Adamantinoma-like Ewing Sarcoma of the thyroid gland: Cytomorphologic, phenotypic and molecular features.

Adamantinoma-like Ewing Sarcoma (ALES) is a rare subtype of Ewing sarcoma family of tumors (EFTs) which are defined by their EWSR1 gene rearrangements. We present a case of a 15-year old female with a swelling in her anterior neck of 4 months duration which had recently begun to rapidly grow in size. Fine needle aspiration showed a small blue round cell tumor with immunoreactivity for cytokeratin, CD99 and FLI1. Material for molecular testing was available on the resection specimen. Demonstration of t(11;22) (EWS-FLI1) was helpful in establishing the diagnosis.

[Histopathology and molecular profile of a case of prostatic Ewing sarcoma]. / Histopatología y perfil molecular de un caso de sarcoma de Ewing prostático.

We report a case of Ewing sarcoma localized in the prostate gland of a 33-year-old patient without bone or soft tissue involvement. Evidence of EWS and FLI1 gene translocation was detected by fluorescence in situ hybridization (FISH). This is an unusual case with an interesting clinical presentation; indeed, only a few cases have been reported to date and not all have the supporting biological studies now considered essential for the diagnosis.

Ewing sarcoma.

Ewing sarcoma is the second most frequent bone tumour of childhood and adolescence that can also arise in soft tissue. Ewing sarcoma is a highly aggressive cancer, with a survival of 70-80% for patients with standard-risk and localized disease and ~30% for those with metastatic disease. Treatment comprises local surgery, radiotherapy and polychemotherapy, which are associated with acute and chronic adverse effects that may compromise quality of life in survivors. Histologically, Ewing sarcomas are composed of small round cells expressing high levels of CD99. Genetically, they are characterized by balanced chromosomal translocations in which a member of the FET gene family is fused with an ETS transcription factor, with the most common fusion being EWSR1-FLI1 (85% of cases). Ewing sarcoma breakpoint region 1 protein (EWSR1)-Friend leukaemia integration 1 transcription factor (FLI1) is a tumour-specific chimeric transcription factor (EWSR1-FLI1) with neomorphic effects that massively rewires the transcriptome. Additionally, EWSR1-FLI1 reprogrammes the epigenome by inducing de novo enhancers at GGAA microsatellites and by altering the state of gene regulatory elements, creating a unique epigenetic signature. Additional mutations at diagnosis are rare and mainly involve STAG2, TP53 and CDKN2A deletions. Emerging studies on the molecular mechanisms of Ewing sarcoma hold promise for improvements in early detection, disease monitoring, lower treatment-related toxicity, overall survival and quality of life.

[Pulmonary microcystic fibromyxoma: report of a case with review of literature].

Objective: To study the clinicopathologic features, diagnosis and differential diagnosis of pulmonary microcystic fibromyxoma. Methods: In March 2014, at the First Affiliated Hospital to Nanjing Medical University a 58-year-old female patient of pulmonary microcystic fibromyxoma was collected. The clinicopathologic, immunohistochemical and genetic profile of a case of pulmonary microcystic fibromyxoma were studied, and the relevant literature reviewed. Results: The patient was a 58-year-old female who presented with cough and sputum for 1 month. CT scan disclosed a 15 mm nodule in her right middle lobe of lung. The patient underwent a wedge resection with negative margin. Grossly, a well-demarcated peripheral lung nodule was detected, measuring 1.5 cm×1.5 cm×1.0 cm, with myxoid tan-white cut surface containing microcysts. Microscopically, the tumor was composed of bland spindled to stellate-shaped cells widely spaced within prominent fibromyxoid stroma with prominent cystic change. No mitosis or necrosis was present. There were inconspicuous slim curvilinear capillaries and occasional collection of stromal lymphocytes and plasma cells. Immunohistochemically, the tumor cells were positive for vimentin, but negative for CD34, SMA, desmin, S-100 protein, ALK, CKpan, EMA, calretinin and TTF1. Fluorescence in situ hybridization did not show chromosomal translocation involving EWSR1, DDIT3 or FUS genes. The patient was recurrence or metastasis free after follow-up for 38 months. Conclusion: Pulmonary microcystic fibromyxoma is a rare benign lesion that should be differentiated from other lung tumors with myxoid characteristics.

The Ewing sarcoma protein regulates DNA damage-induced alternative splicing.

The Ewing sarcoma (EWS) protein is a member of the TET (TLS/EWS/TAF15) family of RNA- and DNA-binding proteins whose expression is altered in cancer. We report that EWS depletion results in alternative splicing changes of genes involved in DNA repair and genotoxic stress signaling, including ABL1, CHEK2, and MAP4K2. Chromatin and RNA crosslinking immunoprecipitation results indicate that EWS cotranscriptionally binds to its target RNAs. This association is reduced upon irradiation of cells with ultraviolet light, concomitant with transient enrichment of EWS in nucleoli and with alternative splicing changes that parallel those induced by EWS depletion and that lead to reduced c-ABL protein expression. Consistent with the functional relevance of EWS-mediated alternative splicing regulation in DNA damage response, EWS depletion reduces cell viability and proliferation upon UV irradiation, effects that are attenuated by restoring c-ABL expression. These results provide insights into posttranscriptional mechanisms of DNA damage response by a TET protein.

[An unusual adrenal tumor: Ewing tumor]. / Une tumeur surrénalienne inhabituelle : tumeur d'Ewing.

We report the case of a voluminous tumor of the adrenal diagnosed in a young pregnant woman at 26(th) week of amenorrhea. Morphologically, a soft white tumor with haemorragic areas was observed, made of sheets of monomorphous, medium sized, spindle-shaped to polygonal, with high mitotic activity. Tumorous cells expressed cytokeratins AE1/AE3, EMA, and CD99 (expression of vimentin is not relevant). Contemplated diagnoses included poorly differentiated synovialosarcoma, sarcomatoid carcinoma and Ewing tumor. Thanks to molecular biology, showing the specific transcript of Ewing/peripheral primitive neuroectodermal tumor (pPNET) EWS/FLI1, the diagnosis of this atypical tumor in an unusual location was performed. Indeed, 75% of Ewing tumors involve bones (especially, the diaphysis of long bones) and 20 to 25% soft tissues. Primitive visceral involvement is rare; less than 10 cases of adrenal involvement have been reported. The hypothesis that Ewing cell's origin is a mesenchymal stem cell, which may derive from neural crest cell, could explain the uncommon adrenal involvement. Diagnosis of Ewing tumor is based on pathologic and molecular findings, especially in atypical cases.

Unusual myogenic and melanocytic differentiation of soft tissue pPNETs: an immunohistochemical and molecular study of 3 cases.

All of the members of the peripheral primitive neuroectodermal tumor family (Ewing sarcomas, neuroectodermal tumors of bone, peripheral neuroepitheliomas, and Askin tumors) have similar morphologic and immunophenotypical features (ie, the proliferation of small and medium-sized round cells in a fibrous background showing strong and diffuse immunohistochemical positivity for CD99), and the common cytogenetic abnormality of a nonrandom translocation involving the EWS gene and one of several members of the erythroblastosis virus transforming sequence family of transcription factors. The combination of clinical information and morphologic/immunophenotypical characteristics is usually sufficient for a correct diagnosis, but there are rare cases in which an unusual predominant or multidirectional immunophenotypical differentiation makes diagnosis a challenge and requires the use of molecular cytogenetic or molecular techniques. We describe 3 such cases in which we employed fluorescence in-situ hybridization analysis to detect translocation involving the EWS gene and reverse transcription polymerase chain reaction followed by sequencing to detect the fusion transcript EWS-FLI1.

Dynamic subcellular localization of the Ewing sarcoma proto-oncoprotein and its association with and stabilization of microtubules.

The Ewing sarcoma (EWS) protein is a member of a large family of RNA-binding proteins. Chimeric EWS oncoproteins generated by chromosomal translocations between the EWS protein and several transcription factors cause various malignant tumors. Due to its multifunctional properties, the EWS protein is involved in such processes as meiotic DNA pairing/recombination, cellular senescence, gene expression, RNA processing and transport, and cell signaling. The EWS protein is predominantly located in the nucleus. It was found in the cytoplasm and associated with the cell membrane. In this study, analysis of the localization of endogenous and fluorescently labeled recombinant EWS protein in different phases of the cell cycle in different cell lines revealed a very dynamic subcellular distribution of the EWS protein. In Cos7 and HeLa cells, an association of the EWS protein with the centrosomal compartments was shown. Furthermore, in HEK (human embryonic kidney)-293 (T) cells, an interaction of the overexpressed recombinant EWS-yellow fluorescent protein fusion protein with microtubules, leading to their stabilization and cell cycle arrest, was demonstrated. As an outlook, the present findings provide an important insight into temporally and spatially regulated functions of the EWS protein and, particularly, into its role in the regulation of the cell cycle and possibly cell differentiation.