From epistaxis to bone pain-report of two cases illustrating the clinicopathological spectrum of phosphaturic mesenchymal tumour with fibroblast growth factor receptor 1 immunohistochemical and cytogenetic analyses

Aims: Phosphaturic mesenchymal tumour (PMT) is a rare, recently described neoplastic entity. It is characterized by distinct histological features, which often occur together with oncogenic osteomalacia. Recently, a novel FN1-FGFR1 gene fusion has been described in a subset of PMTs. The aim of this study is to characterise the clinicopathological features of two PMTs, with FGFR1 immunohistochemical and cytogenetic analyses. Methods and results: We present two contrasting cases of PMT, one occurring in the sinonasal region, and the other occurring in bone (proximal femur). In the former, local effects, including epistaxis and anosmia, dominated the clinical presentation, whereas the latter case presented with refractory bone pain, muscle weakness, and occult osteomalacia, the cause of which was only identified after 2years. Both tumours showed characteristic histological features of PMT, including a monomorphic proliferation of round to ovoid cells, osteoclast-like multinucleated giant cells, and areas of smudgy' basophilic calcifications. Chromogenic in-situ hybridization showed fibroblast growth factor FGF-23 expression by the sinonasal tumour. By using immunohistochemistry, we also demonstrated, for the first time, FGF receptor 1 (FGFR1) protein overexpression in this tumour, for which FN1-FGFR1 gene fusion was not detected by fluorescence in-situ hybridization. Conclusions: Our findings indicate that up-regulation of FGFR1 in phosphaturic mesenchymal tumours can occur via mechanisms other than FN1-FGFR1 fusion, raising the possibility of FGFR1 overexpression being a potential common pathway with pathophysiological and therapeutic implications

The Genomics and Molecular Biology of Natural Killer/T-Cell Lymphoma: Opportunities for Translation

Extranodal NK/T-cell lymphoma, nasal type (ENKTL), is an aggressive malignancy with a poor prognosis. While the introduction of L-asparaginase in the treatment of this disease has significantly improved the prognosis, the outcome of patients relapsing after asparaginase-based chemotherapy, which occurs in up to 50% of patients with disseminated disease, remains dismal. There is hence an urgent need for effective targeted therapy especially in the relapsed/refractory setting. Gene expression profiling studies have provided new perspectives on the molecular biology, ontogeny and classification of ENKTL and further identified dysregulated signaling pathways such as Janus associated kinase (/Signal Transducer and activation of transcription (JAK/STAT), Platelet derived growth factor (PDGF), Aurora Kinase and NF-κB, which are under evaluation as therapeutic targets. Copy number analyses have highlighted potential tumor suppressor genes such as PR Domain Zinc Finger Protein 1 (PRDM1) and protein tyrosine phosphatase kappa (PTPRK) while next generation sequencing studies have identified recurrently mutated genes in pro-survival and anti-apoptotic pathways. The discovery of epigenetic dysregulation and aberrant microRNA activity has broadened our understanding of the biology of ENKTL. Importantly, immunotherapy via Programmed Cell Death -1 (PD-1) and Programmed Cell Death Ligand1 (PD-L1) checkpoint signaling inhibition is emerging as an attractive therapeutic strategy in ENKTL. Herein, we present an overview of the molecular biology and genomic landscape of ENKTL with a focus on the most promising translational opportunities