Primary Round Cell Sarcomas of the Urinary Bladder with EWSR1 Rearrangement: A Multi-institutional Study of Thirteen Cases with Review of Literature

Abstract Primary Ewing’s sarcoma (ES) of the urinary bladder is a rare and aggressive small blue round cell malignant neoplasm associated primarily with translocation involving EWSR1 and FLI1 genes located in the 22nd and 11th chromosomes, respectively. To date 18 cases have been published in the literature as single case reports, based chiefly on CD99 positivity (17 patients). Molecular confirmation by fluorescence in situ hybridization (FISH) was performed in 9 patients and FLI1 immunohistochemistry (IHC) was not done in any of these published cases. Herein, we present thirteen patients of more comprehensive primary round cell sarcomas of the urinary bladder with EWSR1 rearrangement. Clinicopathologic parameters including demographics, clinical presentation, histopathologic, IHC, and molecular profiles, and management and follow up data on 13 patients of primary round cell sarcomas with EWSR1 rearrangement {Ewing’s family of tumor (EFT)} of the urinary bladder were analysed. The studied patients (n=13) included 6 females and 7 males; age ranged from 4 years to 81 years (median = 30 years). The most common clinical presentation was hematuria (n=7), followed by hydronephrosis (n=2, one with renal failure). The tumor size ranged from 2.9 cm to 15 cm in maximum dimension. Conventional ES architecture and histology was observed in 6 cases and diverse histology in 7 cases {adamantinomatous pattern (n=1), alveolar pattern (n=1), “ganglioneuroblastoma-like”(n=2), and “small cell carcinoma-like” (n=3)}. All the tumors were muscle invasive (invasion into the muscularis propria). All expressed immunohistochemical stains FLI1, CD99, and at least one neuroendocrine marker. Focal cytokeratin staining was seen in 2 patients and RB1 was retained in all patients. EWSR1 rearrangement was seen in 12 of 12 tumors (in 12 patients) tested. A combined multimodal approach that included surgery with chemotherapy was instituted in all patients. Follow up was available in 11 patients (ranging from 5 to 24 months). Six patients either died of disease (n=3) or other causes (n=3). Five patients were alive with metastases to liver (n=1), liver, and lung (n=2), liver and abdominal wall (n=1), and kidney (n=1). Based on our experience with the largest series to date and aggregate of published data, ES/round cell sarcomas with EWSR1 rearrangement occurring in the bladder have bimodal age distribution with poor prognosis despite aggressive therapy. Due to its rarity and age distribution, the differential diagnosis is wide and requires a systematic approach for ruling out key age-dependent differential diagnoses aided with molecular confirmation.