383 Adamantinoma-Like Ewing Sarcoma Mimicking Poorly Differentiated Squamous Cell Carcinoma in the Larynx: A Diagnostic Pitfall and Literature Review

Abstract Introduction/Objective ALES is a recently recognized, rare subtype of Ewing sarcoma that shows overlapping features with basaloid carcinomas, particularly in the head and neck region. It is defined by EWSR1 gene rearrangements and complex epithelial differentiation, which includes cytokeratin and p40 expression. Given its morphologic mimicry of SCC, especially when keratinization is present, misdiagnosis is common without molecular testing. Methods/Case Report A 59-year-old woman with a past medical history of breast cancer, rheumatoid arthritis, and uterine leiomyoma presented with persistent cough and congestion. Imaging revealed a 4 cm mass in the right vallecula with significant supraglottic airway stenosis. Initial biopsy revealed poorly differentiated SCC with basaloid features and patchy p16 positivity. She underwent total laryngectomy and modified bilateral neck dissection. Histopathology confirmed a 4.7 cm poorly differentiated keratinizing SCC. Postoperative imaging six months later revealed scattered bilateral pulmonary nodules, raising suspicion for metastasis. Wedge resection of a right lung nodule confirmed recurrence. RNA sequencing of the tumor revealed EWSR1::FLI1 fusion, consistent with ALES. Results ALES is most commonly found in head and neck region, particularly in the salivary glands, thyroid, and sinonasal tract. The tumor’s complex epithelial differentiation, including expression of cytokeratin makes it difficult to distinguish from SCC without molecular confirmation. A Johns Hopkins case series of 10 salivary gland ALES tumors, 9 were initially misclassified as different epithelial neoplasms. Similarly, a 2023 systematic review of 21 salivary gland ALES cases reported that approximately 62% were misdiagnosed at presentation as some other tumor type. The presence of EWSR1::FLI1 fusion — a hallmark of Ewing sarcoma — is diagnostic of ALES. Recent studies using DNA methylation profiling have even suggested that ALES is molecularly distinct from classical Ewing sarcoma, supporting the view of ALES as a unique pathologic entity. Conclusion This case underscores the diagnostic complexity of ALES in the head and neck. Molecular analysis including EWSR1 rearrangement testing is essential for accurate diagnosis. Greater awareness and reporting of ALES may refine its classification and guide optimal treatment strategies, which typically follow Ewing sarcoma protocols.