymph node metastases at the time of diagnosis were noted in 10 cases and 7 demonstrated distant metastases or locoregional recurrence. To date, 25 patients are alive, and one has died from disease., Conclusions: Our institutional experience demonstrates that DHGTC is a rare, but aggressive thyroid tumor subtype that requires consideration in the setting of a well-differentiated thyroid neoplasm to appropriately assess for possible disease recurrence and determination of patient prognosis., Competing Interests: Declaration of competing interest The authors of this manuscript have no conflicts of interest to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Current management of patients with noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) is lobectomy with close clinical follow-up. Because this entity is still young, we present our 5-year institutional experience with NIFTP since that time. Cases of NIFTP diagnosed from 2017 to 2022 were identified. Data points including patient demographics, radiology, cytologic and pathologic diagnoses, molecular profiles, and clinical follow-up were documented. A literature review of NIFTP case series was performed. A total of 379 cases were included (mean age: 52 years, female:male ratio 3.3:1). Ultrasound findings were available for 260 patients, and 247 underwent fine-needle aspiration (FNA). The FNA diagnoses per the Bethesda System for Reporting Thyroid Cytology were nondiagnostic (n = 2), benign (n = 16), atypia of undetermined significance/follicular lesion of undetermined significance (n = 119), follicular neoplasm/suspicious for follicular neoplasm (n = 68), suspicious for malignancy (n = 31), and malignant (n = 11). Molecular testing was performed in 179 cases. Lobectomy was performed for 183, total thyroidectomy for 192, and nodulectomy for 4 cases. The average size of NIFTP was 2.3 cm, and 232 cases had additional nodules (including benign and malignant neoplasms). Multifocal NIFTP occurred in 32 patients. Lymph nodes were evaluated in 196 cases with metastatic carcinoma in 29 cases (all with concurrent diagnoses of carcinoma). Most patients were alive at follow-up, 100 were lost to follow-up, and three died from other causes. Literature review revealed 2870 NIFTP cases with similar patient demographics and pathologic findings. We confirm that NIFTP is a low-risk neoplasm with indolent clinical behavior, which can be managed conservatively., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Patient safety education is a mandated Common Program Requirement of the Accreditation Council for Graduate Medical Education and for the Royal College of Physicians and Surgeons of Canada in all medical residency and fellowship programs. Although many hospitals and healthcare environments have general patient safety education tools for trainees, few to none focus on the unique training milieu of pathologists, including a mix of highly automated and manual error-prone processes, frequent multiplicity of events, and lack of direct patient relationships for error disclosure. We established a national Association of Pathology Chairs-Program Directors Section Workgroup focused on patient safety education for pathology trainees entitled Training Residents in Patient Safety (TRIPS). TRIPS included diverse representatives from across the United States, as well as representatives from pathology organizations including the American Board of Pathology, the American Society for Clinical Pathology, the United States and Canadian Academy of Pathology, the College of American Pathologists, and the Society to Improve Diagnosis in Medicine. Objectives of the workgroup included developing a standardized patient safety curriculum, designing teaching and assessment tools, and refining them with pilot sites. Here we report the establishment of TRIPS as well as data from national needs assessment of Program Directors across the country, who confirmed the need for a standardized patient safety curriculum., (© 2023 The Authors.)

Objectives: To provide an institutional experience with cases diagnosed as carcinoma ex pleomorphic adenoma (CXPA), including the cytologic and histologic findings and clinical follow-up, followed by a comparison to the experience documented in the literature., Methods: We identified cases of CXPA diagnosed at our institution from 2011 to 2021 and reviewed the cytologic and histologic diagnoses, as well as the treatment and clinical outcomes. Additionally, a literature review of the English literature was performed on CXPAs from 2011 to 2021., Results: Forty-one cases of CXPA were identified, with the majority subclassified as adenocarcinoma, not otherwise specified. Five tumors underwent cytogenetic studies and five underwent molecular studies. To date, 36 patients are alive, 8 of whom experienced locoregional recurrence or distant metastasis., Conclusions: Our institutional experience was comparable to that reported in the literature. Further studies are required to inquire about the role of molecular profiles of CXPAs in clinical risk assessment., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

While amoebic infection is widely known as a cause of gastroenteritis, keratitis, and meningoencephalitis, amoebae are challenging to recognize at unexpected sites. Despite multiple case reports of sinonasal amoebiasis, amoebic infection is not regularly considered in the differential diagnosis of sinonasal necroinflammatory disease. Here, we aim to characterize the pathologic features of sinonasal amoebiasis to facilitate better recognition. We identified sinonasal amoebiasis in 4 men, median age of 67 years (range: 37 to 71 y). All were immunocompromised, including 2 with chronic lymphocytic leukemia, 1 with human immunodeficiency virus, and 1 with human immunodeficiency virus and kidney transplant. Patients presented with nasal mucosal necrosis or polypoid masses, with facial ulceration in 1 patient and distant dermal nodules in another. Biopsies displayed extensive necrotic debris and inflammation. Although amoebic cysts were abundant in 3 cases, they were mistaken for yeast at frozen section in 1 case; 1 case showed only rare trophozoites that were not recognized on initial biopsy. Periodic acid Schiff and Grocott Methenamine Silver stains highlighted the organisms, and polymerase chain reaction confirmed Acanthamoeba species in 3 cases tested. 2 patients responded well to antiprotozoal medications, but 2 died of disease. Overall, sinonasal amoebiasis presents as a necroinflammatory process in patients immunocompromised for various reasons. Amoebae can mimic other organisms or be incredibly scarce, requiring active consideration to recognize amoebiasis and differentiate it from overlapping conditions like invasive fungal sinusitis, granulomatosis with polyangiitis, and natural killer/T-cell lymphoma. Because sinonasal amoebiasis is highly treatable when diagnosed promptly, pathologists play a critical role in the recognition of this rare necroinflammatory disease., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Although several therapeutics are used to treat coronavirus disease 2019 (COVID-19) patients, there is still no definitive metabolic marker to evaluate disease severity and recovery or a quantitative test to end quarantine. Because severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infects human cells via the angiotensin-converting-enzyme 2 (ACE2) receptor and COVID-19 is associated with renin-angiotensin system dysregulation, we evaluated soluble ACE2 (sACE2) activity in the plasma/saliva of 80 hospitalized COVID-19 patients and 27 non-COVID-19 volunteers, and levels of ACE2/Ang (1-7) in plasma or membrane (mACE2) in lung autopsy samples. sACE2 activity was markedly reduced (p < 0.0001) in COVID-19 plasma (n = 59) compared with controls (n = 27). Nadir sACE2 activity in early hospitalization was restored during disease recovery, irrespective of patient age, demographic variations, or comorbidity; in convalescent plasma-administered patients (n = 45), restoration was statistically higher than matched controls (n = 22, p = 0.0021). ACE2 activity was also substantially reduced in the saliva of COVID-19 patients compared with controls (p = 0.0065). There is a strong inverse correlation between sACE2 concentration and sACE2 activity and Ang (1-7) levels in participant plasmas. However, there were no difference in membrane ACE2 levels in lungs of autopsy tissues of COVID-19 (n = 800) versus other conditions (n = 300). These clinical observations suggest sACE2 activity as a potential biomarker and therapeutic target for COVID-19., Competing Interests: Authors declare no competing interests., (© 2022 The Authors.)

Objectives: Increasing use of transoral robotic surgery (TORS) is likely to impact outcomes for HPV+ oropharyngeal squamous cell carcinomas (OPSCCs). We aimed to describe oncologic outcomes for a large HPV+ OPSCC cohort after TORS and develop a risk prediction model for recurrence under this treatment paradigm., Materials and Methods: 634 HPV+ OPSCC patients receiving TORS-based therapy at a single institution were reviewed retrospectively to describe survival across the entire cohort and for patients suffering recurrence. Risks for distant metastatic recurrence (DMR) and locoregional recurrence (LRR) were modeled using multivariate logistic regression analyses of case-control sub-cohorts., Results: 5-year overall and recurrence-free survival were 91.2% and 86.1%, respectively. 5-year overall survival was 52.5% following DMR and 83.3% after isolated LRR (P = .01). In case-control analyses, positive surgical margins were associated with DMR (adjusted OR 5.8, CI 2.1-16.0, P = .001), but not isolated LRR, and increased DMR risk 4.2 fold in patients with early clinical stage disease. By contrast, LRR was associated with not receiving recommended adjuvant therapy (OR 13.4, CI 6.3-28.5, P < .001)., Conclusions: This study sets a benchmark for oncologic outcomes from HPV+ OPSCC after TORS-based therapy. Under this treatment paradigm, margins are relevant for assessing lethal recurrence risk during clinical trial design and post-treatment surveillance., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

By combining 6 druggable genome resources, we identify 6,083 genes as potential druggable genes (PDGs). We characterize their expression, recurrent genomic alterations, cancer dependencies, and therapeutic potentials by integrating genome, functionome, and druggome profiles across cancers. 81.5% of PDGs are reliably expressed in major adult cancers, 46.9% show selective expression patterns, and 39.1% exhibit at least one recurrent genomic alteration. We annotate a total of 784 PDGs as dependent genes for cancer cell growth. We further quantify 16 cancer-related features and estimate a PDG cancer drug target score (PCDT score). PDGs with higher PCDT scores are significantly enriched for genes encoding kinases and histone modification enzymes. Importantly, we find that a considerable portion of high PCDT score PDGs are understudied genes, providing unexplored opportunities for drug development in oncology. By integrating the druggable genome and the cancer genome, our study thus generates a comprehensive blueprint of potential druggable genes across cancers., Competing Interests: Declaration of interests L.Z. and X.H. report having received research funding from AstraZeneca, Bristol-Myers Squibb/Celgene, and Prelude Therapeutics. O.T. and H.M.C. are employees of AstraZeneca. R.H.V. is an inventor on a licensed patent relating to cancer cellular immunotherapy and receives royalties from Children's Hospital Boston for a licensed research-only monoclonal antibody., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Persistent human papillomavirus (HPV) infection of stratified squamous epithelial cells causes nearly 5% of cancer cases worldwide. HPV-positive oropharyngeal cancers harbor few mutations in the Hippo signaling pathway compared to HPV-negative cancers at the same anatomical site, prompting the hypothesis that an HPV-encoded protein inactivates the Hippo pathway and activates the Hippo effector yes-associated protein (YAP1). The HPV E7 oncoprotein is required for HPV infection and for HPV-mediated oncogenic transformation. We investigated the effects of HPV oncoproteins on YAP1 and found that E7 activates YAP1, promoting YAP1 nuclear localization in basal epithelial cells. YAP1 activation by HPV E7 required that E7 binds and degrades the tumor suppressor protein tyrosine phosphatase non-receptor type 14 (PTPN14). E7 required YAP1 transcriptional activity to extend the lifespan of primary keratinocytes, indicating that YAP1 activation contributes to E7 carcinogenic activity. Maintaining infection in basal cells is critical for HPV persistence, and here we demonstrate that YAP1 activation causes HPV E7 expressing cells to be retained in the basal compartment of stratified epithelia. We propose that YAP1 activation resulting from PTPN14 inactivation is an essential, targetable activity of the HPV E7 oncoprotein relevant to HPV infection and carcinogenesis., Competing Interests: JH, PC, HK, SS, KM, DB, EW No competing interests declared, (© 2022, Hatterschide et al.)

The nuclear receptor (NR) superfamily is one of the major druggable gene families, representing targets of approximately 13.5% of approved drugs. Certain NRs, such as estrogen receptor and androgen receptor, have been well demonstrated to be functionally involved in cancer and serve as informative biomarkers and therapeutic targets in oncology. However, the spectrum of NR dysregulation across cancers remains to be comprehensively characterized. Through computational integration of genetic, genomic, and pharmacologic profiles, we characterized the expression, recurrent genomic alterations, and cancer dependency of NRs at a large scale across primary tumor specimens and cancer cell lines. Expression levels of NRs were highly cancer-type specific and globally downregulated in tumors compared with corresponding normal tissue. Although the majority of NRs showed copy-number losses in cancer, both recurrent focal gains and losses were identified in select NRs. Recurrent mutations and transcript fusions of NRs were observed in a small portion of cancers, serving as actionable genomic alterations. Analysis of large-scale CRISPR and RNAi screening datasets identified 10 NRs as strongly selective essential genes for cancer cell growth. In a subpopulation of tumor cells, growth dependencies correlated significantly with expression or genomic alterations. Overall, our comprehensive characterization of NRs across cancers may facilitate the identification and prioritization of potential biomarkers and therapeutic targets, as well as the selection of patients for precision cancer treatment. SIGNIFICANCE: Computational analysis of nuclear receptors across multiple cancer types provides a series of biomarkers and therapeutic targets within this protein family., (©2021 American Association for Cancer Research.)

The mechanisms regulating exhaustion of tumor-infiltrating lymphocytes (TIL) and responsiveness to PD-1 blockade remain partly unknown. In human ovarian cancer, we show that tumor-specific CD8 + TIL accumulate in tumor islets, where they engage antigen and upregulate PD-1, which restrains their functions. Intraepithelial PD-1 + CD8 + TIL can be, however, polyfunctional. PD-1 + TIL indeed exhibit a continuum of exhaustion states, with variable levels of CD28 costimulation, which is provided by antigen-presenting cells (APC) in intraepithelial tumor myeloid niches. CD28 costimulation is associated with improved effector fitness of exhausted CD8 + TIL and is required for their activation upon PD-1 blockade, which also requires tumor myeloid APC. Exhausted TIL lacking proper CD28 costimulation in situ fail to respond to PD-1 blockade, and their response may be rescued by local CTLA-4 blockade and tumor APC stimulation via CD40L., Competing Interests: Declaration of interests G.C. has received grants from Celgene, Boehringer-Ingelheim, BMS, and Tigen, and participated in advisory board or presented at Roche, MSD Merck, BMS, AstraZeneca, and Geneos Tx-sponsored symposia (fees received by G.C.’s institution). G.C. has patents in the domain of antibodies, vaccines, T cell expansion, and engineering technologies, and receives royalties from UPenn. P.K.S. is a member of the SAB or Board of Directors of Applied Biomath, Glencoe Software, RareCyte Inc., and has equities in these companies; he is a member of the SAB of NanoString Inc. and a consultant for Merck and Montai Health. P.K.S. has received research funding from Novartis and Merck. D.J.P. receives research funding from Incyte and serves as an adviser, receives fees, stock options, and research funding from InsTIL Bio. R.G. holds a patent for TCR sequencing. J.D. is presently a US FDA employee. R.T., C.N., V.A., and M.A.D. are current employees of Ichnos Sciences Biotherapeutics SA. None of the above declared relationships has influenced the content of this manuscript. The other authors declare no competing financial interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Cell-surface proteins (SPs) are a rich source of immune and targeted therapies. By systematically integrating single-cell and bulk genomics, functional studies and target actionability, in the present study we comprehensively identify and annotate genes encoding SPs (GESPs) pan-cancer. We characterize GESP expression patterns, recurrent genomic alterations, essentiality, receptor-ligand interactions and therapeutic potential. We also find that mRNA expression of GESPs is cancer-type specific and positively correlates with protein expression, and that certain GESP subgroups function as common or specific essential genes for tumor cell growth. We also predict receptor-ligand interactions substantially deregulated in cancer and, using systems biology approaches, we identify cancer-specific GESPs with therapeutic potential. We have made this resource available through the Cancer Surfaceome Atlas ( http://fcgportal.org/TCSA ) within the Functional Cancer Genome data portal., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Infection by SARS-CoV-2 produces significant pulmonary pathology including endothelial damage with resultant thrombotic events. While pathologic features were described, there are limited data on the relationship of these changes to the inflammatory response and the production of thromboses., Objective: To investigate pathology of COVID-19-related immunothrombosis., Patients/methods: Tissue samples from lung, kidney, brain and heart that were collected from 45 patients who died of COVID-19. Histopathological examination was performed after H&E and Picro-Mallory staining in combination with (immuno)fluorescence to visualize neutrophil extracellular traps. Ultrastructural alterations in lungs were studied with scanning and transmission electron microscopy., Results: Inflammatory changes and thrombosis were substantially more pronounced in the lung than in the kidney, heart, and brain. The most common pathologic finding was diffuse alveolar damage. In addition, most lung samples showed thrombi in vessels. The cause of death in single cases was massive pulmonary embolism. Ultrastructural examination revealed neutrophils attached to endothelium, perhaps as a step towards transendothelial migration. In addition, platelets were identified in the midst of fibrin as individual procoagulant balloon-like cells. Ultrastructural examination demonstrated numerous virion-like particles., Conclusions: Studying (ultra)structural features of the autopsy lung samples from patients with COVID-19 has provided evidence for a pathogenic link between inflammation and thrombosis. The major features in the lungs of COVID-19 patients comprised primary inflammatory thrombosis associated with diffuse alveolar damage. The lungs had pronounced circulatory changes with inflammation-dependent intravascular blood clotting, whereas heart, brain, and kidneys had predominantly degenerative changes that were distinct from the lung pathology., (© 2021 International Society on Thrombosis and Haemostasis.)

The inflammatory response to SARS/CoV-2 (COVID-19) infection may contribute to the risk of thromboembolic complications. α-Defensins, antimicrobial peptides released from activated neutrophils, are anti-fibrinolytic and prothrombotic in vitro and in mouse models. In this prospective study of 176 patients with COVID-19 infection, we found that plasma levels of α-defensins were elevated, tracked with disease progression/mortality or resolution and with plasma levels of interleukin-6 (IL-6) and D-dimers. Immunohistochemistry revealed intense deposition of α-defensins in lung vasculature and thrombi. IL-6 stimulated the release of α-defensins from neutrophils, thereby accelerating coagulation and inhibiting fibrinolysis in human blood, imitating the coagulation pattern in COVID-19 patients. The procoagulant effect of IL-6 was inhibited by colchicine, which blocks neutrophil degranulation. These studies describe a link between inflammation and the risk of thromboembolism, and they identify a potential new approach to mitigate this risk in patients with COVID-19 and potentially in other inflammatory prothrombotic conditions., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

Background: High-grade transformation (HGT) is a rare process whereby conventional low- to intermediate-grade salivary gland carcinomas (SGC) transform into high-grade, poorly or undifferentiated malignancies with focal or complete loss of their conventional histomorphologic features. Because tumors with HGT are associated with a worse prognosis than their conventional counterparts, preoperative recognition of HGT may be of benefit for optimal patient management. Using a multi-institutional approach, we describe the largest fine needle aspiration (FNA) cohort of salivary gland carcinomas with HGT., Methods: The archives of 9 large academic medical centers were searched, and 22 cases of SGC with HGT were identified by surgical excision accompanied by preoperative FNA. Clinical and cytomorphologic features were retrospectively reviewed., Results: The male-to-female ratio was 14:8, and the mean patient age was 60.2 years. The average tumor size was 3.6 cm, and 19 cases were from the parotid gland. Acinic cell carcinoma with HGT was the most common tumor subtype, comprising 12 cases with HGT, followed by adenoid cystic carcinoma, secretory carcinoma, and other subtypes. Eighteen cases were classified as malignant; however, a specific diagnosis of HGT was not made. Sixteen cases contained a high-grade cytologic component, and 7 cases had a mixture of both conventional and high-grade components retrospectively., Conclusions: SGC with HGT should be considered in the differential diagnosis of a salivary gland aspirate exhibiting high-grade cytomorphologic features. The presence of distinct tumor populations, conventional and high-grade, should prompt consideration of HGT, especially when the conventional component is acinic cell carcinoma or adenoid cystic carcinoma., (© 2020 American Cancer Society.)

The widespread coronavirus disease 2019 (COVID-19) is caused by infection with the novel coronavirus SARS-CoV-2. Currently, we have limited understanding of which cells become infected with SARS-CoV-2 in human tissues and where viral RNA localizes on the subcellular level. Here, we present a platform for preparing autopsy tissue for visualizing SARS-CoV-2 RNA using RNA fluorescence in situ hybridization (FISH) with amplification by hybridization chain reaction. We developed probe sets that target different regions of SARS-CoV-2 (including ORF1a and N), as well as probe sets that specifically target SARS-CoV-2 subgenomic mRNAs. We validated these probe sets in cell culture and tissues (lung, lymph node, and placenta) from infected patients. Using this technology, we observe distinct subcellular localization patterns of the ORF1a and N regions. In human lung tissue, we performed multiplexed RNA FISH HCR for SARS-CoV-2 and cell-type-specific marker genes. We found viral RNA in cells containing the alveolar type 2 (AT2) cell marker gene ( SFTPC ) and the alveolar macrophage marker gene ( MARCO ) but did not identify viral RNA in cells containing the alveolar type 1 (AT1) cell marker gene ( AGER ). Moreover, we observed distinct subcellular localization patterns of viral RNA in AT2 cells and alveolar macrophages. In sum, we demonstrate the use of RNA FISH HCR for visualizing different RNA species from SARS-CoV-2 in cell lines and FFPE (formalin fixation and paraffin embedding) autopsy specimens. We anticipate that this platform could be broadly useful for studying SARS-CoV-2 pathology in tissues, as well as extended for other applications, including investigating the viral life cycle, viral diagnostics, and drug screening. IMPORTANCE Here, we developed an in situ RNA detection assay for RNA generated by the SARS-CoV-2 virus. We found viral RNA in lung, lymph node, and placenta samples from pathology specimens from COVID patients. Using high-magnification microscopy, we can visualize the subcellular distribution of these RNA in single cells.

Therapeutic innovation for human papilloma virus-related (HPV+) head and neck squamous cell carcinomas (HNSCCs) is impaired by inadequate preclinical models and the absence of accurate biomarkers. Our study establishes the first well-characterized panel of patient-derived xenografts (PDXs) and organoids from HPV+ HNSCCs while determining fidelity of the models to the distinguishing genetic features of this cancer type. Despite low engraftment rates, whole exome sequencing showed that PDXs retain multiple distinguishing features of HPV+ HNSCC lost in existing cell lines, including PIK3CA mutations, TRAF3 deletion and the absence of EGFR amplifications. Engrafted HPV+ tumors frequently contained NOTCH1 mutations, thus providing new models for a negatively prognostic alteration in this disease. Genotype-phenotype associations in the models were then tested for prediction of tumor progression and survival in published clinical cohorts. Observation of high tumor mutational burdens (TMBs) in the faster-growing models facilitated identification of a novel association between TMB and local progression in both HPV+ and HPV- patients that was prognostic in HPV- cases. In addition, reduced E7 and p16 INK4A levels found in a PDX from an outlier case with lethal outcome led to detection of similar profiles among recurrent HPV+ HNSCCs. Transcriptional data from the Cancer Genome Atlas was used to demonstrate that the lower E2F target gene expression predicted by reduced E7 levels has potential as a biomarker of disease recurrence risk. Our findings bridge a critical gap in preclinical models for HPV+ HNSCCs and simultaneously reveal novel potential applications of quantifying mutational burden and viral oncogene functions for biomarker development., (© 2020 UICC.)

The use of social media at academic conferences is expanding, and platforms such as Twitter are used to share meeting content with the world. Pathology conferences are no exception, and recently, pathology organizations have promoted social media as a way to enhance meeting exposure. A social media committee was formed ad hoc to implement strategies to enhance social media involvement and coverage at the 2018 and 2019 annual meetings of the Association of Pathology Chairs. This organized approach resulted in an 11-fold increase in social media engagement compared to the year prior to committee formation (2017). In this article, the social media committee reviews the strategies that were employed and the resultant outcome data. In addition, we categorize tweets by topic to identify the topics of greatest interest to meeting participants, and we discuss the differences between Twitter and other social media platforms. Lastly, we review the existing literature on this topic from 23 medical specialties and health care fields., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Recurrent copy-number alterations, mutations, and transcript fusions of the genes encoding CDKs/cyclins are characterized in >10,000 tumors. Genomic alterations of CDKs/cyclins are dominantly driven by copy number aberrations. In contrast to cell-cycle-related CDKs/cyclins, which are globally amplified, transcriptional CDKs/cyclins recurrently lose copy numbers across cancers. Although mutations and transcript fusions are relatively rare events, CDK12 exhibits recurrent mutations in multiple cancers. Among the transcriptional CDKs, CDK7 and CDK12 show the most significant copy number loss and mutation, respectively. Their genomic alterations are correlated with increased sensitivities to DNA-damaging drugs. Inhibition of CDK7 preferentially represses the expression of genes in the DNA-damage-repair pathways and impairs the activity of homologous recombination. Low-dose CDK7 inhibitor treatment sensitizes cancer cells to PARP inhibitor-induced DNA damage and cell death. Our analysis provides genomic information for identification and prioritization of drug targets for CDKs and reveals rationales for treatment strategies., Competing Interests: Declaration of Interests Drs. Lin Zhang, Xiaowen Hu, and Youyou Zhang report having received research funding from Bristol-Myers Squibb/Celgene and Prelude Therapeutics., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

The recently adopted terminology of "Noninvasive follicular thyroid neoplasm with papillary-like nuclear features" (NIFTP) reflects the indolent behavior of these tumors. In contrast to conventional papillary thyroid carcinomas, NIFTP can be managed conservatively. The purpose of this study was to investigate changes in surgical and pathologic practice patterns at our institution since the introduction of the NIFTP diagnosis in 2016. A retrospective analysis of all thyroid specimens received in our laboratory between January 2015 and April 2017 was performed. The final cohort consisted of 1508 thyroidectomy specimens from 1508 patients (1153 (76.5%) women and 355 (23.5%) men), of which 1011 (67%) were total thyroidectomies and 497 (33%) were partial thyroidectomies. There were 558 (69.2%) total thyroidectomies and 248 (30.8%) partial thyroidectomies performed prior to introduction of the NIFTP diagnosis and 453 (64.5%) and 249 (35.5%) total and partial thyroidectomies, respectively, after the change in nomenclature. Within a year following the initial use of this diagnosis, 67 NIFTP cases were identified (9.5% of all thyroidectomies), whereas compared with the year preceding it, malignant diagnoses decreased from 54.5 (439) to 44.6% (313), and the benign category remained unchanged from 44.5 (367) to 45.9% (322). For the entirely submitted 67 NIFTP cases, the mean number of blocks submitted was 14.7 (0.98 blocks/g); for malignant lesions 17.7 (0.92 blocks/g); and for benign lesions 16.6 (0.75 blocks/g). The results of our study suggest that NIFTP are encountered in almost 10% of thyroidectomies at our institution with expected shifts in cytology and surgical pathology diagnoses as a result of the change in nomenclature. During this time period, significant shifts towards less aggressive surgical management were not observed. All 67 NIFTP nodules were submitted entirely with no significant difference in the number of cassettes submitted for NIFTP nodules as compared with follicular variant papillary thyroid carcinoma (PTC), classic variant PTC, or follicular adenoma.

Mucoepidermoid carcinoma (MEC) is the most common malignant salivary gland tumor. Differences inprognosis can be noted owing to the tumor grade determined using multiple grading schemes (2-tier: low- and high-grade vs. 3-tier: low-, intermediate-, and high-grade). We studied clinicopathologic features of MEC using a 3-tier grading system and retrospectively categorized cytologic diagnoses as per the Milan System for Reporting Salivary Gland Cytopathology (MSRSGC).A total of 69 cases of MEC were identified, and most were seen in the parotid gland. Aggressive clinical behavior was seen in high-grade MEC compared with intermediate- and low-grade MEC. By fluorescence in situ hybridization (FISH) analysis, MAML2 rearrangements were seen in 78% of cases.The MSRSGC subcategorized the majority (63.8%) of MEC as salivary gland neoplasm of uncertain malignant potential, suspicious for malignancy, or malignant. Clustering intermediate- with low-grade cases did not significantly impact the clinical behavior. Both high-grade and oncocytic MEC can be MAML2 FISH negative., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: In patients with head and neck carcinoma of unknown primary (HNCUP;pT0) following TORS-assisted workup, we have adopted a pharyngeal-sparing radiation therapy (PSRT) approach targeting only the at-risk neck and omitting treatment of the pharynx. We report outcomes following PSRT, and compare to institutional historical control subjects who received pharyngeal-targeted RT (PRT)., Methods: Between 2009 and 2018, 172 patients underwent TORS-assisted endoscopy as part of their workup for HNCUP. Following TORS, 54 patients had pT0 disease, of which 45 received RT. Forty-nine percent received PSRT and 51% received PRT., Results: No statistically significant differences existed between the PSRT and PRT groups with respect to overall nodal distribution, p16 positivity (55% vs. 43%, P = .12), neck dissection rates (77% vs. 65%, P = .51), and administration of chemotherapy (55% vs. 65%, P = .55). Median follow-up for PSRT and PRT groups were 24 and 28 months, respectively (P = .04). Two-year RFS was 86% and 74% for PSRT and PRT patients, respectively (log-rank P = .30). Three and six patients recurred after PSRT and PRT, respectively. Two-year OS for PSRT and PRT patients was 91% and 74%, respectively (log-rank P = .31). Compared to PRT, PSRT was associated with statistically significantly less: grade 2+ mucositis (18% vs. 91%, P < .01), new opioid requirement (27% vs. 91%, P < .01), mean weight loss during RT (6.2 lbs vs. 17.4 lbs, P < .01), feeding tube placement during RT (5% vs. 43%, P < .01), and treatment-related unplanned hospitalizations (9% vs. 39%, P = .04)., Conclusion: Following TORS-assisted management of patients with pT0 HNCUP, we observed reduced toxicity following PSRT compared to PRT without apparent compromise of disease cure., Level of Evidence: Level 3 evidence, retrospective review comparing cases and controls Laryngoscope, 130:691-697, 2020., (© 2019 The American Laryngological, Rhinological and Otological Society, Inc.)

Men of predominantly African Ancestry (AA) have higher prostate cancer (CaP) incidence and worse survival than men of predominantly European Ancestry (EA). While socioeconomic factors drive this disparity, genomic factors may also contribute to differences in the incidence and mortality rates. To compare the prevalence of prostate tumor genomic alterations and transcriptomic profiles by patient genetic ancestry, we evaluated genomic profiles from The Cancer Genome Atlas (TCGA) CaP cohort (n = 498). Patient global and local genetic ancestry were estimated by computational algorithms using genotyping data; 414 (83.1%) were EA, 61 (12.2%) were AA, 11 (2.2%) were East Asian Ancestry (EAA), 10 (2.0%) were Native American (NA), and 2 (0.4%) were other ancestry. Genetic ancestry was highly concordant with self-identified race/ethnicity. Subsequent analyses were limited to 61 AA and 414 EA cases. Significant differences were observed by ancestry in the frequency of SPOP mutations (20.3% AA vs. 10.0% EA; p = 5.6×10-03), TMPRSS2-ERG fusions (29.3% AA vs. 39.6% EA; p = 4.4×10-02), and PTEN deletions/losses (11.5% AA vs. 30.2% EA; p = 3.5×10-03). Differentially expressed genes (DEGs) between AAs and EAs showed significant enrichment for prostate eQTL target genes (p = 8.09×10-48). Enrichment of highly expressed DEGs for immune-related pathways was observed in AAs, and for PTEN/PI3K signaling in EAs. Nearly one-third of DEGs (31.3%) were long non-coding RNAs (DE-lncRNAs). The proportion of DE-lncRNAs with higher expression in AAs greatly exceeded that with lower expression in AAs (p = 1.2×10-125). Both ChIP-seq and RNA-seq data suggested a stronger regulatory role for AR signaling pathways in DE-lncRNAs vs. non-DE-lncRNAs. CaP-related oncogenic lncRNAs, such as PVT1, PCAT1 and PCAT10/CTBP1-AS, were found to be more highly expressed in AAs. We report substantial heterogeneity in the prostate tumor genome and transcriptome between EA and AA. These differences may be biological contributors to racial disparities in CaP incidence and outcomes., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: Drs. Lin Zhang and Xiaowen Hu received research grant from Bristol-Myers Squibb/Celgene. The other authors declare no potential conflicts of interest.

Fine needle aspiration samples and small biopsies provide a minimally invasive diagnostic modality for mass lesions. When an infectious process is suspected based on initial evaluation, ancillary techniques can assist in making a specific diagnosis. Here we review the cytopathology that should prompt additional testing and review the availability and interpretation of special stains, immunohistochemistry, and in situ hybridization. In addition, this review addresses when special cultures may be necessary and the use of newer molecular techniques for pathogen identification., (© 2019 S. Karger AG, Basel.)

We investigated the role of chemokines in regulating T cell accumulation in solid tumors. CCL5 and CXCL9 overexpression was associated with CD8 + T cell infiltration in solid tumors. T cell infiltration required tumor cell-derived CCL5 and was amplified by IFN-γ-inducible, myeloid cell-secreted CXCL9. CCL5 and CXCL9 coexpression revealed immunoreactive tumors with prolonged survival and response to checkpoint blockade. Loss of CCL5 expression in human tumors was associated with epigenetic silencing through DNA methylation. Reduction of CCL5 expression caused tumor-infiltrating lymphocyte (TIL) desertification, whereas forced CCL5 expression prevented Cxcl9 expression and TILs loss, and attenuated tumor growth in mice through IFN-γ. The cooperation between tumor-derived CCL5 and IFN-γ-inducible CXCR3 ligands secreted by myeloid cells is key for orchestrating T cell infiltration in immunoreactive and immunoresponsive tumors., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The increasing complexity of the practice of pathology and health care in general requires that pathology residents acquire a vast number of skills during their training. This has been reflected by the broad range of skills addressed in the Accreditation Council for Graduate Medical Education (ACGME) milestones. In order to address some of these milestones, our residency program instituted an introductory didactic series in surgical pathology that focused on 2 objectives. First, the didactics provided basic grossing and histology training to first year residents transitioning from medical school. Second, the sessions allowed upper level residents to refine their teaching and communication skills at the microscope and therefore served as an important career development tool. Surveys of both first year residents and the upper level residents that led these sessions confirm the utility of these didactics and the use of upper level residents to teach junior trainees. In addition, these sessions led to a dramatic increase in RISE scores among first year trainees. An introductory series with upper level residents leading slide sessions could easily be replicated at other institutions and provide similar benefits.

A growing emphasis in anticancer drug discovery efforts has been on targeting histone acetylation modulators. Here we comprehensively analyze the genomic alterations of the genes encoding histone acetylation modulator proteins (HAMPs) in the Cancer Genome Atlas cohort and observe that HAMPs have a high frequency of focal copy number alterations and recurrent mutations, whereas transcript fusions of HAMPs are relatively rare genomic events in common adult cancers. Collectively, 86.3% (63/73) of HAMPs have recurrent alterations in at least 1 cancer type and 16 HAMPs, including 9 understudied HAMPs, are identified as putative therapeutic targets across multiple cancer types. For example, the recurrent focal amplification of BRD9 is observed in 9 cancer types and genetic depletion of BRD9 inhibits tumor growth. Our systematic genomic analysis of HAMPs across a large-scale cancer specimen cohort may facilitate the identification and prioritization of potential drug targets and selection of suitable patients for precision treatment.

Objective: To perform a retrospective investigation of our institutional experience with salivary gland fine needle aspirations (FNA) through the framework of The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) and assess the risks of neoplasm and malignancy for each diagnostic category., Methods: All salivary gland FNAs performed from January 2009 to December 2016 were retrospectively categorised according to the MSRSGC. When available, pre-operative cytological results were correlated with subsequent histological follow-up., Results: In total, 893 FNAs were reviewed. The specimens were retrospectively classified as nondiagnostic (ND: 13.5%), non-neoplastic (NN: 16.1%), atypia of undetermined significance (AUS: 10.8%), benign neoplasm (BN: 34.9%), salivary gland neoplasm of uncertain malignant potential (SUMP: 8.2%), suspicious for malignancy (SM: 2.7%) and malignant (M: 13.8%). Histological follow-up was available for 429 cases (48%); the majority (68.1%) were benign. The risks of neoplasm and malignancy for each category were as follows: ND: 64.5%, 16.1%; NN: 42.9%, 17.9%; AUS: 79.6%, 30.6%; BN: 100%, 2.2%; SUMP: 100%, 46.6%; SM: 94.7%, 78.9%; and M: 100%, 98.5%., Conclusions: The MSRSGC is a useful classification scheme for stratifying salivary gland lesions according to their associated risk of malignancy and guiding clinicians toward appropriate management. Diagnostic pitfalls are seen in a small proportion of cases and a multidisciplinary approach for assessing salivary gland pathology is essential in their evaluation., (© 2018 John Wiley & Sons Ltd.)

Disparities in cancer care have been a long-standing challenge. We estimated the genetic ancestry of The Cancer Genome Atlas patients, and performed a pan-cancer analysis on the influence of genetic ancestry on genomic alterations. Compared with European Americans, African Americans (AA) with breast, head and neck, and endometrial cancers exhibit a higher level of chromosomal instability, while a lower level of chromosomal instability was observed in AAs with kidney cancers. The frequencies of TP53 mutations and amplification of CCNE1 were increased in AAs in the cancer types showing higher levels of chromosomal instability. We observed lower frequencies of genomic alterations affecting genes in the PI3K pathway in AA patients across cancers. Our result provides insight into genomic contribution to cancer disparities., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives/hypothesis: Delineate factors impacting the creation and use of patient-derived xenografts (PDXs) of human papilloma virus-related (HPV+) head and neck squamous cell carcinomas (HNSCCs)., Study Design: Laboratory-based translational study., Methods: Fifty-one surgically resected HNSCCs, including 31 HPV + cancers, were implanted into NOD/SCID/IL-2Rγ -/- (NSG) mice using standardized methodology. Clinical and pathologic factors were tested for association with engraftment. The gross, histologic, and molecular features of established HPV + PDXs were analyzed in comparison to their tumors of origin., Results: Negative HPV status and perineural invasion (PNI) were independent, additive factors associated with increased PDX formation. Epstein-Barr virus-positive (EBV+) human large B-cell lymphomas grew from 32% of HPV + HNSCC cases that failed to engraft. Successfully established HPV + PDXs retained basaloid histology and often developed cystic growth patterns typical of HPV + nodal metastases. They also maintained elevated p16 INK4A levels and expression of E6/E7 viral oncogene transcripts., Conclusion: Reduced engraftment by HPV + tumors lacking PNI likely results in selection biases in HNSCC PDX models. Formation of EBV + lymphomas in NSG mice further reduces the generation of HPV + models and must be ruled out before long-term use of PDXs. Nevertheless, the retention of distinctive pathologic traits and viral oncogene expression by HPV + PDXs provides a viable in vivo platform for basic and translational studies as well as a resource for generating advanced in vitro models., Level of Evidence: NA. Laryngoscope, 127:2777-2783, 2017., (© 2017 The American Laryngological, Rhinological and Otological Society, Inc.)

Changes in the field of pathology and resident education necessitate ongoing evaluation of residency training. Evolutionary change is particularly important for surgical pathology rotations, which form the core of anatomic pathology training programs. In the past, we organized this rotation based on subjective insight. When faced with the recent need to restructure the rotation, we strove for a more evidence-based process. Our approach involved 2 primary sources of data. We quantified the number of cases and blocks submitted per case type to estimate workload and surveyed residents about the time required to gross specimens in all organ systems. A multidisciplinary committee including faculty, residents, and staff evaluated the results and used the data to model how various changes to the rotation would affect resident workload, turnaround time, and other variables. Finally, we identified rotation structures that equally distributed work and created a point-based system that capped grossing time for residents of different experience. Following implementation, we retrospectively compared turnaround time and duty hour violations before and after these changes and surveyed residents about their experiences with both systems. We evaluated the accuracy of the point-based system by examining grossing times and comparing them to the assigned point values. We found overall improvement in the rotation following the implementation. As there is essentially no literature on the subject of surgical pathology rotation organization, we hope that our experience will provide a road map to improve pathology resident education at other institutions., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Currently, there is no uniform classification scheme available for reporting of salivary gland fine-needle aspiration (FNA) specimens. Recently, an International group of pathologists has recommended a tiered classification scheme for reporting of salivary gland FNA results known as the "Milan System for Reporting Salivary Gland Cytopathology (MSRSGC)." We performed a comprehensive review of the published literature on FNA of salivary gland lesions by employing the diagnostic categories of the MSRSGC to evaluate their reliability in the management of salivary gland lesions. A comprehensive review of the literature was carried out through PubMed from 1987 to 2015 to identify studies which categorized the cytologic diagnoses and included surgical follow-up. Only cases with histopathologic follow-up were included in the analysis. Twenty-nine studies comprising 4514 cases of salivary gland FNAs with surgical follow-up were included in this study. The cytologic diagnoses were categorized into the following categories proposed by MSRSGC. The number of cases in each diagnostic category and the risk of malignancy (ROM) were as follows: Non-Diagnostic-100 cases (ROM- 25.0% ± 16.7%), Non-Neoplastic-587 cases (ROM: 10.2% ± 5.5%), Benign Neoplasm -2673 cases (ROM: 3.4% ± 1.3%), Salivary Gland Neoplasm of Undetermined Malignant Potential (SUMP)-64 cases(ROM: 37.5% ± 24.7%), Suspicious for Malignant neoplasm-70 cases(ROM: 58.6% ± 19.5%), and Malignant-1012 cases(ROM: 91.9% ± 3.5%). A tiered classification scheme as proposed by MSRSGC may prove helpful in effectively guiding clinical management of patients with salivary gland lesions., (© 2017 Wiley Periodicals, Inc.)

The sinonasal tract is frequently affected by nonneoplastic inflammatory diseases. Inflammatory lesions of the sinonasal tract can be divided into 3 main categories: chronic rhinosinusitis, which encompasses a heterogeneous group of entities, all of which result in mucosal inflammation with or without polyps-eosinophils; infectious diseases; and autoimmune diseases and vasculitides, which can result in midline necrosis and facial deformities. This article reviews the common inflammatory lesions of the sinonasal tract with emphasis on infectious diseases, vasculitis, iatrogenic, and diseases of unknown cause. Many of these lesions can result in midline destruction and result in facial deformity., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Importance: Management of cervical lymph node metastasis without a known primary tumor is a diagnostic and treatment challenge for head and neck oncologists. Identification of the occult mucosal primary tumor minimizes the morbidity of treatment., Objective: To analyze the role of transoral robotic surgery (TORS) in facilitating the identification of a primary tumor site for patients presenting with squamous cell carcinoma of unknown primary (CUP). In addition, we assessed treatment deintensification by determining the number of patients who did not undergo definitive radiation therapy and chemotherapy., Design, Setting, and Participants: In this retrospective case series from January 2011 to September 2015, 60 consecutive patients with squamous cell CUP who underwent TORS-assisted endoscopy and ipsilateral neck dissection were included from an academic medical center and studied to study the rate success rate of TORS identifying occult mucosal malignancy., Main Outcomes and Measures: Success rate of identifying occult mucosal malignancy; usage of radiation therapy and chemotherapy., Results: Overall, 60 patients (mean [SD] age, 55.5 [8.9] years) were identified; 48 of the 60 patients (80.0%) had a mucosal primary identified during their TORS-assisted endoscopic procedure. The mean (SD) size of the identified mucosal primary lesions was 1.3 (0.1) cm. All mucosal primaries, when found, originated in the oropharynx including the base of tongue in 28 patients (58%), palatine tonsil in 18 patients (38%), and glossotonsillar sulcus in 2 patients (4%). Among patients in this study, 40 (67%) did not receive chemotherapy, and 15 (25%) did not receive radiation therapy., Conclusions and Relevance: Advances in transoral surgical techniques have helped identify occult oropharyngeal malignancies that traditionally have been treated with comprehensive radiation to the entire pharyngeal axis. We demonstrate the efficacy of a TORS-assisted approach to identify and surgically treat the primary tumor in patients presenting with CUP. In addition, patients managed with the TORS-assisted endoscopic approach benefit from surgical and pathological triage, which in turn results in deintensification of treatment by eliminating the need for chemotherapy in the majority of patients, as well as avoiding radiation therapy in select patients.

Medullary thyroid carcinoma (MTC) harbors rearranged during transfection (RET) gene and rarely RAS gene mutations. The knowledge of the type of gene mutation in MTC is important to determine the treatment of the patients and the management of their family members. Targeted next-generation sequencing with a panel of 47 genes was performed in a total of 12 cases of sporadic (9/12) and hereditary MTC (3/12). Two of three hereditary MTCs had RET/C634R mutation, while the other one harbored two RET mutations (L790F and S649L). All the sporadic MTC had RET/M918T mutation except one case with HRAS mutation. Next-generation sequencing (NGS) can provide comprehensive analysis of molecular alterations in MTC in a routine clinical setting, which facilitate the management of the patient and the family members.