Clinical practice guidelines for the treatment of Ewing sarcoma (Spanish Sarcoma Research Group-GEIS).

Ewing sarcoma is a small round-cell sarcoma characterized by gene fusion involving EWSR1 (or another TET family protein like FUS) and an ETS family transcription factor. The estimated incidence of this rare bone tumor, which occurs most frequently in adolescents and young adults, is 0.3 per 100,000/year. Although only 25% of patients with Ewing sarcoma are diagnosed with metastatic disease, historical series show that this is a systemic disease. Patient management requires multimodal therapies-including intensive chemotherapy-in addition to local treatments (surgery and/or radiotherapy). In the recurrent/refractory disease setting, different approaches involving systemic treatments and local therapies are also recommended as well as patient inclusion in clinical trials whenever possible. Because of the complexity of Ewing sarcoma diagnosis and treatment, it should be carried out in specialized centers and treatment plans should be designed upfront by a multidisciplinary tumor board. These guidelines provide recommendations for diagnosis, staging, and multimodal treatment of Ewing sarcoma.

Primary sclerosing epitheloid fibrosarcoma of the kidney: First case reported in Mexico.

Here we reported a case of primary sclerosing epitheloid fibrosarcoma (SEF) of the kidney, an extremely rare and aggressive tumor. The patient presented a mass in the upper part of the right kidney with pulmonary metastasis at the time of diagnosis, a right radical nephrectomy was performed, it was a solid tumor of 15 cm × 9 cm affecting almost the entire kidney. Histological study revealed a neoplasm of uniform epithelioid cells with scant cytoplasm with dense and sclerotic stroma. immunohistochemistry positive for MUC-4, detection by fusion of EWSR1-CREB3L1 by FISH positive.

A rare case of vulvar extraskeletal myxoid chondrosarcoma: mimics and diagnostic clues.

Only 14 cases of extraskeletal myxoid chondrosarcoma (EMC) of the vulva have been documented in the literature. We report a case of a 63-year-old woman with EMC of the vulva confirmed by both EWSR1 and NR4A3 fluorescence in situ hybridization, the latter of which is a more specific probe for this entity. The unusual location of this tumor of prominent myxoid morphology gave rise to a wide differential diagnosis, which necessitated thorough histologic evaluation and confirmatory ancillary testing in the form of immunohistochemistry and cytogenetic studies. This article aims to review extraskeletal myxoid chondrosarcoma of the vulva and various diagnostic clues to help differentiate it from its histologic mimics. This is the fifth case of vulvar EMC in the literature with confirmation of a NR4A3 gene rearrangement.

EWSR1-ATF1 Fusion in a Myoepithelial Carcinoma of Soft Tissue With Small Round Cell Morphology: A Potential Diagnostic Pitfall.

Myoepithelial tumors of soft tissue are rare mesenchymal neoplasms that overlap with their salivary gland and skin counterparts at both the histopathologic and molecular levels. EWSR1 gene rearrangements with various fusion partners represent a common genetic event in myoepithelial tumors of soft tissue, whether benign or malignant, and may prove useful as a diagnostic tool in difficult cases. However, the number of diagnostic entities with EWSR1 gene rearrangements has grown considerably in recent years, and there is significant morphologic and immunophenotypic overlap amongst this group, underscoring the importance of fusion testing to detect fusion partners that are characteristic of discrete diagnostic entities. Herein, we report a malignant myoepithelial tumor of soft tissue/myoepithelial carcinoma with an undifferentiated round cell morphology arising in a pediatric patient with a EWSR1-ATF1 gene fusion.

The spectrum of rare central nervous system (CNS) tumors with EWSR1-non-ETS fusions: experience from three pediatric institutions with review of the literature.

The group of CNS mesenchymal (non-meningothelial) and primary glial/neuronal tumors in association with EWSR1-non-ETS rearrangements comprises a growing spectrum of entities, mostly reported in isolation with incomplete molecular profiling. Archival files from three pediatric institutions were queried for unusual cases of pediatric (≤21 years) CNS EWSR1-rearranged tumors confirmed by at least one molecular technique. Extra-axial tumors and cases with a diagnosis of Ewing sarcoma (EWSR1-ETS family fusions) were excluded. Additional studies, including anchored multiplex-PCR with next-generation sequencing and DNA methylation profiling, were performed as needed to determine fusion partner status and brain tumor methylation class, respectively. Five cases (median 17 years) were identified (M:F of 3:2). Location was parenchymal (n = 3) and undetermined (n = 2) with topographic distributions including posterior fossa (n = 1), frontal (n = 1), temporal (n = 1), parietal (n = 1) and occipital (n = 1) lobes. Final designation with fusion findings included desmoplastic small round cell tumor (EWSR1-WT1; n = 1) and tumors of uncertain histogenesis (EWSR1-CREM, n = 1; EWSR1-CREB1, n = 1; EWSR1-PLAGL1, n = 1; and EWSR1-PATZ1, n = 1). Tumors showed a wide spectrum of morphology and biologic behavior. For EWSR1-CREM, EWSR1-PLAGL1 and EWSR1-PATZ1 tumors, no significant methylation scores were reached in the known brain tumor classes. Available outcome (4/5) was reported as favorable (n = 2) and unfavorable (n = 2) with a median follow-up of 30 months. In conclusion, we describe five primary EWSR1-non-ETS fused CNS tumors exhibiting morphologic and biologic heterogeneity and we highlight the clinical importance of determining specific fusion partners to improve diagnostic accuracy, treatment and monitoring. Larger prospective clinicopathological and molecular studies are needed to determine the prognostic implications of histotypes, anatomical location, fusion partners, breakpoints and methylation profiles in patients with these rare tumors.

A rare case of vulvar extraskeletal myxoid chondrosarcoma: mimics and diagnostic clues

Only 14 cases of extraskeletal myxoid chondrosarcoma (EMC) of the vulva have been documented in the literature. We report a case of a 63-year-old woman with EMC of the vulva confirmed by both EWSR1 and NR4A3 fluorescence in situ hybridization, the latter of which is a more specific probe for this entity. The unusual location of this tumor of prominent myxoid morphology gave rise to a wide differential diagnosis, which necessitated thorough histologic evaluation and confirmatory ancillary testing in the form of immunohistochemistry and cytogenetic studies. This article aims to review extraskeletal myxoid chondrosarcoma of the vulva and various diagnostic clues to help differentiate it from its histologic mimics. This is the fifth case of vulvar EMC in the literature with confirmation of a NR4A3 gene rearrangement.

Hyalinizing clear cell carcinoma of the soft palate: a review of literature review.

Hyalinizing clear cell carcinoma (HCCC), also known as clear cell carcinoma, not otherwise specified [CCC, (NOS)], is a rare minor salivary gland tumor characterized by proliferation of clear cells, organized in trabecular cords, or solid nests within loose to densely hyalinized stroma. It is considered a diagnosis of exclusion by the World Health Organization (WHO) because other salivary tumors may also have a clear cell component. Hence, there is a wide differential diagnosis. EWSR1-ATF1 gene rearrangements are fairly specific for this tumor, however, one of the recent studies have described its presence in clear cell odontogenic carcinoma (CCOC) one of its histologic mimickers. EWSR1 and CREM fusions have recently been described in these tumors but its importance is still not well described. Here we present a case of a 33-year-old woman who presented with a recurrent lesion of the soft palate. Her initial lesion was resected and diagnosed as low-grade myoepithelial tumor. Surgical margins at the time of initial resection were positive and the re-excision was recommended but the patient did not undergo surgery. Two years later, local recurrence at the same site was found and an excision was performed yielding negative margins. Histopathologic examination revealed features consistent with hyalinizing clear cell carcinoma. The patient remains disease free 1 year after the re-excision. The pathology, clinical characteristics, differential diagnosis and treatment of hyalinizing clear cell carcinoma are reviewed.

Hyalinizing clear cell carcinoma of the soft palate: a review of literature review

Hyalinizing clear cell carcinoma (HCCC), also known as clear cell carcinoma, not otherwise specified [CCC, (NOS)], is a rare minor salivary gland tumor characterized by proliferation of clear cells, organized in trabecular cords, or solid nests within loose to densely hyalinized stroma. It is considered a diagnosis of exclusion by the World Health Organization (WHO) because other salivary tumors may also have a clear cell component. Hence, there is a wide differential diagnosis. EWSR1-ATF1 gene rearrangements are fairly specific for this tumor, however, one of the recent studies have described its presence in clear cell odontogenic carcinoma (CCOC) one of its histologic mimickers. EWSR1 and CREM fusions have recently been described in these tumors but its importance is still not well described. Here we present a case of a 33-year-old woman who presented with a recurrent lesion of the soft palate. Her initial lesion was resected and diagnosed as low-grade myoepithelial tumor. Surgical margins at the time of initial resection were positive and the re-excision was recommended but the patient did not undergo surgery. Two years later, local recurrence at the same site was found and an excision was performed yielding negative margins. Histopathologic examination revealed features consistent with hyalinizing clear cell carcinoma. The patient remains disease free 1 year after the re-excision. The pathology, clinical characteristics, differential diagnosis and treatment of hyalinizing clear cell carcinoma are reviewed.

Clear Cell Odontogenic Carcinoma Harboring the EWSR1-ATF1 Fusion Gene: Report of a Rare Case.

Clear cell odontogenic carcinoma (CCOC) is a rare and aggressive malignant epithelial neoplasm, which occurs most frequently in the mandible of elderly patients. Morphologically, CCOC shares similar characteristics with other clear cell tumors, especially hyalinizing clear cell carcinoma of the salivary glands (HCCC). Both CCOC and HCCC are known to harbor EWSR1 rearrangements, especially the EWSR1-ATF1 gene fusion, which indicates a possible link between the two lesions. So far, this fusion has been demonstrated in five cases of CCOC in the literature. Herein, we add another CCOC case to the literature, which arose in the mandible of an 82-year-old female patient and was proven to harbor the EWSR1-ATF1 gene fusion. Immunohistochemically, this case was focally positive for CK7, CK14, CK19 and p63. The patient was referred to surgical treatment; however, she died of disease 2 months after the diagnosis, thereby demonstrating the aggressive nature of this tumor.

Pulmonary extraskeletal myxoid chondrosarcoma: A case report and literature review.

BACKGROUND: Extraskeletal myxoid chondrosarcoma (EMC) accounts for the 3% of all soft tissue sarcomas and it's categorized as a tumour of uncertain differentiation. This entity has shown to have the recurrent balanced chromosomal translocation t(9;22) (q22;q12.2), which leads to the oncogenic fusion gene EWSR1-NR4A3. This sarcoma usually presents as a slow growing, palpable mass in the extremities. EMC arising from the lung is extremely infrequent. We report one case of pulmonary extraskeletal mixoid chondrosarcoma and a review of the world literature. CASE REPORT: A 69-year-old male patient presented with intermittent hemoptysis for the last 6 months. A PET/CT scan showed a hypermetabolic solid mass with lobulated borders of approximately 29×26mm in the inferior right lobe. We performed a right thoracotomy with inferior lobectomy and lymphadenectomy of levels VII, VIII, X, and XI levels. The neoplasm was constituted by cords of small cells with small round nucleus and scarce cytoplasm immerse in an abundant myxoid matrix. The immunophenotype was positive for MUM-1, CDK4, MDM2, and showed focal expression for S-100 protein and CD56. The final pathology report revealed a pulmonary extraskeletal mixoid chondrosarcoma. No further surgical interventions or adjuvant therapies were needed. CONCLUSION: EMC is an intermediate-grade neoplasm, characterized by a long clinical course with high potential for local recurrence and distant metastasis. Treatment for EMC is surgical and non-surgical treatment is reserved for recurrence or metastatic disease. Pulmonary extraskeletal myxoid chondrosarcoma is a rare neoplasm with only isolated case reports found in the literature.

Molecular signature of salivary gland tumors: potential use as diagnostic and prognostic marker.

Salivary gland tumors are a highly heterogeneous group of lesions with diverse microscopic appearances and variable clinical behavior. The use of clinical and histological parameters to predict patient prognosis and survival rates has been of limited utility, and the search for new biomarkers that could not only aid in a better understanding of their pathogenesis but also be reliable auxiliaries for prognostic determination and useful diagnostic tools has been performed in the last decades with very exciting results. Hence, gene rearrangements such as CRTC1-MAML2 in mucoepidermoid carcinomas have shown excellent specificity, and more than that, it has been strongly correlated with low-grade tumors and consequently with an increased survival rate and better prognosis of patients affected by neoplasms carrying this translocation. Moreover, MYB-NFIB and EWSR1-ATF1 gene fusions were shown to be specifically found in cases of adenoid cystic carcinomas and hyalinizing clear cell carcinomas, respectively, in the context of salivary gland tumors, becoming reliable diagnostic tools for these entities and potential therapeutic targets for future therapeutic protocols. Finally, the identification of ETV6-NTRK3 in cases previously diagnosed as uncommon acinic cell carcinomas, cystadenocarcinomas, and adenocarcinomas not otherwise specified led to the characterization of a completely new and now widely accepted entity, including, therefore, mammary analogue secretory carcinoma in the list of well-recognized salivary gland carcinomas. Thus, further molecular investigations of salivary gland tumors are warranted, and the recognition of other genetic abnormalities can lead to the acknowledgment of new entities and the acquirement of reliable biomarkers.

Nasopharyngeal hyalinizing clear cell carcinoma: report of the histopathologic features of a case showing EWSR1 rearrangements by FISH and literature review.

BACKGROUND: Hyalinizing clear cell carcinoma (HCCC) is a rare low-grade malignant tumor affecting the minor salivary glands; nasopharyngeal involvement is uncommon. METHODS AND RESULTS: A 38-year-old male patient presented with a 3.2 × 4.5 × 4.4 cm expansile mass obliterating the lumen of the nasopharynx and extending into the left nasal cavity. Histopathologically, the tumor was characterized by clear round to polygonal epithelial cells arranged in anastomosing trabeculae and solid nests. The stroma consisted of fibromyxoid connective tissue with areas of intense hyalinization and desmoplasia. Immunohistochemically, strong and diffuse reactivity for AE1/AE3, CK5/6, and p63 was observed. EWSR1 gene rearrangement was confirmed by fluorescence in situ hybridization. The diagnosis of nasopharyngeal HCCC was rendered. Surgical excision was performed along with adjuvant radiotherapy and chemotherapy. CONCLUSIONS: HCCC generally demonstrates good prognosis with low metastatic potential. Identification of EWSR1 gene disruption is usefulin discerning HCCC from other neoplasms with overlapping microscopic features.