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Though the primary diagnostic utility of urine cytology is in the detection of high grade urothelial carcinoma, malignancies other than those of urinary tract origin may also be present. Direct invasion of the bladder by an adjacent neoplasm, metastasis from a distant primary, or inadvertent contamination during specimen collection may all result in nonurothelial tumor cells being present in a urine cytology specimen. Here, we report a case of endometrial adenocarcinoma that was first identified in a voided urine specimen collected for the routine evaluation of hematuria. The presence of cohesive clusters with apparent glandular differentiation raised the possibility of a nonurothelial neoplasm and prompted an additional workup. Immunohistochemical stains performed on cell block material demonstrated that the glandular cells were positive for PAX8 and negative for GATA3, suggestive of gynecologic origin. A subsequent endometrial curettage and hysterectomy revealed endometrial adenocarcinoma. When faced with papillary groups in a voided urine specimen, the cytopathologist must remember to consider a broad differential diagnosis to include malignancies outside of the urinary tract. It was our awareness of valuable clinical information and keen cytologic assessment which allowed for an accurate diagnosis in the setting of this unexpected finding.

Lipoblastomatosis is an extremely rare condition and is often not recognized prior to final pathologic analysis. In this case, a two-year-old female child presented with a non-tender, submental midline neck mass which had enlarged very slowly over the course of five months. The differential diagnosis included lipoma, lymphatic malformation, and thyroglossal duct cycst and a surgical excision was planned. The child was consented for a possible Sistrunk procedure if necessary. Intraoperatively, the mass was adherent to the hyoid bone and clear mucoid drainage was noted during resection leading the team to further weight the possibility of thyroglossal duct cyst and proceed with a Sistrunk procedure. Ultimately, final pathology revealed the diagnosis of lipoblastomatosis.

SUMMARY Mucoepidermoid carcinoma (MEC) is a life-threatening salivary gland cancer that is driven primarily by a transcriptional coactivator fusion composed of cyclic AMP-regulated transcriptional coactivator 1 (CRTC1) and mastermind-like 2 (MAML2). The mechanisms by which the chimeric CRTC1/MAML2 (C1/M2) oncoprotein rewires gene expression programs that promote tumorigenesis remain poorly understood. Here, we show that C1/M2 induces transcriptional activation of the non-canonical peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) splice variant PGC-1α4, which regulates peroxisome proliferator-activated receptor gamma (PPARγ)-mediated insulin-like growth factor 1 (IGF-1) expression. This mitogenic transcriptional circuitry is consistent across cell lines and primary tumors. C1/M2-positive tumors exhibit IGF-1 pathway activation, and small-molecule drug screens reveal that tumor cells harboring the fusion gene are selectively sensitive to IGF-1 receptor (IGF-1R) inhibition. Furthermore, this dependence on autocrine regulation of IGF-1 transcription renders MEC cells susceptible to PPARγ inhibition with inverse agonists. These results yield insights into the aberrant coregulatory functions of C1/M2 and identify a specific vulnerability that can be exploited for precision therapy., Graphical Abstract, In brief Musicant et al. demonstrate that the CRTC1-MAML2 gene fusion aberrantly regulates expression of the minor splice variant PGC-1α4, which in turn coactivates PPARγ to induce IGF-1 expression. This synthetic signal circuit establishes pro-growth and pro-survival signaling in mucoepidermoid carcinomas, sensitizing tumors to drugs that disable IGF-1 signaling by targeting PPARγ.

SUMMARYMucoepidermoid carcinoma (MEC) is a life-threatening salivary gland cancer that is driven primarily by the transcriptional co-activator fusion CRTC1-MAML2. The mechanisms by which the chimeric CRTC1-MAML2 oncoprotein rewires gene expression programs that promote tumorigenesis remain poorly understood. Here, we show that CRTC1-MAML2 induces transcriptional activation of the non-canonical PGC-1α splice variant PGC-1α4, which regulates PPARγ-dependent IGF-1 expression. This mitogenic transcriptional circuitry is consistent across cell lines and primary tumors. CRTC1-MAML2 positive tumors are dominated by IGF-1 pathway activation and small molecule drug screens reveal that tumor cells harboring the fusion gene are selectively sensitive to IGF-1R inhibition. Furthermore, this dependence on autocrine regulation of IGF-1 transcription renders MEC cells susceptible to PPARγinhibition with inverse agonists. These results yield insights into the aberrant co-regulatory functions of CRTC1-MAML2 and identify a specific vulnerability that can be exploited for precision therapy.

Appropriate therapy for lymphomas of all types depends on accurate and timely diagnosis. However, challenges faced in rare lymphoma classification underscore the need for continued clinical and biologic investigation and a careful interdisciplinary approach to patient care. This chapter introduces the complexity and nuance involved in the diagnosis of lymphoma. There will be a particular emphasis on uncommon lymphoma subtypes and diagnostic pitfalls.

Highlights • Angiosarcoma is a rare endothelial malignancy associated with radiation exposure. • Very rarely, angiosarcoma has been reported to arise in the uterine cervix. • We report the first case of post-radiation angiosarcoma of the cervix.

Background and aims Updated diagnostic guidelines for eosinophilic esophagitis (EoE) have eliminated the requirement for a proton pump inhibitor (PPI) trial, but there are no models to identify patients with EoE based on these new criteria. We aimed to develop a predictive model for diagnosis of EoE based on the updated EoE diagnostic guidelines. Methods We performed a secondary analysis of a prospective study of adult patients referred for outpatient esophagogastroduodenoscopy at University of North Carolina who had symptoms of esophageal dysfunction; patients with prevalent EoE were excluded. We analyzed data from 206 EoE cases (mean age 40.1, 62.6% male, 93.2% white) and 306 controls (mean age 52.3, 37.9% male, 79.7% white). We built predictive models for case-control status, using clinical, endoscopic, and histologic features, and defining EoE by either the new or historical definition of PPI non-response. Model discrimination was assessed by the area under the receiver-operator characteristic curve (AUC). Results Before endoscopy, younger age, male sex, history of atopic condition or food allergy, and dysphagia identified patients with EoE with an AUC of 0.83. When we included endoscopy findings suggestive of EoE, the model identified patients with EoE with an AUC of 0.92; this increased to 0.99 when histology was included. Conclusion We developed a model to identify patients with EoE, without a trial of PPIs, based on updated diagnostic guidelines. Clinical features and endoscopic findings identified patients with EoE with an AUC of 0.92—even without histologic data and in the absence of dysphagia. This model can be used to select patients with upper gastrointestinal symptoms but without dysphagia for early diagnostic endoscopy. The model can also be used to identify cases of EoE when eosinophil counts are greater than 15 in biopsies but other causes of esophageal eosinophilia cannot necessarily be excluded.

Background Peripheral and mucosal eosinophilia may be associated with more aggressive disease in inflammatory bowel disease (IBD) patients. Vedolizumab blocks T lymphocytes, eosinophil adhesion, and extravasation in the gastrointestinal tract. It is not known if mucosal eosinophilia is a predictor for the therapeutic efficacy of vedolizumab. Methods This was a retrospective cohort study of IBD patients with ileal or colonic biopsies who were off steroids before starting vedolizumab. Biopsies were rereviewed by pathologists, and mean eosinophil density was quantified. Patient characteristics and steroid-free clinical response 6 months after beginning vedolizumab were determined. Features were compared between nonresponders and responders, and multivariable logistic regression was performed to identify predictors of clinical response. Results Of 251 IBD patients starting vedolizumab therapy, 65 patients (48% Crohn’s disease, 52% ulcerative colitis) met inclusion criteria. All IBD patients not responding to vedolizumab were more likely to have a higher baseline mean eosinophil count (340 ± 156 vs 236 ± 124; P = 0.004), be previously exposed to an anti-TNF (96% vs 56%; P = 0.001), and be male (58% vs 28%; P = 0.02). Mean eosinophil counts were significantly increased in colonic biopsies in UC nonresponders (438 ± 149 vs 299 ± 145; P = 0.01). A similar trend was seen in CD nonresponders. On multivariable analysis, colonic eosinophil density and prior anti-TNF exposure—and the combination of both—were independent predictors of response. Conclusion In ulcerative colitis, colonic eosinophilia and prior anti-TNF exposure were independent predictors of 6-month clinical nonresponse to vedolizumab. Mucosal eosinophil density as a novel biomarker should be explored in larger patient cohorts. Aside from the previous anti-TNF exposure, eosinophil density in the colon of patients with UC is a negative predictor for a steroid-free long-term response to vedolizumab. The degree colonic eosinophilia may be a novel biomarker that should be further explored.

SUMMARY Non-dysphagia symptoms, such as heartburn and dyspepsia, are poorly characterized in adults with eosinophilic esophagitis (EoE). It is unclear if treatment improves these symptoms. The aim of this paper was to assess (i) heartburn and dyspepsia symptom severity in adult EoE patients using validated symptom measures; (ii) change in symptoms after treatment; and (iii) symptom association with endoscopic and histologic features. In a prospective cohort of adult EoE patients who were not responsive to proton pump inhibitor therapy, non-dysphagia symptoms were assessed with heartburn items from the validated GERD-HRQL (gastroesophageal reflux disease health-related quality of life) and SODA (severity of dyspepsia assessment) instruments. Subjects completed the questionnaires at baseline and after treatment. Association of baseline symptoms with endoscopic and histologic features, and before and after treatment with diet or topical steroids, was assessed. Eighty-six EoE patients (mean age 39 years, 57% male, 95% white) completed a baseline questionnaire and 62 completed the follow-up questionnaire. The mean baseline GERD-HRQL score was 4.5 ± 6.5 and the mean total SODA score was 41.0 ± 12.6. At baseline, there was a weak but significant correlation between peak eosinophils and the SODA score (r = 0.28; p = 0.03) and no association between heartburn and SODA scores and endoscopic or other histologic findings. After treatment, there was a decrease in GERD-HRQL heartburn (4.3 vs. 2.6; p = 0.04) and SODA (49.5 vs. 35.5; p = 0.04) scores in histologic responders, but not in nonresponders. In a prospective cohort of EoE patients, baseline eosinophils positively correlated with dyspepsia severity. Heartburn and dyspepsia symptoms improved after treatment in histologic responders.

Mortality rates associated with C. gattii infections are estimated to be between 13% and 33%, depending on an individual’s predisposition, and C. gattii has caused at least 39 deaths in the PNW region. There have been four other international travel cases reported in patients from Europe and Asia with travel history to the PNW, but this report describes the first North American traveler who acquired C. deuterogattii infection presenting within the United States and the first case of a C. deuterogattii outbreak infection associated with anti-GM-CSF autoantibodies. Early and accurate diagnoses are important for disease prevention and treatment and for control of infectious diseases. Continual reporting of C. deuterogattii infections is necessary to raise awareness of the ongoing outbreak in the PNW and to alert travelers and physicians to the areas of endemicity with potential risks., The region encompassing the Pacific Northwest (PNW), Vancouver Island, Oregon, and Washington has been the location of an ongoing Cryptococcus gattii outbreak since the 1990s, and there is evidence that the outbreak is expanding along the West Coast into California. Here we report a clinical case of a 69-year-old, HIV-negative man from North Carolina who was diagnosed with a fungal brain mass by magnetic resonance imaging (MRI) and pathology. He had traveled to Seattle and Vancouver 3 years earlier and to Costa Rica 4 months prior to presentation. Phenotypic evidence showed that the fungal mass isolated from the patient’s brain represented C. gattii. In agreement with the phenotypic results, multilocus sequence typing (MLST) provided genotypic evidence that assigned the infecting organism within the C. gattii species complex and to the C. deuterogattii VGIIa clade. Whole-genome sequencing revealed >99.99% identity with the C. deuterogattii reference strain R265, indicating that the infecting strain is derived from the highly clonal outbreak strains in the PNW. We conclude that the patient acquired the C. gattii infection during his travel to the region 3 years prior and that the infection was dormant for an extended period of time before causing disease. The patient tested positive for anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies, supporting earlier reports that implicate these autoantibodies as a risk factor associated with C. gattii infection.

The Pacific Northwest (PNW), Vancouver Island, Oregon, and Washington have been the location of an ongoing Cryptococcus gattii outbreak since the 1990s, and there is evidence that the outbreak is expanding along the West Coast into California. Here we report a clinical case of a 69-year-old, HIV-negative man from North Carolina who was diagnosed with a fungal brain mass by magnetic resonance imaging (MRI) and pathology. He had traveled to Seattle and Vancouver three years earlier and Costa Rica four months prior to presentation. Phenotypic evidence shows the fungal mass isolated from the patient’s brain is C. gattii. In agreement with the phenotypic results, MLST provides genotypic evidence that assigns the infecting organism within in the C. gattii species complex and belonging to the C. deuterogattii VGIIa clade. Whole genome sequencing revealed >99.99% identity to the C. deuterogattii reference strain R265, indicating that the infecting strain is derived from the highly clonal outbreak strains in the PNW. We conclude the patient acquired the C. gattii infection during his travel to region three years prior and the infection was dormant for an extended period of time before causing disease. The patient tested positive for anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies, supporting earlier reports that implicate these autoantibodies as a risk factor a risk factor associated with C. gattii infection.ImportanceMortality rates associated with C. gattii infections are estimated to be between 13% and 33% depending on an individual’s predisposition, and C. gattii has caused more at least 39 deaths in the PNW region. There have been four other international travel cases reported in patients from Europe and Asia with travel history to the PNW, but this study describes the first North American travel who acquired C. deuterogattii infection presenting within the United States, and the first case of a C. deuterogattii outbreak infection associated with anti-GM-CSF autoantibodies. Early and accurate diagnoses are important for disease prevention, treatment, and control of infectious diseases. Continual reporting of C. deuterogattii infections is necessary to raise awareness of the ongoing outbreak in the PNW and alert travelers and physicians to the endemic areas with potential risks.

Introduction: The presence of the t(11;19) chromosomal translocation and its CRTC1-MAML2 (C1/M2) fusion product occurs frequently in salivary mucoepidermoid carcinoma (MEC) and has been correlated with a favorable prognosis. Recently, whole-exome sequencing studies found genomic alterations in MEC to be infrequent, which supports the role of C1/M2 as an early driver event. However, when present, TP53 and PIK3CA alterations may represent alternative driver mutations in fusion-negative cases. To better understand the MEC transcriptional landscape by fusion status and histologic grade, we performed RNA deep sequencing. Methods: 16 parotid MEC (8 low-grade and 8-high grade) tumors, 12 adjacent normal, and 6 age-matched normal parotid tissues were retrospectively analyzed from UNC Surgical Pathology specimens collected from 2000-2019. H&E and mucicarmine stained slides were independently reviewed by pathology for diagnostic confirmation. The Air Force Institute of Pathology (AFIP) classification system by Ellis and Auclair was utilized for histologic grading. RNA was extracted from FFPE tissue sections and quality checked prior to library preparation. RNA-seq (HS2500) was then performed on all samples and computational methods were used to determine C1/M2 fusion status. Gene set variation analyses (GSVA) were performed on genes differentially expressed between MEC tumor versus normal, or according to tumor grade, and/or fusion status. Results: Compared to matched normals, MEC tumors display significant changes in ERBB2 and PI3K signaling cascades (FC=-3.2, p=0.049). We also noted significant upregulation of inflammatory and apoptosis markers including interferon gamma, IL-4, NOS1, and programmed cell death (p Discussion: This is the first study to perform transcriptome analyses of salivary MEC comparing to normal parotid tissue, while accounting for histologic grade. While C1/M2 fusion status is considered pathognomonic of low-grade MEC, we identified the expression of C1/M2 fusion transcripts in high-grade MEC. This confirms recent reports challenging the prognostic value of fusion status. Our study also confirms that reprogramming TP53 and PI3K signaling is a universal feature of MEC and epigenetic mechanisms may repress p53 in the absence of TP53 driver mutations seen in fusion negative tumors. Lastly, we report that VEGF and TGF-β pathway activation are associated with cancer pathogenesis in high-grade MEC. The evaluation of anticancer therapies targeting these pathways should be evaluated further. Citation Format: Siddharth Sheth, Renee Betancourt, Joel Parker, Kshitij Sharma, Adele Musicant, Wendell Yarbrough, Trevor Hackman, Antonio Amelio. RNA sequencing of salivary mucoepidermoid carcinoma reveals distinct molecular profiles based on histologic grade [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr PR04.

BACKGROUND AND AIMS: Few factors have been identified that can be used to predict response of patients with eosinophilic esophagitis (EoE) to topical steroid treatment. We aimed to determine whether baseline clinical, endoscopic, histologic, and molecular features of EoE can be used to predict histologic response. METHODS: We collected data from 97 patients with EoE, from 2009 through 2015, treated with a topical steroid for 8 weeks; 59 patients had a histologic response to treatment. Baseline clinicopathologic features and gene expression patterns were compared between patients with a histologic response to treatment (

This study describes the development of general scales to measure self-efficacy and outcome expectancy at both the individual and group level. Factor analysis of an initial application of these scales in work settings was used for scale revision. Results from a second work sample provide evidence of the revised scales' factorial validity, reliability, and criterion validity in reference to work satisfaction, organizational commitment, and work performance based on peer evaluations. These scales are proposed as tools to enhance the use of these constructs in job-related research.