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Biphenotypic sinonasal sarcoma (BSNS) is a rare, low grade spindle cell sarcoma, recently recognized in the WHO classification of head and neck tumors, which is characterized by a dual myogenic and neural differentiation and recurrent gene fusions, often involving PAX3‐MAML3, and less commonly PAX3 fusions with other partners such as NCOA1, NCOA2, or WWTR1. Yet, in about 4% of tumors no gene rearrangements are identified. Herein, we describe a RREB1‐MKL2 fusion in a BSNS lesion occurring in a 73‐year‐old female patient with a right maxillo‐ethmoidal angle lesion. The polypoid, moderately cellular tumor with infiltrative submucosal growth was composed of fascicles of relatively bland spindle cells embedded in a loose collagenous matrix. The tumor cells showed moderate amounts of eosinophilic cytoplasm with indistinct borders and uniform, pale, ovoid to slender nuclei. The slowly proliferating neoplastic cells co‐expressed smooth muscle actin and S100, and showed focal nuclear positivity for ß‐catenin, while lacking staining for cytokeratins, desmin, myogenin, caldesmon, glial fibrillary acid protein, and SOX‐10. Molecular analysis by targeted RNA‐based next‐generation sequencing identified an in‐frame fusion between exon 8 of RREB1 and exon 11 of MKL2, a genetic event that was reported to be a molecular hallmark of ectomesenchymal chondromyxoid tumor. Gene rearrangements in both genes were independently verified by fluorescence in situ hybridization (FISH). To evaluate its recurrent potential an additional group of 15 fusion negative BSNS were tested for abnormalities in RREB1 and MKL2 genes by FISH, but no additional positive cases were identified.

Anlässlich von aktuellen Diskussionen über die Durchführung von Tonsillotomien in Deutschland haben die Autoren wichtige wissenschaftliche Aspekte zusammengetragen und mit den Mitgliedern der Kommission "Ambulante Operationen" der Deutschen Gesellschaft für HNO-Heilkunde, Kopf-und Halschirurgie, abgestimmt. Der Gemeinsame Bundesausschuss (G-BA) hat im Jahr 2018 das Verfahren der Gaumenmandel-Teilentfernung (Tonsillotomie) als Leistung der gesetzlichen Krankenkassen für die Behandlung im Krankenhaus und in der ambulanten Medizin beschlossen. Für die ambulante Teilentfernung vergrößerter Gaumenmandeln legte der G-BA zur Indikationsstellung fest, dass der operative Eingriff nur bei Patientinnen und Patienten ab dem vollendeten ersten Lebensjahr durchgeführt werden darf, bei denen die Hyperplasie eine symptomatische, klinisch relevante Beeinträchtigung verursacht und eine konservative Behandlung nicht ausreicht. Im Anschluss an die Tonsillotomie müsse eine ausreichend lange Überwachung sichergestellt sein. Die Operation dürfe zudem nur von Fachärztinnen und Fachärzten für Hals-Nasen-Ohrenheilkunde durchgeführt werden, die eine Genehmigung ihrer Kassenärztlichen Vereinigung entsprechend der Qualitätssicherungsvereinbarung "Ambulantes Operieren" besitzen. Um in den Katalog ambulant durchführbarer Operationen aufgenommen zu werden, muss noch festgelegt werden, ob die Tonsillotomie als obligat ambulant (Kategorie 1) oder optional ambulant (Kategorie 2) eingeordnet wird. Wir sind der Ansicht, dass die Tonsillotomie nur in Kategorie 2 eingeordnet werden kann. Medizinische Gründe verbieten nach unserer Meinung eine Einordnung in Kategorie 1.

The onset of numerous cancers is strongly associated with exposure to genotoxic agents and is counteracted by cellular DNA repair mechanisms. However, the tumorigenic potential of genotoxic carcinogens varies widely among individuals. It is still uncertain which genetic and epigenetic traits shape cancer onset and progression in the general population. While genetic aberrations in DNA repair genes have been linked to cancer risk, less is known about the importance of epigenetics for the regulation of these genes. In order to identify DNA methylation alterations in laryngeal cancer we carried out targeted DNA methylation analysis at single CpG sites via mass spectrometry. We focused our analysis on five DNA repair-associated gene loci previously found to be altered in head and neck squamous cell carcinoma. We report loss of DNA methylation at the three prime repair exonuclease 2 (TREX2) gene locus in laryngeal cancer (n=161) and adjacent normal tissue (n=58) samples of patients from a German population-based case-control study. Following screening of tumor tissues from Chinese colorectal cancer patients as well as previously published data from the Cancer Genome Atlas (TCGA), we identified TREX2 methylation loss as a frequent trait in multiple cancers. We further characterized the regulatory activity of the affected TREX2 site using chromatin immunoprecipitation and luciferase reporter assays in cell models from different tumor types. Differential TREX2 methylation affects a CCAAT/enhancer binding protein alpha (CEBPA) binding site serving as a gene enhancer which drives the expression of TREX2 from a previously uncharacterized gene promoter. We also observed a strong association between TREX2 methylation and TREX2 protein expression determined via immunohistochemistry in laryngeal tumors. Finally, we found a significant association between overall survival and loss of TREX2 methylation in laryngeal cancer, with TREX2 methylation loss being a protective factor. Our findings highlight a profound regulatory role of epigenetic mechanisms for TREX2 in tumors, and underline the usefulness of TREX2 DNA methylation as a biomarker for patient stratification. Citation Format: Christoph Weigel, Jittiporn Chaisaingmongkol, Christine Kuhmann, Irene Santi, Volker Winkler, Olga Bogatyrova, Justo L. Bermejo, Tsun L. Chan, Felix Lasitschka, Manfred H. Bohrer, Alexander Marx, Frank Autschbach, Roland Heyni-von Haußen, Gerhard Dyckhoff, Klaus-Wolfgang Delank, Karl Hoermann, Burkard M. Lippert, Gerald Baier, Andreas Dietz, Christopher C. Oakes, Christoph Plass, Heiko Becher, Peter Schmezer, Heribert Ramroth, Odilia Popanda. DNA methylation loss at an enhancer site of the DNA repair gene TREX2 is an epigenetic feature in multiple cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3364. doi:10.1158/1538-7445.AM2017-3364

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