A recurrent novel fusion identifies a new subtype of high-grade spindle cell sarcoma.

-rearranged tumors are defined by the presence of a gene fusion between and various gene partners and typically follow a clinically aggressive disease course with poor outcomes despite conventional multimodality therapy. -rearranged tumors display histologic features of a poorly differentiated carcinoma with areas of focal squamous differentiation and typically express the fusion gene defining a distinct clinicopathologic entity-NUT carcinoma (NC). NCs with mesenchymal differentiation have rarely been described in the literature.

Expanding the Molecular Characterization of Thoracic Inflammatory Myofibroblastic Tumors beyond ALK Gene Rearrangements.

Introduction: Half of inflammatory myofibroblastic tumors (IMTs) regardless of anatomic location harbor anaplastic lymphoma kinase gene (ALK) rearrangements and overexpress anaplastic lymphoma kinase protein. The wide application of next-generation sequencing and the clinical benefit to tyrosine kinase inhibitors have opened new opportunities for investigation of ALK-negative IMTs.

Methods: In this study, we have investigated a series of pediatric and adult thoracic IMTs for abnormalities in a wide spectrum of actionable kinases by applying a variety of molecular and next-generation sequencing techniques, including fluorescence in situ hybridization (FISH), targeted RNA sequencing, and NanoString assay.

Novel PLAG1 Gene Rearrangement Distinguishes a Subset of Uterine Myxoid Leiomyosarcoma From Other Uterine Myxoid Mesenchymal Tumors.

Genetic alterations in uterine myxoid leiomyosarcoma are unknown. We investigate the clinicopathologic features of 19 uterine tumors previously diagnosed as myxoid leiomyosarcomas in which tumoral RNA was subjected to targeted RNA sequencing. PLAG1, BCOR, BCORL1, HMGA2, and ALK break-apart fluorescence in situ hybridization (FISH) and BCOR, PLAG1, and ALK immunohistochemistry were performed in cases which failed or lacked fusions by sequencing.

Adamantinoma-like Ewing Sarcoma of the Salivary Glands: A Newly Recognized Mimicker of Basaloid Salivary Carcinomas.

Adamantinoma-like Ewing sarcoma (ALES) is a rare tumor that demonstrates the EWSR1-FLI1 translocation characteristic of Ewing sarcoma despite overt epithelial differentiation including diffuse expression of cytokeratins and p40. Most cases of ALES described to date have occurred in the head and neck where they can mimic a wide range of small round blue cell tumors. Because distinguishing ALES from basaloid salivary gland carcinomas can be particularly difficult, we analyzed a series of 10 ALESs that occurred in the salivary glands with the aim of identifying features that allow for better recognition of this entity.

Genomic and transcriptomic characterisation of undifferentiated pleomorphic sarcoma of bone.

Undifferentiated pleomorphic sarcoma of bone (UPSb) is a rare primary bone sarcoma that lacks a specific line of differentiation. There is very little information about the genetic alterations leading to tumourigenesis or malignant transformation. Distinguishing between UPSb and other malignant bone sarcomas, including dedifferentiated chondrosarcoma and osteosarcoma, can be challenging due to overlapping features.

A novel group of spindle cell tumors defined by S100 and CD34 co-expression shows recurrent fusions involving RAF1, BRAF, and NTRK1/2 genes.

Tumors characterized by co-expression of S100 and CD34, in the absence of SOX10, remain difficult to classify. Triggered by a few index cases with monomorphic cytomorphology and distinctive stromal and perivascular hyalinization, immunopositivity for S100 and CD34, and RAF1 and NTRK1 fusions, the authors undertook a systematic review of tumors with similar features. Most of the cases selected were previously diagnosed as low-grade malignant peripheral nerve sheath tumors, while others were deemed unclassified.

Uterine Tumor Resembling Ovarian Sex Cord Tumor: A Distinct Entity Characterized by Recurrent NCOA2/3 Gene Fusions.

Uterine tumor resembling ovarian sex-cord tumor (UTROSCT) is a rare and distinctive neoplasm of unclear histogenesis, and uncertain malignant potential. These neoplasms morphologically resemble sex-cord stromal tumors of the ovary, and possess a polyphenotypic immunophenotype. Their molecular pathogenesis has yet to be elucidated; notably, however, tumors lack alterations found in other uterine tumors bearing sex-cord-like differentiation, such as endometrial stromal sarcoma.

Expanding the Spectrum of Genetic Alterations in Pseudomyogenic Hemangioendothelioma With Recurrent Novel ACTB-FOSB Gene Fusions.

Pseudomyogenic hemangioendothelioma (PHE) is an uncommon, rarely metastasizing vascular neoplasm with predilection to affect young adults. The tumors often present as multiple nodules involving various tissue planes, including superficial and deep soft tissues as well as bone. Recurrent SERPINE1-FOSB gene fusions have been reported as the hallmark genetic abnormality in PHE, however, in our experience, a number of cases with typical histology lack this genetic abnormality.

New advances in the molecular classification of pediatric mesenchymal tumors.

Pediatric soft tissue tumors are relatively rare and show significant overlap in morphology and immunoprofile, often posing diagnostic and management challenges. Thus, their classification remains often subjective or lumped under "unclassified categories," as a number of lesions lack objective and reproducible criteria in diagnosis. Although in a subset of cases immunohistochemistry has been proved useful to identify a specific line of differentiation, most tumors lack a readily defined histogenesis, being characterized by a rather non-specific immunoprofile.

MYOD1-mutant spindle cell and sclerosing rhabdomyosarcoma: an aggressive subtype irrespective of age. A reappraisal for molecular classification and risk stratification.

Sclerosing and spindle cell rhabdomyosarcoma is a rare histologic subtype, designated in the latest WHO classification as a stand-alone pathologic entity. Three genomic groups have been defined: an infantile subset of spindle cell rhabdomyosarcoma harboring VGLL2-related gene fusions, a MYOD1-mutant subset commonly associated with sclerosing morphology, and a subset lacking recurrent genetic abnormalities. In this study, we focus on MYOD1-mutant rhabdomyosarcoma to further define their clinicopathologic characteristics and behavior in a larger patient cohort.

Novel MEIS1-NCOA2 Gene Fusions Define a Distinct Primitive Spindle Cell Sarcoma of the Kidney.

We describe 2 cases of a distinct sarcoma characterized by a novel MEIS1-NCOA2 gene fusion. This gene fusion was identified in the renal neoplasms of 2 adults (21-y-old male, 72-y-old female). Histologically, the resected renal neoplasms had a distinctively nodular appearance, and while one renal neoplasm was predominantly cystic, the other demonstrated solid architecture, invasion of perirenal fat, and renal sinus vasculature invasion.

Plexiform fibrohistiocytic tumor: imaging features and clinical findings.

Objective: To describe the imaging features of plexiform fibrohistiocytic tumor and its associated clinical findings.

Materials And Methods: An institutional database was searched to identify all patients with a pathological diagnosis of plexiform fibrohistiocytic tumor. The electronic medical record was reviewed for relevant clinical data.

A Phase II Trial of Sorafenib and Dacarbazine for Leiomyosarcoma, Synovial Sarcoma, and Malignant Peripheral Nerve Sheath Tumors.

Background: Sorafenib and dacarbazine have low single-agent response rates in metastatic sarcomas. As angiogenesis inhibitors can enhance the efficacy of chemotherapy, we investigated the combination of sorafenib and dacarbazine in select sarcoma subtypes.

Materials And Methods: Patients with leiomyosarcoma (LMS), synovial sarcoma (SS), or malignant peripheral nerve sheath tumors (MPNST) with up to two previous lines of therapy and adequate hepatic, renal, and marrow function received 3-week cycles of sorafenib at 400 mg oral twice daily and dacarbazine 1,000 mg/m intravenously (later reduced to 850 mg/m).

A phase Ib study of BGJ398, a pan-FGFR kinase inhibitor in combination with imatinib in patients with advanced gastrointestinal stromal tumor.

Background Preclinical studies suggest that imatinib resistance in gastrointestinal stromal tumor (GIST) can be mediated by MAP-kinase activation via fibroblast growth factor (FGF) signaling. In FGF stimulated GIST cell lines, BGJ398, a pan-FGFR kinase inhibitor in combination with imatinib, was cytotoxic and superior to imatinib therapy alone. In FGF-dependent GIST, the combination of BGJ398 and imatinib may provide a mechanism to overcome imatinib resistance.

mTOR complex 1 controls the nuclear localization and function of glycogen synthase kinase 3β.

Glycogen synthase kinase 3β (GSK3β) phosphorylates and thereby regulates a wide range of protein substrates involved in diverse cellular functions. Some GSK3β substrates, such as c-Myc and Snail, are nuclear transcription factors, suggesting the possibility that GSK3β function is controlled through its nuclear localization. Here, using ARPE-19 and MDA-MB-231 human cell lines, we found that inhibition of mTOR complex 1 (mTORC1) leads to partial redistribution of GSK3β from the cytosol to the nucleus and to a GSK3β-dependent reduction of the levels of both c-Myc and Snail.

Dermatofibrosarcoma protuberans with a novel COL6A3-PDGFD fusion gene and apparent predilection for breast.

Dermatofibrosarcoma protuberans is a locally aggressive superficial mesenchymal neoplasm. It typically occurs in adulthood, and has been reported to have a slight male predilection. Tumors have a characteristic histopathologic appearance, including: storiform architecture, infiltrative "honeycomb" growth within subcutaneous adipose tissue, and immunoreactivity for CD34.

Uterine PEComas: A Morphologic, Immunohistochemical, and Molecular Analysis of 32 Tumors.

Uterine perivascular epithelioid cell tumors (PEComas) are rare neoplasms that may show overlapping morphology and immunohistochemistry with uterine smooth muscle tumors. In this study, we evaluated the morphologic, immunohistochemical, and molecular features of 32 PEComas, including 11 with aggressive behavior. Two distinct morphologies were observed: classic (n=30) and those with a lymphangioleiomyomatosis appearance (n=2).

Ectomesenchymal Chondromyxoid Tumor: A Neoplasm Characterized by Recurrent RREB1-MKL2 Fusions.

Ectomesenchymal chondromyxoid tumor is a rare and benign neoplasm with a predilection for the anterior dorsal tongue. Despite morphologic heterogeneity, most cases are characterized by a proliferation of bland spindle cells with a distinctive reticular growth pattern and myxoid stroma. The immunophenotype of these neoplasms is likewise variable; most cases express glial fibrillary acid protein and S100 protein, with inconsistent reports of keratin and myoid marker expression.

Lipofibromatosis-like neural tumor: Case report of a unique infantile presentation.

A 14-month-old boy presented with a slow-growing, asymptomatic back plaque, which was biopsied and found to have S100 positivity, sparse CD34 staining, and no significant mitotic activity, nuclear pleomorphism, or necrosis; genetic workup found gene fusion, overall consistent with lipofibromatosis-like neural tumor (LPF-NT). LPF-NT is rare, with 14 cases previously reported, and our patient is the first report of this diagnosis in infancy. This case report and literature review includes comparison of similar diagnoses including lipofibromatosis, low-grade malignant peripheral nerve sheath tumor, infantile fibrosarcoma, and dermatofibrosarcoma protuberans and serves to aid detection of LPF-NT presenting in pediatric patients by highlighting similarities and differences that should prompt consideration.

Recurrent rearrangements of FOS and FOSB define osteoblastoma.

The transcription factor FOS has long been implicated in the pathogenesis of bone tumours, following the discovery that the viral homologue, v-fos, caused osteosarcoma in laboratory mice. However, mutations of FOS have not been found in human bone-forming tumours. Here, we report recurrent rearrangement of FOS and its paralogue, FOSB, in the most common benign tumours of bone, osteoblastoma and osteoid osteoma.

PDLIM7 and CDH18 regulate the turnover of MDM2 during CDK4/6 inhibitor therapy-induced senescence.

CDK4/6 inhibitors are being used to treat a variety of human malignancies. In well-differentiated and dedifferentiated liposarcoma their clinical promise is associated with their ability to downregulate the MDM2 protein. The downregulation of MDM2 following treatment with CDK4/6 inhibitors also induces many cultured tumor cell lines derived from different types of malignancies to progress from quiescence into senescence.

Small Rho GTPases and the Effector VipA Mediate the Invasion of Epithelial Cells by Filamentous .

(Lp) exhibits different morphologies with varying degrees of virulence. Despite their detection in environmental sources of outbreaks and in respiratory tract secretions and lung autopsies from patients, the filamentous morphotype of Lp remains poorly studied. We previously demonstrated that filamentous Lp invades lung epithelial cells (LECs) and replicates intracellularly in a containing vacuole.