Clinicopathologic and Molecular Characteristics of Epstein-Barr Virus-Associated Smooth Muscle Tumor Compared With Those of Leiomyoma and Leiomyosarcoma.

Epstein-Barr virus (EBV)-associated smooth muscle tumors (EBV-SMTs) are rare smooth muscle neoplasms exclusively associated with immunosuppression, such as in patients with HIV/AIDS, posttransplant, and congenital immunodeficiency. However, the genomic landscape of EBV-SMTs is poorly understood. Leiomyosarcomas harbor genomic instability and multiple recurrent DNA copy number alterations, whereas leiomyomas lack such changes. Thus, this study aimed to fill this knowledge gap by characterizing copy number alterations in EBV-SMTs and correlating this information with clinicopathologic characteristics. Our study investigated and compared the pathologic characteristics and copy number profiles of 9 EBV-SMTs (from 7 post-transplant and AIDS patients), 6 leiomyomas, and 7 leiomyosarcomas, using chromosomal microarray platforms. Our results showed a lower copy number alteration burden in EBV-SMTs and leiomyoma than in leiomyosarcoma. This contrast in the molecular profile between EBV-SMTs and leiomyosarcoma is concordant with the different clinical behaviors and pathologic characteristics exhibited by these tumors. Despite having an overall copy number alteration profile closer to leiomyoma, recurrent copy number gain of oncogenes, such as RUNX1, CCND2, and ETS2, was found in EBV-SMTs. Epigenetic alterations may play an important role in tumorigenesis as recurrent copy number gains were found in histone deacetylases. A gene enrichment analysis also demonstrated enrichment of genes involved in the host response to viral infection, suggesting that the tumor immune microenvironment may play an important role in EBV-SMT tumorigenesis.

Primary Renal Hybrid Low-grade Fibromyxoid Sarcoma-Sclerosing Epithelioid Fibrosarcoma: An Unusual Pediatric Case With EWSR1-CREB3L1 Fusion.

Low-grade fibromyxoid sarcoma (LGFMS) and sclerosing epithelioid fibrosarcoma (SEF) are rare tumors with distinct sets of morphological features, both characterized by MUC4 immunoreactivity. Tumors exhibiting features of both entities are considered hybrid LGFMS-SEF lesions. While the majority of LGFMS cases are characterized by FUS-CREB3L2 gene fusions, most cases of pure SEF show EWSR1 gene rearrangements. In the largest study of hybrid LGFMS-SEF tumors to date, all cases exhibited FUS rearrangements, a similar genetic profile to LGFMS. We herein describe the clinicopathological features and genetic findings of a case of primary renal hybrid LGFMS-SEF occurring in a 10-year-old child, with disseminated metastases. Fusion gene detection using a next-generation sequencing-based anchored multiplex PCR technique (Archer FusionPlex Sarcoma Panel) was performed on both the primary renal tumor that showed the morphology of a LGFMS, and a cervical metastasis that showed the morphology of SEF. An EWSR1-CREB3L1 gene fusion occurring between exon 11 of EWSR1 and exon 6 of CREB3L1 was present in both the LGFMS and SEF components. This unusual case provides evidence that a subset of hybrid LGFMS-SEF harbor EWSR1-CREB3L1 gene fusions. In this case, these features were associated with an aggressive clinical course, with disease-associated mortality occurring within 12 months of diagnosis.

High-grade myoepithelial carcinoma can show histologically undifferentiated/anaplastic features.

High grade malignant tumors with a poorly-/un-differentiated morphology pose significant diagnostic challenges. Increasingly, the use of adjunct immunohistochemical and molecular tests to characterize and delineate the histopathologic phenotype of these tumors has become necessary, particularly in head and neck tumors. Recently, several entities with a poorly-/un-differentiated light microscopic morphology have been defined based on specific immunohistochemical and genetic characteristics. We herein describe two cases of high-grade myoepithelial carcinoma, one occurring in the submandibular gland and the other occurring in the left nasal cavity, both showing undifferentiated histological and anaplastic cytomorphological features. This led to very broad differential diagnostic considerations and the diagnosis was only established after extensive immunohistochemical studies. Molecular testing for HPV was negative in both cases. Gene fusion analysis using a targeted sequencing assay (Archer® FusionPlex® system) did not identify fusions involving PLAG1, HMGA2, EWSR1 or ALK genes in either case. The submandibular tumor showed an aggressive clinical course, with diffuse pulmonary metastases at presentation, whilst the nasal cavity tumor showed only localized disease. Awareness of a subcategory of high-grade myoepithelial carcinomas with undifferentiated light microscopical features is of significant importance in antibody selection for immunohistochemical investigation of poorly-/undifferentiated malignant tumors in the head and neck region. This histological variant of myoepithelial carcinoma adds to the growing list of differential diagnoses in this diagnostically complex and multifaceted field.

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.

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 2 years. 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.

MiR-210 is induced by Oct-2, regulates B cells, and inhibits autoantibody production.

MicroRNAs (MiRs) are small, noncoding RNAs that regulate gene expression posttranscriptionally. In this study, we show that MiR-210 is induced by Oct-2, a key transcriptional mediator of B cell activation. Germline deletion of MiR-210 results in the development of autoantibodies from 5 mo of age. Overexpression of MiR-210 in vivo resulted in cell autonomous expansion of the B1 lineage and impaired fitness of B2 cells. Mice overexpressing MiR-210 exhibited impaired class-switched Ab responses, a finding confirmed in wild-type B cells transfected with a MiR-210 mimic. In vitro studies demonstrated defects in cellular proliferation and cell cycle entry, which were consistent with the transcriptomic analysis demonstrating downregulation of genes involved in cellular proliferation and B cell activation. These findings indicate that Oct-2 induction of MiR-210 provides a novel inhibitory mechanism for the control of B cells and autoantibody production.

Locally Aggressive Rib Hemangioma With Glomeruloid and Papillary Features - Expanding the Clinicopathologic spectrum of Bone Hemangiomas.

Intra-osseous hemangiomas are uncommon tumors that can present diagnostic and treatment dilemmas. Bone hemangiomas with papillary and glomeruloid growth patterns are exceptionally rare. We present an example of an intra-osseous hemangioma of the rib displaying aggressive features on both radiology and histology. Morphologically, prominent papillary and glomeruloid architectural patterns were observed, in addition to features of cavernous and capillary hemangiomas. Extensive extra-osseous soft tissue involvement was seen. Awareness of the diverse histological features and locally aggressive behavior of bone hemangiomas is important in avoiding over-interpretation as a malignant lesion.

Long-term survival of transplanted allogeneic cells engineered to express a T cell chemorepellent.

BACKGROUND: Alloantigen specific T cells have been shown to be required for allograft rejection. The chemokine, stromal cell derived factor-1 (SDF-1) at high concentration, has been shown to act as a T-cell chemorepellent and abrogate T-cell infiltration into a site of antigen challenge in vivo via a mechanism termed fugetaxis or chemorepulsion. We postulated that this mechanism could be exploited therapeutically and that allogeneic cells engineered to express a chemorepellent protein would not be rejected. METHODS: Allogeneic murine insulinoma beta-TC3 cells and primary islets from BALB/C mice were engineered to constitutively secrete differential levels of SDF-1 and transplanted into allogeneic diabetic C57BL/6 mice. Rejection was defined as the permanent return of hyperglycemia and was correlated with the level of T-cell infiltration. The migratory response of T-cells to SDF-1 was also analyzed by transwell migration assay and time-lapse videomicroscopy. The cytotoxicity of cytotoxic T cell (CTLs) against beta-TC3 cells expressing high levels of SDF-1 was measured in standard and modified chromium-release assays in order to determine the effect of CTL migration on killing efficacy. RESULTS: Control animals rejected allogeneic cells and remained diabetic. In contrast, high level SDF-1 production by transplanted cells resulted in increased survival of the allograft and a significant reduction in blood glucose levels and T-cell infiltration into the transplanted tissue. CONCLUSIONS: This is the first demonstration of a novel approach that exploits T-cell chemorepulsion to induce site specific immune isolation and thereby overcomes allograft rejection without the use of systemic immunosuppression.

Hybrid Intercalated Duct Lesion of the Parotid: Diagnostic Challenges of a Recently Described Entity with Fine Needle Aspiration Findings.

Intercalated duct lesions (IDL) of the salivary glands are recently described, and encompass both hyperplasia and benign neoplasms that remain incompletely understood. IDLs have been linked to various benign and low-grade malignant salivary gland neoplasms. We herein present a case of a 77 year old woman with an IDL of the parotid composed of both a hyperplastic and an adenomatous component and report, for the first time, the fine needle aspiration findings of such a lesion. This case illustrates the morphologic spectrum of an IDL, as well as challenges in rendering an accurate cytological and histologic diagnosis. The potential diagnostic pitfalls presented by the hybrid pattern of this lesion are also discussed.

Minimally invasive carcinosarcoma ex pleomorphic adenoma: A case report and literature review with cytohistological correlation.

BACKGROUND: Carcinosarcoma of the salivary glands is a rare neoplasm, and the minimally invasive form constitutes a subgroup with a more favorable prognosis. The cytomorphologic features of this neoplasm can be appreciated on fine-needle aspiration biopsy. METHODS AND RESULTS: We present a patient with a minimally invasive carcinosarcoma ex non-recurrent pleomorphic adenoma (Ca ex PA) who underwent initial fine-needle aspiration biopsy followed by surgical resection. The tumor was composed predominantly of a light microscopic pleomorphic high-grade sarcoma exhibiting partial myoepithelial immunohistochemical features, with a minor component of in situ and invasive salivary duct carcinoma (10%). A limited area with features of a hyalinized pleomorphic adenoma was identified. CONCLUSION: This is the third case report of the cytological features of Ca ex PA of the salivary gland, with histologic correlation. It further illustrates the oncogenic relationship between epithelial and myoepithelial elements in the early stages of carcinosarcomatous transformation. © 2016 Wiley Periodicals, Inc. Head Neck 38: E2483-E2489, 2016.

Drug sensitivity testing platforms for gastric cancer diagnostics.

Gastric cancer diagnostics has traditionally been histomorphological and primarily the domain of surgical pathologists. Although there is an increasing usage of molecular and genomic techniques for clinical diagnostics, there is an emerging field of personalised drug sensitivity testing. In this review, we describe the various personalised drug sensitivity testing platforms and discuss the challenges facing clinical adoption of these assays for gastric cancer.