Loss of SMARCB1 Expression Confers Poor Prognosis to Sinonasal Undifferentiated Carcinoma.

Background Due to the diverse histopathologic features and variable survival rates seen in sinonasal undifferentiated carcinoma (SNUC), it is likely that this diagnostic entity is comprised of a heterogonous group of morphologically undifferentiated tumors. As advancements in molecular testing have led to a better understanding of tumor biology, it has become increasingly evident that SNUC may actually encompass several tumor subtypes with different clinical behavior. As a result, it is also likely that all SNUC patients cannot be treated in the same fashion. Recent investigations have identified loss of the tumor suppressor SMARCB1 (INI1) expression in a subset of undifferentiated sinonasal tumors and extrasinonasal tumors and, studies have suggested that this genetic aberration may be a poor prognostic marker. The objective of this study was to identify differential expression of SMARCB1 in SNUC and to analyze and compare the survival outcomes in SNUC patients with and without SMARCB1 expression. Methods All cases of undifferentiated or poorly differentiated neoplasms of the sinonasal tract treated between 2007 and 2018 at a single tertiary care institution were selected. All cases of SNUC were tested for SMARCB1 status by immunohistochemistry (IHC). Clinical parameters were analyzed using Student's t -test and Fischer's test. Kaplan-Meier methods were used to estimate survival durations, while comparison between both the subgroups was done using the log-rank test. Statistical analysis was performed with the use of SPSS software, Version 25 (IBM, New York, NY, United States). Results Fourteen cases of SNUC were identified. Approximately two-thirds (64%; n = 9) of patients were male and the majority (79%; n = 11) were between fifth to seventh decade. Skull base and orbital invasion were seen in 79% ( n = 11) and 93% ( n = 13) of cases, respectively. Fifty-seven percent of tumors ( n = 8) retained SMARCB1 expression by IHC (SR-SNUC), while the remaining 43% ( n = 6) showed loss of SMARCB1 expression and, thus, were considered as SMARCB1 -deficient (SD-SNUC). Although clinicopathological features and treatment modalities were similar, SD-SNUC showed poorer (OS: p = 0.07; disease free survival [DFS]: p = 0.02) overall survival (OS) and DFS on Kaplan-Meier curves. Additionally, SD-SNUC showed higher recurrence (75 vs. 17%) and mortality (67 vs. 14%) (hazard rate = 8.562; p = 0.05) rates. Both OS (28.82 ± 31.15 vs. 53.24 ± 37.50) and DFS durations (10.62 ± 10.26 vs. 43.79 ± 40.97) were consistently worse for SD-SNUC. Five-year survival probabilities were lower for SD-SNUC (0.33 vs. 0.85). Conclusion SNUC represents a heterogeneous group of undifferentiated sinonasal malignancies. Based on the status of SMARCB1 expression, the two subgroups SD-SNUC and SR-SNUC appear to represent distinct clinical entities, with loss of SMARCB1 expression conferring an overall worse prognosis.

Utility of Tumor Capsule Thickness as a Predictor of Invasion in Encapsulated Follicular Variant of Papillary Thyroid Carcinoma and a Diagnostic Tool for Noninvasive Follicular Thyroid Neoplasm With Papillary-Like Nuclear Features.

Context. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is an extremely indolent subset of noninvasive encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC). These lesions share certain features including a delimiting fibrous capsule, and they are distinguished by detailed histological criteria. Objective. We sought to identify whether tumor capsule thickness differs significantly between NIFTP and noninvasive EFVPTC lesions. We also compared tumor capsule thickness between noninvasive and invasive EFVPTC in order to evaluate its utility as a predictive marker of invasion. Design. Encapsulated follicular thyroid neoplasms with papillary-like nuclear features diagnosed over a 3-year period at a single institution were subcategorized into NIFTP, noninvasive EFVPTC, and invasive EFVPTC based on current diagnostic criteria. Maximum tumor capsule thickness for each lesion was measured. Results. A total of 92 lesions (39 NIFTP, 15 noninvasive EFVPTC, and 38 invasive EFVPTC) were evaluated. Tumor capsule thickness was significantly thinner in NIFTP (P = .022) and significantly thicker in invasive EFVPTC (P = .0006) when compared with noninvasive EFVPTC. Conclusions. Tumor capsule thickness may be an additional useful marker when distinguishing between NIFTP and noninvasive EFVPTC. A capsule thickness of greater than 0.2 mm should raise suspicion for EFVPTC and thus prompt more thorough review of the submitted tissue for NIFTP exclusionary criteria. Additionally, if capsular and/or vascular invasion are not present on initial slides of an entirely evaluated capsule of EFVPTC that exceeds 0.5 mm in thickness, the pathologist should order additional tissue levels to ensure that a small focus of invasion is not missed.

Assessment of quality and consistency of monoclonal antibodies for CB1 and CB2 in head and neck squamous cell carcinoma.

BACKGROUND: Marijuana has numerous roles as an agonist in the endocannabinoid signaling system (ESS). This study evaluated monoclonal antibodies across experimental techniques to establish a framework for studying ESS receptors, CB1 and CB2. METHODS: Tissue from five patients with head and neck cancer were used to generate cell lines and formalin-fixed paraffin-embedded (FFPE) sections, which were analyzed by western blot (WB), immunohistochemistry (IHC), and immunofluorescence (IF). Subgroup analysis was performed on FFPE sections from 8 marijuana users and 10 controls by IHC. Results were compared across methods for consistency. RESULTS: In all patients, WB and IF were CB1 positive, whereas IHC was negative. Select samples were CB2 positive by WB, but failed IF and IHC applications. In subgroup analysis, 1 of 8 users and 3 of 10 nonusers were CB1 positive. CONCLUSIONS: Interpretation of CB1/CB2 antibody data should be performed cautiously and confirmation of findings across multiple experimental methods is recommended.

Multifocal Metastatic Breast Carcinoma to the Thyroid Gland Histologically Mimicking C Cell Lesions.

The thyroid gland is an uncommon site of metastatic disease. Renal cell carcinoma is the most common primary source, while metastasis from breast carcinoma is very rare. However, given that thyroid nodules are more common in women, and women with a history of breast cancer are at higher risk of developing thyroid cancer, the possibility of metastatic breast carcinoma must be considered when evaluating a thyroid nodule. We present the case of a 67-year-old woman who presented with dysphonia and dysphagia secondary to multinodular goiter and was found to have multifocal metastatic breast carcinoma in her surgical resection specimen. The histologic appearance focally mimicked C cell hyperplasia and medullary thyroid carcinoma, so immunohistochemistry was critical for establishing the diagnosis. Metastasis to the thyroid should always be included in the differential diagnosis for a thyroid nodule in a patient with a history of previous malignancy.

Two Cases of Sinonasal Non-Intestinal-Type Adenocarcinoma with Squamoid Morules Expressing Nuclear ß-Catenin and CDX2: A Curious Morphologic Finding Supported by Molecular Analysis.

Sinonasal non-intestinal-type adenocarcinoma (non-ITAC) is a rare, morphologically diverse neoplasm of the head and neck. Squamoid morular metaplasia has recently been reported as an occasional finding in non-ITAC. Interestingly, these squamoid morules often show aberrant expression of CDX2 as well as nuclear expression of ß-catenin, similar to other tumors that show this type of metaplasia, but the underlying mechanism responsible for this finding is not completely understood. We present two cases of low-grade non-ITAC with squamoid morules coexpressing CDX2 and nuclear ß-catenin by immunohistochemistry, both of which were found to harbor a mutation in CTNNB1, the gene encoding ß-catenin. This finding provides support that an alteration in the ß-catenin pathway, including mutations in the ß-catenin gene itself, is responsible for this recently described morphologic phenomenon in non-ITAC.

Paranasal sinus lymphoma: Retrospective review with focus on clinical features, histopathology, prognosis, and relationship to systemic lymphoma.

BACKGROUND: Paranasal sinus lymphoma is a rare clinical entity. METHODS: We conducted a retrospective case series of 68 patients with biopsy-confirmed paranasal sinus lymphoma with attention on systemic disease association. RESULTS: Of 63 patients with paranasal sinus lymphoma, 35 (56%) had systemic involvement. Four patient groups were identified: (1) primary paranasal sinus lymphoma (44%); (2) systemic disease occurring concurrently with paranasal sinus lymphoma (25%); (3) paranasal sinus lymphoma with relapse of preexisting systemic lymphoma (22%); and (4) progression to systemic disease after primary paranasal sinus lymphoma (8%). Most of the patients with systemic disease were diagnosed at 50 + years and had positive smoking histories. There was a trend toward disease activity in the neighboring ocular location. For patients with preexisting systemic lymphoma, the mean time to paranasal sinus lymphoma was 65 months. When systemic lymphoma developed after localized paranasal sinus lymphoma, mean time to progression was 23 months. Diffuse large B cell lymphoma was the most common paranasal sinus lymphoma. CONCLUSION: There is a risk of systemic involvement during the disease course of paranasal sinus lymphoma. Biopsy is the preferred first management step and should precede debulking or mass resection in nonemergent cases. © 2017 Wiley Periodicals, Inc. Head Neck 39: 1065-1070, 2017.

Ductal carcinoma in situ of the breast: the importance of morphologic and molecular interactions.

Ductal carcinoma in situ (DCIS) of the breast is a lesion characterized by significant heterogeneity, in terms of morphology, immunohistochemical staining, molecular signatures, and clinical expression. For some patients, surgical excision provides adequate treatment, but a subset of patients will experience recurrence of DCIS or progression to invasive ductal carcinoma (IDC). Recent years have seen extensive research aimed at identifying the molecular events that characterize the transition from normal epithelium to DCIS and IDC. Tumor epithelial cells, myoepithelial cells, and stromal cells undergo alterations in gene expression, which are most important in the early stages of breast carcinogenesis. Epigenetic modifications, such as DNA methylation, together with microRNA alterations, play a major role in these genetic events. In addition, tumor proliferation and invasion is facilitated by the lesional microenvironment, which includes stromal fibroblasts and macrophages that secrete growth factors and angiogenesis-promoting substances. Characterization of DCIS on a molecular level may better account for the heterogeneity of these lesions and how this manifests as differences in patient outcome and response to therapy. Molecular assays originally developed for assessing likelihood of recurrence in IDC are recently being applied to DCIS, with promising results. In the future, the classification of DCIS will likely incorporate molecular findings along with histologic and immunohistochemical features, allowing for personalized prognostic information and therapeutic options for patients with DCIS. This review summarizes current data regarding the molecular characterization of DCIS and discusses the potential clinical relevance.

Diagnostic Options and Challenges for Dengue and Chikungunya Viruses.

Dengue virus (DENV) and Chikungunya virus (CHIKV) are arboviruses that share the same Aedes mosquito vectors and thus overlap in their endemic areas. These two viruses also cause similar clinical presentations, especially in the initial stages of infection, with neither virus possessing any specific distinguishing clinical features. Because the outcomes and management strategies for these two viruses are vastly different, early and accurate diagnosis is imperative. Diagnosis is also important for surveillance, outbreak control, and research related to vaccine and drug development. Available diagnostic tests are aimed at detection of the virus, its antigenic components, or the host immune antibody response. In this review, we describe the recent progress and continued challenges related to the diagnosis of DENV and CHIKV infections.

Severe human parechovirus type 3 myocarditis and encephalitis in an adolescent with hypogammaglobulinemia.

Human parechovirus (HPeV) belongs to the Picornaviridae family of RNA viruses. HPeV infections can be asymptomatic, lead to mild respiratory and/or gastrointestinal symptoms, or less frequently cause severe diseases such as sepsis, meningitis, encephalitis, and myocarditis. Severe neurological HPeV infections occur most commonly in infants and neonates. There are currently 16 recognized types of HPeV. HPeV type 3 (HPeV3) has been the predominant type associated with severe central nervous system disease in neonates and newborns since its discovery in 1999. Although HPeV-related infections have been reported in adults, symptomatic HPeV3 infections in adolescents and adults are uncommon. A case of severe HPeV3 myocarditis and encephalitis in an adolescent is described.

Malignant sarcomatous transformation of fibrous dysplasia.

A case of osteosarcoma developing from fibrous dysplasia of the sphenoid bone in a 59-year-old female will be discussed. The characteristic radiologic and histologic features of the entity will be described.

Comparison of Chromogenic In Situ Hybridization and Fluorescence In Situ Hybridization for the Evaluation of MDM2 Amplification in Adipocytic Tumors.

BACKGROUND: Atypical lipomatous tumor/well-differentiated liposarcoma (ALT-WDLPS) and dedifferentiated liposarcoma (DDLPS) are characterized cytogenetically by a 12q13-15 amplification involving the mouse double minute 2 (MDM2) oncogene. Fluorescence in situ hybridization (FISH) is used frequently to detect this amplification and aid with the diagnosis of these entities, which is difficult by morphology alone. Recently, bright-field in situ hybridization techniques such as chromogenic in situ hybridization (CISH) have been introduced for the determination of MDM2 amplification status. METHODS: The present study compared the results of FISH and CISH for detecting MDM2 amplification in 41 cases of adipocytic tumors. Amplification was defined in both techniques as a MDM2/CEN12 ratio of 2 or greater. RESULTS: Eleven cases showed amplification with both FISH and CISH, and 26 cases showed no amplification with both methods. Two cases had discordant results between CISH and FISH, and two cases were not interpretable by CISH. CONCLUSION: CISH is advantageous for allowing pathologists to evaluate the histologic and molecular alterations occurring simultaneously in a specimen. Moreover, CISH is found to be more cost- and time-efficient when used with automation, and the signals do not quench over time. CISH technique is a reliable alternative to FISH in the evaluation of adipocytic tumors for MDM2 amplification.

Ovarian leydig cell hyperplasia: an unusual case of virilization in a postmenopausal woman.

Objective. To report an unusual case of ovarian Leydig cell hyperplasia resulting in virilization in a postmenopausal woman. Methods. Patient's medical history and pertinent literature were reviewed. Results. A 64-year-old woman presented with virilization with worsening hirsutism, deepening of her voice, male musculature, and male pattern alopecia. Her pertinent past medical history included type 1 diabetes, hyperlipidemia, and hypertension. Her pertinent past surgical history included hysterectomy due to fibroids. On further work-up, her serum total testosterone was 506 ng/dL (nl range: 2-45) and free testosterone was 40 pg/mL (nl range: 0.1-6.4). After ruling out adrenal causes, the patient underwent an empiric bilateral oophorectomy that showed Leydig cell hyperplasia on pathology. Six weeks postoperatively, serum testosterone was undetectable with significant clinical improvement. Conclusion. Postmenopausal hyperandrogenism can be the result of numerous etiologies ranging from normal physiologic changes to ovarian or rarely adrenal tumors. Our patient was found to have Leydig cell hyperplasia of her ovaries, a rarely reported cause of virilization.

Homonymous hemianopia due to Erdheim-Chester disease.

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis typically affecting multiple organ systems. We report 2 patients who presented with homonymous hemianopia and were ultimately diagnosed with biopsy-confirmed ECD. We review the spectrum of ECD and its treatment as well as histopathological and immunohistochemical differentiation from other histiocytic disorders.

Two Cases of Spinal, Extraosseous, Intradural Ewing's sarcoma/Peripheral Neuroectodermal Tumor: Radiologic, Pathologic, and Molecular Analysis.

Extraosseous Ewing's sarcoma/peripheral neuroectodermal tumors (ES/PNETs) are rare neoplasms that account for approximately 10%-15% of soft tissue sarcomas in children and 5% of soft tissue sarcomas in adults. Primary spinal, extraosseous, intradural ES/PNETs are even less common. The diagnosis of ES/PNET is extremely challenging, because the tumor can have a nonspecific radiologic appearance, and the histologic features are shared by many other "small round cell tumors." Thus, ES/PNET should be included in the radiologic and pathologic differential diagnosis, even in older patients and in unusual tumor sites. We report two cases of spinal, extraosseous, intradural ES/PNETs in adults who presented with back pain. Magnetic resonance imaging revealed contrast enhancing, intradural lesions in the area of the conus medullaris. The tumor in Case 1 was partially intramedullary, while the tumor in Case 2 was exclusively extramedullary. In both cases, the radiologic and intraoperative surgical impression favored ependymoma. The diagnosis of ES/PNET was established in both cases by histopathologic, immunohistochemical, and molecular analysis.

Bupropion differentially alters the aversive, locomotor and rewarding properties of nicotine in CD-1 mice.

The present experiments determined the effects of bupropion on the motivational (aversive and rewarding) and locomotor properties of nicotine in CD-1 mice. Preliminary experiments determined effective nicotine doses (0.1-2.0 mg/kg) to produce a conditioned taste aversion (CTA) or conditioned place preference (CPP; Experiments 1a and 2a, respectively). Mice were administered vehicle or bupropion (1-20 mg/kg) followed by vehicle or nicotine after drinking saccharin during CTA training (Experiment 1b). Mice were administered vehicle or bupropion (1-20 mg/kg) 15 (Experiment 2b) or 30 (Experiment 2c) minutes (min) prior to vehicle or nicotine during CPP training. The two highest nicotine doses produced CTAs and a moderate nicotine dose (0.4 mg/kg) produced a CPP. Bupropion dose-dependently blocked nicotine CTA. For the 15-min pretreatment interval, bupropion dose-dependently increased locomotor activity and produced CPPs when administered alone; whereas for the 30-min pretreatment interval, only the highest bupropion dose increased locomotor activity and produced a CPP. However, bupropion failed to alter nicotine CPP and the co-administration of bupropion and nicotine did not increase locomotor activity more so than when bupropion was administered alone regardless as to the pretreatment interval. Thus, bupropion selectively altered the aversive properties of nicotine in CD-1 mice.

Wistar Kyoto and Wistar rats differ in the affective and locomotor effects of nicotine.

Anhedonia is a characteristic of clinical depression and has been associated with dysfunction of the mesolimbic dopaminergic system, a system also involved in mediating nicotine reward. To further examine the relationship between anhedonia, clinical depression and nicotine reward, the present experiment determined if Wistar Kyoto (WKY) rats, an animal model of clinical depression, differed from Wistar rats in nicotine conditioned place preference (CPP). Strain differences in nicotine-induced changes in locomotor activity also were determined simultaneously. To determine if strain differences were specific to reward-based learning, nicotine or lithium chloride (LiCl) conditioned taste avoidance (CTA) experiments were conducted. Rats received vehicle or nicotine (0.4 or 0.8 mg/kg) during a multi-trial, biased CPP training procedure or received vehicle, nicotine (0.2, 0.4 or 0.8 mg/kg) or lithium chloride (LiCl; 0.0375, 0.075 or 0.15 M) during a multi-trial CTA training procedure. Whereas both nicotine doses (0.4 and 0.8 mg/kg) initially induced hypoactivity, only the moderate nicotine dose (0.4 mg/kg) induced hyperactivity with repeated administration and produced a CPP in Wistar rats. Both nicotine doses failed to alter locomotor activity or produce a CPP in WKY rats. WKY rats also acquired a LiCl CTA more slowly and less robustly compared to Wistar rats. In contrast, nicotine dose-dependently produced a CTA in both strains and WKY rats were more sensitive to the avoidance effects of nicotine compared to Wistar rats. Collectively, these results suggest that WKY rats show deficits in nicotine reward and specific aversive drug stimuli compared to Wistar rats.