Adamantinoma-like Ewing Sarcoma: An Underrecognized Mimicker in the Head and Neck With Divergent Clinicopathologic Features from Ewing Sarcoma.

Adamantinoma-like Ewing sarcoma (ALES) is a cytokeratin-positive member of the Ewing sarcoma (ES) family with a predilection for the head and neck (HN). Its rarity and overlapping immunophenotype with carcinomas contribute to frequent misclassification, while its biologic behavior and response to standard ES therapy remain incompletely defined. We conducted a 25-year retrospective review to characterize the clinicopathologic spectrum of ALES and compare HN ALES with non-HN ALES and HN ES, incorporating histologic, immunophenotypic, molecular, and clinical outcome data. Twenty-three cases were identified; ALES (n=20) and HN ES (n=3). ALES occurred in older patients (median age 49 vs. 29 years) and demonstrated a marked HN predilection (17/20), with a substantial proportion involving glandular sites. In contrast, HN ES arose in the skull base and sinonasal tract. ALES showed basaloid, epithelioid, or round cell morphology, with occasional palisading and rare squamous differentiation. Diffuse cytokeratin expression was present in all ALES, with frequent p40/p63 positivity, whereas ES showed only focal cytokeratin staining. Nodal metastases occurred in 9/20 ALES cases. EWSR1 rearrangement was identified in all ALES and ES cases, with FLI1 fusion identified in 18/20 ALES and 1/3 ES cases. With a mean follow-up of 60.6 months, outcomes varied by site: salivary gland ALES showed a more favorable course (4/5 in remission), whereas thyroid (6/8) and non-HN ALES (3/3) more often progressed. HN ES demonstrated poor outcomes. ALES is a distinct entity that frequently mimics carcinoma and extends beyond classic morphologic patterns. Site-specific differences observed in our study may aid in diagnosis; however, accurate recognition remains difficult, and a high index of suspicion at specific anatomical sites may be important for diagnosis and management.