EWSR1 rearrangement in papillary thyroid microcarcinoma is related to classic morphology and the presence of small-cell phenotype

The EWSR1 rearrangements with unknown genes were detected in a high percentage of classic variants of papillary thyroid carcinoma. The small-cell carcinoma of the thyroid with Ewing family tumor elements (CEFTE) typically presents with EWSR1-FLI1 rearrangement suggesting the possible role of EWSR-FLI1 translocation in the loss of thyroid differentiation and acquisition of a small-cell phenotype. In order to determine the frequency and association of EWSR1 rearrangements, particularly the EWSR1-FLI1 fusion with clinicopathological features of papillary thyroid microcarcinoma (m-PTC) and the presence of small cells, we analyzed a series of 99 m-PTCs using the fluorescence in situ hybridization method. Ninety cases (90.9%) of m-PTC were positive for small cells. This group of m-PTC has shown more often invasive growth, lymphatics invasion, and moderate/extended intratumoral fibrosis. Three cases out of 99 were inconclusive for EWSR1 rearrangement. Eighty-nine (92.7%) and twenty-seven (28.1%) out of 96 m-PTC cases were positive for EWSR1 rearrangement and EWSR1-FLI1 fusion, respectively. m-PTC with classical architectural pattern presented more frequently with EWSR1 rearrangement relative to m-PTC with other patterns (p = 0.005). Other clinicopathological features were not related to the presence of EWSR1 rearrangement or EWSR1-FLI1 fusion. The percentage of small cells present significantly correlated with the percentage of cells positive for EWSR1-FLI1 fusion (p = 0.05) and EWSR1 rearrangement (p <0.001). EWSR1-FLI1 fusion is not rare in m-PTC and it is associated with the acquisition of small-cell phenotype. The EWSR1 gene rearrangement is a frequent event in m-PTC and is related to the classical pattern of m-PTC.

Clear Cell Odontogenic Carcinoma of the Mandible Harboring EWSR1 Rearrangement: Report of a Massive Jaw Tumor and Review of Diagnostic Considerations

Clear cell odontogenic carcinoma (CCOC) is a low-grade malignant neoplasm that affects the jaws. We report an 18 cm massive case of mandibular CCOC in a 43-year-old female. The tumor was composed of nests and cords of round to polygonal monomorphic clear cells separated by prominent stromal hyalinization. Immunohistochemically, the tumor cells showed focal cytokeratin 5/6 positivity and intracytoplasmic PAS-positive granules and were negative for S100 and after diastase treatment (PAS-D). Molecularly, this case was positive for EWSR1 rearrangement by FISH. The following should be included in the histopathological differential diagnosis: hyalinizing clear cell carcinoma of the salivary gland, clear cell variant of central mucoepidermoid carcinoma, clear cell variant of calcifying epithelial odontogenic tumor, and metastatic renal cell carcinoma. CCOC is a rare entity, with only 79 cases reported in the mandible. This case highlights the propensity for CCOC to exhibit invasiveness, destructive nature, and facial disfigurement if left untreated.

Clear Cell Sarcoma of the Premaxillary Soft Tissue: A Case Report

Casestudy: Clear cell sarcoma of soft tissue (CCSST) is a rare translocation-associated sarcoma which uncommonly presents in the head and neck region. Because the tumor expresses markers of melanocytic differentiation, it can be difficult to distinguish from malignant melanoma and epithelioid malignant peripheral nerve sheath tumor (MPNST), necessitating clinical correlation and ancillary testing specifically fluorescence in situ hybridization (FISH) for EWSR1 rearrangement. Here we report a case of CCSST involving the premaxillary soft tissue. A 61-year-old male without significant past medical history presented with a right premaxillary subcutaneous mass which was slowly enlarging over the course of three years. During surgical resection of the mass, the infraorbital nerve was noted to course into the tumor. Histologic sections revealed a 2.5 cm mass composed of a nodular proliferation of epithelioid tumor cells with pale eosinophilic to vacuolated cytoplasm, large vesicular nuclei with prominent nucleoli, areas of punctate necrosis, and a mitotic rate of 10 mitoses per 10 high power fields. Scattered multinucleated tumor giant cells were also present. No pigment was identified. By immunohistochemistry, the tumor cells were diffusely positive for SOX-10 and S-100 and negative for HMB45, MART1, MITF, inhibin, calretinin, p63 and smooth muscle actin. FISH was positive for EWSR1 rearrangement. Altogether, the morphologic, immunohistochemical and cytogenetic findings supported the diagnosis of CCSST. Because the surgical margins were negative for malignancy, the patient did not require additional surgery but will be receiving adjuvant radiation therapy. Although rare in the head and neck, CCSST should be considered in the differential diagnosis when dealing with an epithelioid soft tissue tumor that expresses any melanocytic markers, and a definitive distinction from malignant melanoma and epithelioid MPNST can be achieved by utilizing FISH for EWSR1 rearrangement.

Comprehensive genomic profiling in malignant myoepithelioma to suggest potential alternative diagnosis.

e23530 Background: Malignant myoepithelioma of soft tissue (MM) is a rare tumor affecting patients (pts) of any age without sex predilection. MM has varied histopathologic findings, with epithelioid and spindle components and differentiation along osseous, chondroid or other lineages. Morphologic features suggest MM, however histologic overlap with other lesions exists. Diagnosis requires ancillary immunohistochemical &/or molecular studies; EWSR1 rearrangement with various fusion partners has been reported. Clinical behavior is varied and poorly understood due to disease rarity. Here, we undertook comprehensive genomic profiling (CGP) of MM to evaluate for potential targetable molecular alterations and report clinical outcomes. Methods: We identified pts with MM treated at University of Michigan (UM) from 2000-2017, obtained clinical data and reviewed pathology on 10 available samples and performed integrative sequencing through Michigan Oncology Sequencing Program (MI-ONCOSEQ) on 6. For 31 additional FFPE samples, hybrid capture-based DNA CGP (n = 16) or DNA+RNA CGP (n = 15) was performed (Foundation Medicine, FM). Results: 13 pts were treated at UM; median age at diagnosis was 52 (22-88) with male predominance (9/13). Primary tumor size was 3 cm (2-9.5) and most common location was trunk (4/13) and extremity (3/13). Four pts with metastatic disease (mets) underwent systemic chemotherapy with 0 responses. Median progression free and overall survival in mets was 20 (5-75) and 57 (12-91) months, respectively. CGP analyses of all samples (Table) revealed EWSR1 rearrangement in 8.1% (3/37) and presence of PHF1-TFE3 and CIC:DUX4 rearrangements in 16% (6/37). Independent blinded histopathology review of whole slides and tissue is underway. Conclusions: MM is a rare malignancy with variable clinical course. In our series, pts with mets derived little benefit from systemic therapy. CGP revealed CDKN2A/B alteration as the most prevalent with few harboring EWSR1 rearrangement. PHF1-TFE3 was recently described in ossifying fibromyxoid tumor (OFMT) that may represent a subset of OFMT not yet expressing bone markers. The presence of hypermutation and CIC:DUX4 fusions also suggests potential alternate diagnosis. These results indicate that CGP could complement histopathologic evaluation to aid in diagnoses and treatment of this entity. [Table: see text]

Intracranial Myxoid Mesenchymal Tumor With EWSR1-ATF1 Fusion

Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue tumor that arises primarily in the extremities of young adults. Recurrent gene fusions involving EWSR1 with members of the cAMP response element binding protein (CREB) family have been reported in a diverse group of tumors, including AFH. AFH-like lesions have been reported to occur intracranially and the reported cases show low proliferation indices, frequently have a connection with the dura, and show recurrent EWSR1 rearrangements. These tumors have been termed intracranial myxoid mesenchymal tumor with EWSR1-CREB family gene fusions. A literature search identified 11 reported cases of intracranial AFH-like lesions with an EWSR1 rearrangement. Here, we report a case of intracranial myxoid mesenchymal tumor with an EWSR1-ATF1 fusion in an adult patient, and review the existing literature on this recently described entity.