A model for classification of invasive fungal rhinosinusitis by computed tomography.

Our purpose was to classify acute invasive fungal rhinosinusitis (AIFR) caused by Mucor versus Aspergillus species by evaluating computed tomography radiological findings. Two blinded readers retrospectively graded radiological abnormalities of the craniofacial region observed on craniofacial CT examinations obtained during initial evaluation of 38 patients with eventually pathology-proven AIFR (13:25, Mucor:Aspergillus). Binomial logistic regression was used to analyze correlation between variables and type of fungi. Score-based models were implemented for analyzing differences in laterality of findings, including the 'unilateral presence' and 'bilateral mean' models. Binary logistic regression was used, with Score as the only predictor and Group (Mucor vs Aspergillus) as the only outcome. Specificity, sensitivity, positive predictive value, negative predictive value and accuracy were determined for the evaluated models. Given the low predictive value of any single evaluated anatomical site, a 'bilateral mean' score-based model including the nasal cavity, maxillary sinuses, ethmoid air cells, sphenoid sinus and frontal sinuses yielded the highest prediction accuracy, with Mucor induced AIFR correlating with higher prevalence of bilateral findings. The odds ratio for the model while integrating the above anatomical sites was 12.3 (p < 0.001). PPV, NPV, sensitivity, specificity and accuracy were 0.85, 0.82, 0.92, 0.69 and 0.84 respectively. The abnormal radiological findings on craniofacial CT scans of Mucor and Aspergillus induced AIFR could be differentiated based on laterality, with Mucor induced AIFR associated with higher prevalence of bilateral findings.

Molecular characterization of tumors meeting diagnostic criteria for the non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP).

"Follicular variant" papillary thyroid carcinomas (FV-PTC) that do not histologically invade have a miniscule risk of metastasis, and thus been reclassified as a tumor of low malignant potential, the non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). There are few molecular studies of this tumor type. We performed gene expression analysis, by RNA sequencing, on a series of FV-PTCs, NIFTPs, and follicular adenomas. A training set comprised tumors from The Cancer Genome Atlas (TCGA) repository (n = 46), digital slides from which were reviewed and classified as invasive or non-invasive FV-PTC. A validation set comprised in-house NIFTPs, invasive FV-PTCs, and follicular adenomas (n = 26). In the training set, unsupervised clustering separated tumors into three distinct expression subtypes, which associated with invasion and characteristic molecular alterations. Specifically, the "BRAF-like" subtype was enriched in invasive FV-PTCs and tumors with BRAF V600E mutations. The "THADA-like" subtype was enriched in non-invasive tumors and those with rearrangements involving THADA. The "RAS-family-like" subtype included many invasive and non-invasive FV-PTCs and was enriched in tumors with mutations in RAS family genes. In the validation set, nearest centroid analysis classified all invasive FV-PTCs as "BRAF-like" and all follicular adenomas as either "RAS-like" or "THADA-like." NIFTPs were the most molecularly diverse histologic type, with cases classified as "BRAF-like," "THADA-like," and "RAS-family-like." In conclusion, tumors fitting criteria for NIFTP are molecularly diverse, making it difficult to diagnose them with molecular studies, likely including matrial from cytopathology samples.

Acute Invasive Fungal Rhinosinusitis: Frozen Section Histomorphology and Diagnosis with PAS Stain.

Acute invasive fungal rhinosinusitis (AIFRS) is a fulminant infection in immunocompromised patients requiring rapid diagnosis (DX), frequently made on frozen section (FS) of sinonasal biopsies, followed by prompt surgical debridement. However, FS interpretation is often difficult and DX sometimes not possible. In this study we sought to characterize reasons for misinterpretation and methods to improve diagnostic accuracy. The FS slides from 271 biopsies of suspected AIFRS in a 16-year period were reviewed and the morphologic features evaluated for their utility in DX. Recurring specific patterns of necrosis were identified, which to our knowledge have not been described in the literature. Although they provide strong evidence for AIFRS, identifying fungus consistently in necrotic tissue is essential for DX. Clues to identifying fungus and pitfalls in misidentification were identified, but even with expert knowledge of these, a gap in accurate DX remained. The key to FS DX of AIFRS is to improve fungus identification in necrotic tissues. Methods had been sought in the past to stain fungus at FS without consistent success. The Periodic Acid Schiff's Reaction for Fungi was modified by our histopathology department for use on frozen tissue (PASF-fs) resulting in effective staining of the fungus. It stained fungus on all 62 positive slides when applied retrospectively over hematoxylin and eosin (H&E) stained FSs and used prospectively at FS for DX. Although knowledge of histologic morphology on FS is important, the crucial value of this study is the novel use of PASF-fs to identify fungus in the DX of AIFRS.

Evidence of a positive association between malpractice climate and thyroid cancer incidence in the United States.

The incidence of thyroid cancer has risen dramatically in the past few decades. The cause of this is unclear, but several lines of evidence indicate it is largely due to overdiagnosis, the diagnosis of tumors that would have never manifest clinically if untreated. Practices leading to overdiagnosis may relate to defensive medicine. In this study, we evaluated the association between malpractice climate and incidence of thyroid, breast, prostate, colon, and lung cancer in U.S. states from 1999-2012 using publicly available government data. State-level malpractice risk was quantified as malpractice payout rate, the number of malpractice payouts per 100,000 people per state per year. Associations between state-level cancer incidence, malpractice payout rate, and several cancer risk factors were evaluated. Risk factors included several social determinants of health, including factors predicting healthcare access. States with higher malpractice payout rate had higher thyroid cancer incidence, on both univariate analysis (r = 0.51, P = 0.009, Spearman) and multivariate analysis (P<0.001, multilevel model). In contrast, state-level malpractice payout rate was not associated with incidence of any other cancer type. Malpractice climate may be a social determinant for being diagnosed with thyroid cancer. This may be a product of greater defensive medicine in states with higher malpractice risk, which leads to increased diagnostic testing of patients with thyroid nodules and potential overdiagnosis. Alternatively, malpractice risk may be a proxy for another, unmeasured risk factor.

Frozen Section as a Rapid and Accurate Method for Diagnosing Acute Invasive Fungal Rhinosinusitis.

Objective Identify methods to improve the frozen-section diagnosis of acute invasive fungal rhinosinusitis. Study Design Biopsies with frozen section for suspected acute invasive fungal rhinosinusitis were reviewed to identify causes for missed diagnoses and evaluate methods for potential improvement. Setting All aspects of the study were performed at the Penn State Milton S. Hershey Medical Center. Subjects and Methods All frozen sections performed for suspected acute invasive fungal rhinosinusitis between 2006 through 2017 were reviewed with their diagnoses compared to the final diagnoses. Sensitivity and specificity were determined for each biopsy specimen to evaluate the diagnostic method and for each patient for its effectiveness on outcome. Causes for frozen-section failures in diagnosis were identified. A periodic acid-Schiff stain for fungus (PASF) was modified for use on frozen tissue (PASF-fs) and applied both retrospectively and prospectively to frozen sections to determine its ability to identify undetected fungus and improve diagnostic sensitivity. Results Of 63 biopsies positive for acute invasive fungal rhinosinusitis, 51 were diagnosed on frozen section, while 61 were identified by including the novel PASF-fs stain, reducing the failure rate from 19% to 3%. Of 41 cases that were positive, 34 were diagnosed on frozen section. Of the 7 that were not, 5 were identified by including the PASF-fs, reducing the failure rate from 17% to 5%. Conclusions Frozen section interpretation of biopsies for suspected acute invasive fungal rhinosinusitis using a PASF-fs stain should enable a rapid and accurate diagnosis with improved outcomes by shortening the time to surgery.

Long-term recurrence-free survival after an unplanned reduction in radiotherapy for HPV-positive oropharyngeal SCC: Two cases and a review of the literature.

There is currently no clear distinction between the treatment of HPV-positive and HPV-negative oropharyngeal squamous cell carcinoma (OPSCC). HPV-positive OPSCC has been demonstrated to be more radiosensitive than its HPV-negative counterpart. Despite this, patients with HPV-positive OPSCC continue to receive a full dose of radiation (70 Gy) outside clinical trials. However, this high dose comes with considerable morbidities, including severe mucositis, dysphagia, and xerostomia. We describe the cases of 2 patients with HPV-positive OPSCC who received two cycles of high-dose cisplatin at 100 mg/m2 on 3 separate days, along with concurrent radiotherapy at 50 Gy in 25 fractions for one and 46 Gy in 23 fractions for the other. During treatment, both patients experienced significant acute-phase toxicities-including grade 3 mucositis, grade 3 nausea, and grade 2 dermatitis-and their treatment regimen was stopped before its planned completion. Nevertheless, after a follow-up of 75 and 78 months, respectively, neither patient exhibited any evidence of disease. Late toxicities included grade 1 xerostomia, grade 1 pharyngeal-phase dysphagia, and grade 1 dysgeusia with some foods. We conclude that de-escalating the dose of radiation for HPV-positive patients by 30% and identifying which patients can safely be treated with this level of dose reduction warrants further study.

Altered molecular profile in thyroid cancers from patients affected by the Three Mile Island nuclear accident.

OBJECTIVES/HYPOTHESIS: In 1979, Three Mile Island (TMI) nuclear power plant experienced a partial meltdown with release of radioactive material. The effects of the accident on thyroid cancer (TC) in the surrounding population remain unclear. Radiation-induced TCs have a lower incidence of single nucleotide oncogenic driver mutations and higher incidence of gene fusions. We used next generation sequencing (NGS) to identify molecular signatures of radiation-induced TC in a cohort of TC patients residing near TMI during the time of the accident. STUDY DESIGN: Case series. METHODS: We identified 44 patients who developed papillary thyroid carcinoma between 1974 and 2014. Patients who developed TC between 1984 and 1996 were at risk for radiation-induced TC, patients who developed TC before 1984 or after 1996 were the control group. We used targeted NGS of paired tumor and normal tissue from each patient to identify single nucleotide oncogenic driver mutations. Oncogenic gene fusions were identified using quantitative reverse transcription polymerase chain reaction. RESULTS: We identified 15 patients in the at-risk group and 29 patients in the control group. BRAFV600E mutations were identified in 53% patients in the at-risk group and 83% patients in the control group. The proportion of patients with BRAF mutations in the at-risk group was significantly lower than predicted by the The Cancer Genome Atlas cohort. Gene fusion or somatic copy number alteration drivers were identified in 33% tumors in the at-risk group and 14% of tumors in the control group. CONCLUSIONS: Findings were consistent with observations from other radiation-exposed populations. These data raise the possibility that radiation released from TMI may have altered the molecular profile of TC in the population surrounding TMI. LEVEL OF EVIDENCE: 4 Laryngoscope, 127:S1-S9, 2017.

Clinical comparison of noninvasive urine tests for ruling out recurrent urothelial carcinoma.

OBJECTIVE: Patients with urothelial carcinoma (UC) undergo rigorous surveillance for recurrence. Noninvasive urine tests are not currently recommended by guideline panels owing to insufficient clinical benefit. The objective of this study was to prospectively compare the performance of the Cxbladder Monitor test to other commonly available urine markers and cytology for surveillance of patients with UC. METHODS AND MATERIALS: A total of 1,036 urine samples were collected from 803 patients undergoing surveillance for UC. Of these, 1,016 samples were directly assessed using cytology, NMP22 Bladderchek and NMP22 enzyme-linked immunosorbent assay (ELISA), and the clinically validated Cxbladder Monitor test. An exploratory analysis was also performed comparing data from 157 samples where UroVysion fluorescence in situ hybridization analysis was performed locally. RESULTS: The sensitivity of Cxbladder Monitor (0.91) significantly outperformed cytology (0.22), NMP22 ELISA (0.26), and NMP22 BladderChek (0.11). The negative predictive value of Cxbladder Monitor was also superior at 0.96 compared with cytology (0.87), NMP22 ELISA (0.87), and NMP22 BladderChek (0.86). All false-negative results (n = 14) observed using Cxbladder Monitor were also negative for cytology, NMP22 ELISA, and NMP22 BladderChek. In the more limited set, UroVysion fluorescence in situ hybridization also had inferior sensitivity (0.33) and negative predictive value (0.92). CONCLUSIONS: The Cxbladder Monitor test significantly outperforms current Food and Drug Administration-approved urine-based monitoring tests, as well as cytology, in a large representative population undergoing surveillance for recurrent UC. This supports using Cxbladder Monitor as a confirmatory negative adjunct to cystoscopy or to justify postponing cystoscopic investigations in patients with a low risk of recurrence.

Clinically localized type 1 and 2 papillary renal cell carcinomas have similar survival outcomes following surgery / Los carcinomas papilares de células renales tipo 1 y 2 localizados clínicamente tienen resultados de supervivencia similares después de la cirugía

Propósito Se intentó determinar la incidencia, hallazgos patológicos, factores pronósticos y resultados clínicos para pacientes con CCR papilar clínicamente localizado. Métodos Demográfico, Se recopilaron hallazgos clínicos y patológicos en todos los pacientes con CCRP sometidos a cirugía en cuatro centros médicos académicos. El punto final primario fue la supervivencia específica del cáncer (CSS). La supervivencia sin recaída (RFS) y la supervivencia general (OS) fueron puntos finales secundarios. Kaplan- Se obtuvieron estimaciones de Meier y se usaron modelos de regresión de riesgos proporcionales de Cox para evaluar predictores de mortalidad y recaída. Resultados Identificamos 626 CCPR, de los cuales 373 (60por ciento) fueron del tipo 1 y 253 (40 por ciento) fueron del tipo 2, con tres cuartas partes de todos los tumores siendo pT1. En comparación con los pacientes con tipo 1, aquellos con tipo 2 eran mayores (edad media: 63 frente a 61; (AU)

Purpose We aimed to determine incidence, pathologic fndings, prognostic factors and clinical outcomes for patients with clinically localized papillary RCC. Methods Demographic, clinical and pathologic fndings were collected on all patients with PRCC undergoing sur-gery at four academic medical centers. The primary end-point was cancer-specifc survival (CSS). Relapse-free survival (RFS) and overall survival (OS) were secondary endpoints. Kaplan­ Meier estimates were obtained, and Cox proportional hazard regression models were used to assess predictors of mortality and relapse. Results We identifed 626 PRCC, of which 373 (60 pertcent) were type 1 and 253 (40 pertcent) were type 2, with three-quar-ters of all tumors being pT1. Compared to patients with type 1, those with type 2 were older (mean age: 63 vs 61; (AU)

Subcutaneous nasal angioleiomyoma: Case of a rare tumor and review of the literature.

We describe the case of a 46-year-old woman with a rare presentation of angioleiomyoma of the subcutaneous nasal tissue. The patient presented with pain and severe nasal obstruction. Her nasal deformity was sufficient to indicate an external rhinoplasty for both extirpation of the tumor and reconstruction of the defect with cartilage grafts. The procedure resulted in successful removal of the tumor and a satisfactory cosmetic outcome.

Clinically localized type 1 and 2 papillary renal cell carcinomas have similar survival outcomes following surgery.

PURPOSE: We aimed to determine incidence, pathologic findings, prognostic factors and clinical outcomes for patients with clinically localized papillary RCC. METHODS: Demographic, clinical and pathologic findings were collected on all patients with PRCC undergoing surgery at four academic medical centers. The primary endpoint was cancer-specific survival (CSS). Relapse-free survival (RFS) and overall survival (OS) were secondary endpoints. Kaplan-Meier estimates were obtained, and Cox proportional hazard regression models were used to assess predictors of mortality and relapse. RESULTS: We identified 626 PRCC, of which 373 (60 %) were type 1 and 253 (40 %) were type 2, with three-quarters of all tumors being pT1. Compared to patients with type 1, those with type 2 were older (mean age: 63 vs 61; p = 0.02), presented more commonly with symptoms (13 vs 7 %; p = 0.02) and had larger mean tumor size (5.2 vs 4.3 cm; p = 0.001). With a median follow-up of 41 months (IQR: 16-68), 92 patients had died of PRCC (15 %), 48 (8 %) experienced relapse, and 101 died from all causes (16 %). The estimated 5-year CSS, RFS and OS were 83, 91 and 82 %, respectively. In multivariable analysis, older age, T stage and nodal status were predictors of CSS and OS. However, PRCC subtype was not a predictor of CSS, RFS or OS. CONCLUSION: While patients with type 2 PRCC appear to present with more advanced disease than patients with type 1, PRCC subtype does not appear to be an independent predictor of CSS, RFS or OS for treated localized disease.

Frozen Section Interpretation of Pancreatic Margins: Subspecialized Gastrointestinal Pathologists Versus General Pathologists.

Intraoperative assessment of pancreatic parenchymal margin during pancreatectomies is challenging and misinterpretation by the pathologist is a cause of incorrect frozen section (FS) diagnosis. Although the current literature supports that pancreatic margin FS diagnosis and its accuracy has no impact on the patient outcome for pancreatic ductal adenocarcinoma (PDAC) patients and reexcision in an attempt to achieve a negative intraoperative pancreatic margin after positive FS is not associated with increased overall survival; still it remains a routine practice in many institutions. To this end, we sought to assess the interobserver variation and accuracy of FS diagnosis between subspecialized gastrointestinal/pancreatobiliary (GI) and general pathologists. Seventy seven consecutive pancreatic parenchymal margin FSs performed on pancreatectomies for PDAC from 2010 to 2013 were retrieved at our institution. These were retrospectively evaluated by 2 GI and 2 general pathologists independently without knowledge of the original FS diagnosis or the final diagnosis. The specificity, sensitivity, positive predictive value, negative predictive value, and accuracy of GI versus general pathologist was 97.8% versus 87.5%, 61.1% versus 66.7%, 78.6% versus 41.4%, 95% versus 95.2%, and 93.5% versus 85.1%, respectively. The interobserver agreement between GI and general pathologists was fair (κ = .337, P < .001). The interobserver agreement between 2 GI pathologists was fair (κ = .373, P = .0005) and between 2 general pathologists was slight (κ = .195, P = .042). Although overall accuracy of subspecialized GI pathologists was higher than that of general pathologists, none had an accuracy of 100%. Our study reaffirms the challenging nature of these FSs.

Unusual sites of metastasis of papillary thyroid cancer: Case series and review of the literature.

Papillary thyroid cancer (PTC) is the most common malignancy of the thyroid gland. It typically spreads via lymphatic extension. The rate of regional PTC metastasis to the neck is relatively high, while metastases outside the deep cervical chain are rare. Distant metastases are found in only 1% of patients with PTC at the time of surgery; the two most common sites are the lung and bone. We report 4 cases of PTC metastasis to unusual sites: (1) the occipital skull and internal jugular vein, (2) the parapharyngeal space, (3) the sternocleidomastoid muscle, and (4) the right atrium of the heart. It has been well documented that aggressive distant metastasis is a characteristic of PTC, and it is known to be an indicator of a poor prognosis. Some of our patients' sites of metastatic disease have not been previously reported. Patients in this series exhibited aggressive histologic findings, including columnar cell and follicular variants of papillary disease. In addition, all 4 patients demonstrated "PET-avid" disease with decreased iodine avidity.

Loss of FOXA1 Drives Sexually Dimorphic Changes in Urothelial Differentiation and Is an Independent Predictor of Poor Prognosis in Bladder Cancer.

We previously found loss of forkhead box A1 (FOXA1) expression to be associated with aggressive urothelial carcinoma of the bladder, as well as increased tumor proliferation and invasion. These initial findings were substantiated by The Cancer Genome Atlas, which identified FOXA1 mutations in a subset of bladder cancers. However, the prognostic significance of FOXA1 inactivation and the effect of FOXA1 loss on urothelial differentiation remain unknown. Application of a univariate analysis (log-rank) and a multivariate Cox proportional hazards regression model revealed that loss of FOXA1 expression is an independent predictor of decreased overall survival. An ubiquitin Cre-driven system ablating Foxa1 expression in urothelium of adult mice resulted in sex-specific histologic alterations, with male mice developing urothelial hyperplasia and female mice developing keratinizing squamous metaplasia. Microarray analysis confirmed these findings and revealed a significant increase in cytokeratin 14 expression in the urothelium of the female Foxa1 knockout mouse and an increase in the expression of a number of genes normally associated with keratinocyte differentiation. IHC confirmed increased cytokeratin 14 expression in female bladders and additionally revealed enrichment of cytokeratin 14-positive basal cells in the hyperplastic urothelial mucosa in male Foxa1 knockout mice. Analysis of human tumor specimens confirmed a significant relationship between loss of FOXA1 and increased cytokeratin 14 expression.

Multifocal inverted papillomas in the head and neck.

Inverted papilloma is a rare benign neoplasm that usually originates in the lateral nasal wall. It can be a locally aggressive lesion and invade nearby structures. While primarily a nasal neoplasm, cases of an inverted papilloma involving the temporal bone, pharynx, nasopharynx, and lacrimal sac have been reported. We describe the case of a 67-year-old man with a history of nasal inverted papilloma who presented with a recurrent nasal mass and a large mass on the left side of his upper neck. The patient's history included inverted papillomas in multiple locations: the temporal bone, the sinonasal tract, and the nasopharynx. The new neck mass raised a concern for malignant degeneration and metastasis, but pathology demonstrated that it was a benign inverted papilloma. No clear etiology for the new neck lesion was evident except for an origin in salivary gland tissue. However, there was no physical connection between the neck mass and the submandibular gland identifiable on pathologic evaluation. This case illustrates the need for an aggressive primary resection to minimize local recurrence, as well as adequate surveillance to address recurrences early. Given the potential for multicentricity, patients with a typical sinonasal inverted papilloma should undergo a complete head and neck examination as part of their follow-up.