Sex determining region Y-box 2 (SOX2) amplification is an independent indicator of disease recurrence in sinonasal cancer.

The transcription factor SOX2 (3q26.3-q27) is an embryonic stem cell factor contributing to the induction of pluripotency in terminally differentiated somatic cells. Recently, amplification of the SOX2 gene locus has been described in squamous cell carcinoma (SCC) of different organ sites. Aim of this study was to investigate amplification and expression status of SOX2 in sinonasal carcinomas and to correlate the results with clinico-pathological data. A total of 119 primary tumor samples from the sinonasal region were assessed by fluorescence in-situ hybridization and immunohistochemistry for SOX2 gene amplification and protein expression, respectively. Of these, 59 were SSCs, 18 sinonasal undifferentiated carcinomas (SNUC), 10 carcinomas associated with an inverted papilloma (INVC), 19 adenocarcinomas (AD) and 13 adenoid cystic carcinomas (ACC). SOX2 amplifications were found in subsets of SCCs (37.5%), SNUCs (35.3%), INVCs (37.5%) and ADs (8.3%) but not in ACCs. SOX2 amplification resulted in increased protein expression. Patients with SOX2-amplified sinonasal carcinomas showed a significantly higher rate of tumor recurrences than SOX2 non-amplified tumors. This is the first study assessing SOX2 amplification and expression in a large cohort of sinonasal carcinomas. As opposed to AD and ACC, SOX2 amplifications were detected in more than 1/3 of all SCCs, SNUCs and INVCs. We therefore suggest that SNUCs are molecularly closely related to SCCs and INVCs and that these entities represent a subgroup of sinonasal carcinomas relying on SOX2 acquisition during oncogenesis. SOX2 amplification appears to identify sinonasal carcinomas that are more likely to relapse after primary therapy, suggesting that these patients might benefit from a more aggressive therapy regime

Fictional biomedical bibliographies in the Era of ChatGPT: Don´t revive Dr. O. Úplavici (1887–1938)

Open Access funding enabled and organized by Projekt DEAL.Universitätsklinikum Erlangen (8546

Proceedings of the North American Society of Head and Neck Pathology, Los Angeles, CA, March 20, 2022: SWI/SNF-deficient Sinonasal Neoplasms: An Overview

The pathology of poorly differentiated sinonasal malignancies has been the subject of extensive studies during the last decade, which resulted into significant developments in the definitions and histo-/pathogenetic classification of several entities included in the historical spectrum of “sinonasal undifferentiated carcinomas (SNUC)” and poorly differentiated unclassified carcinomas. In particular, genetic defects leading to inactivation of different protein subunits in the SWI/SNF chromatin remodeling complex have continuously emerged as the major (frequently the only) genetic player driving different types of sinonasal carcinomas. The latter display distinctive demographic, phenotypic and genotypic characteristics. To date, four different SWI/SNF-driven sinonasal tumor types have been recognized: SMARCB1(INI1)-deficient carcinoma (showing frequently non-descript basaloid, and less frequently eosinophilic, oncocytoid or rhabdoid undifferentiated morphology), SMARCB1-deficient adenocarcinomas (showing variable gland formation or yolk sac-like morphology), SMARCA4-deficient carcinoma (lacking any differentiation markers and variably overlapping with large cell neuroendocrine carcinoma and SNUC), and lastly, SMARCA4-deficient sinonasal teratocarcinosarcoma. These different tumor types display highly variable immunophenotypes with SMARCB1-deficient carcinomas showing variable squamous immunophenotype, while their SMARCA4-related counterparts lack such features altogether. While sharing same genetic defect, convincing evidence is still lacking that SMARCA4-deficient carcinoma and SMARCA4-deficient teratocracinosarcoma might belong to the spectrum of same entity. Available molecular studies revealed no additional drivers in these entities, confirming the central role of SWI/SNF deficiency as the sole driver genetic event in these aggressive malignancies. Notably, all studied cases lacked oncogenic IDH2 mutations characteristic of genuine SNUC. Identification and precise classification of these entities and separating them from SNUC, NUT carcinoma and other poorly differentiated neoplasms of epithelial melanocytic, hematolymphoid or mesenchymal origin is mandatory for appropriate prognostication and tailored therapies. Moreover, drugs targeting the SWI/SNF vulnerabilities are emerging in clinical trials.Open Access funding enabled and organized by Projekt DEAL.Friedrich-Alexander-Universität Erlangen-Nürnberg (1041

Virchows Archiv (The European Journal of Pathology): Past and future

Open Access funding enabled and organized by Projekt DEAL.Friedrich-Alexander-Universität Erlangen-Nürnberg (1041

A functional yeast survival screen of tumor-derived cDNA libraries designed to identify anti-apoptotic mammalian oncogenes

Yeast cells can be killed upon expression of pro-apoptotic mammalian proteins. We have established a functional yeast survival screen that was used to isolate novel human anti-apoptotic genes overexpressed in treatment-resistant tumors. The screening of three different cDNA libraries prepared from metastatic melanoma, glioblastomas and leukemic blasts allowed for the identification of many yeast cell death-repressing cDNAs, including 28% of genes that are already known to inhibit apoptosis, 35% of genes upregulated in at least one tumor entity and 16% of genes described as both anti-apoptotic in function and upregulated in tumors. These results confirm the great potential of this screening tool to identify novel anti-apoptotic and tumor-relevant molecules. Three of the isolated candidate genes were further analyzed regarding their anti-apoptotic function in cell culture and their potential as a therapeutic target for molecular therapy. PAICS, an enzyme required for de novo purine biosynthesis, the long non-coding RNA MALAT1 and the MAST2 kinase are overexpressed in certain tumor entities and capable of suppressing apoptosis in human cells. Using a subcutaneous xenograft mouse model, we also demonstrated that glioblastoma tumor growth requires MAST2 expression. An additional advantage of the yeast survival screen is its universal applicability. By using various inducible pro-apoptotic killer proteins and screening the appropriate cDNA library prepared from normal or pathologic tissue of interest, the survival screen can be used to identify apoptosis inhibitors in many different systems

Insight into Classification and Risk Stratification of Head and Neck Squamous Cell Carcinoma in Era of Emerging Biomarkers with Focus on Histopathologic Parameters

Tumor-node-metastasis (TNM) staging system is the cornerstone for treatment planning of head and neck squamous cell carcinoma (HNSCC). Many prognostic biomarkers have been introduced as modifiers to further improve the TNM classification of HNSCC. Here, we provide an overview on the use of the recent prognostic biomarkers, with a focus on histopathologic parameters, in improving the risk stratification of HNSCC and their application in the next generation of HNSCC staging systems

Inflammatory angiomyolipoma of the liver: an unusual case suggesting relationship to IgG4-related pseudotumor

Hepatic angiomyolipoma (AML) is rare. Based on its wide histomorphological range, several distinctive histological variants have been delineated. However, hepatic AML displaying predominantly or exclusively inflammatory pattern closely mimicking inflammatory pseudotumor (IPT) is exceptionally rare with only 7 cases reported so far. We herein describe a new case of hepatic inflammatory AML in a 51-year-old woman who presented with unexplained constitutional symptoms suggesting an infectious disease. A liver mass was detected during imaging examination and resected (4.3 cm in maximum diameter). The patient’s symptoms resolved completely after surgery. Currently, she is alive and well 7 years after surgery. She has no evidence of other organ manifestations of IgG4-related systemic disease. The tumor displayed a pure IPT-like histological pattern with dense infiltrates of plasma cells, lymphocytes and histiocytes admixed with scattered few adipocytes, irregularly distributed thickwalled vessels (some of them showed obliterative phlebitis) as well as aggregates and fascicles of histiocytoid and spindle-shaped myoid cells that were immunoreactive for HMB45 and Melan A with focal expression of alpha smooth muscle actin. Lesional cells were negative for desmin, protein S100, CD21, CD23, CD15, CD30, HepPar-1, pankeratin (KL-1), ALK1, and EBV in situ hybridization (EBER). The surrounding liver parenchyma showed striking lymphoplasmacytic non-destructive pericholangitis. Numerous scattered and aggregated IgG4 positive plasma cells were seen within the mass and in the peritumoral inflammatory lesions (mean, 37 cells/HPF; IgG4: IgG ratio = 28%). To our knowledge, this is the first report of hepatic inflammatory AML closely resembling IgG4-related IPT of the liver. A possible role for IgG4 seems likely to explain the peculiar histological features and the unusual clinical presentation in this case

Lipomatous Hypertrophy of the Atrial Septum in a Patient Undergoing Coronary Artery Bypass Surgery

Background. Lipomatous hypertrophy of the atrial septum (LHAS) is a rare entity characterized by mass-forming deposition of fatty tissue within the atrial septum. To date, <300 cases have been reported; many of them were autopsy findings. The clinical presentation of LHAS varies from incidental asymptomatic mass (most frequent form) to severe life-threatening cardiovascular complications necessitating emergency cardiac surgery. Case Presentation. Here, we present the successful surgical resection of such a massive LHAS which was found incidentally on preoperative investigation of a 71-year-old patient with progressive coronary heart disease. Histology confirmed the diagnosis of lipomatous hypertrophy of the atrial septum. Conclusions. The described case report illustrates an unusual example of LHAS in a patient undergoing a planned coronary artery bypass surgery. In this case, surgical intervention was justified to avoid later outflow obstructions

Combined DNA methylation and gene expression profiling in gastrointestinal stromal tumors reveals hypomethylation of SPP1 as an independent prognostic factor

Cataloged from PDF version of article.Gastrointestinal stromal tumors (GISTs) have distinct gene expression patterns according to localization, genotype and aggressiveness. DNA methylation at CpG dinucleotides is an important mechanism for regulation of gene expression. We performed targeted DNA methylation analysis of 1.505 CpG loci in 807 cancer-related genes in a cohort of 76 GISTs, combined with genome-wide mRNA expression analysis in 22 GISTs, to identify signatures associated with clinicopathological parameters and prognosis. Principal component analysis revealed distinct DNA methylation patterns associated with anatomical localization, genotype, mitotic counts and clinical follow-up. Methylation of a single CpG dinucleotide in the non-CpG island promoter of SPP1 was significantly correlated with shorter disease-free survival. Hypomethylation of this CpG was an independent prognostic parameter in a multivariate analysis compared to anatomical localization, genotype, tumor size and mitotic counts in a cohort of 141 GISTs with clinical follow-up. The epigenetic regulation of SPP1 was confirmed in vitro, and the functional impact of SPP1 protein on tumorigenesis-related signaling pathways was demonstrated. In summary, SPP1 promoter methylation is a novel and independent prognostic parameter in GISTs, and might be helpful in estimating the aggressiveness of GISTs from the intermediate-risk category. © 2014 UICC