Primary Ewing Sarcoma of the Lung: Integrative Analysis of Clinical, Histopathological, Immunohistochemical, and Cytogenetic Features with Literature Review.

Introduction: Ewing sarcoma (ES) is a highly aggressive malignant neoplasm characterized by small, round, undifferentiated cells presumed neural crest origin, accounting for approximately 10-15% of all primary bone tumors. While it predominantly involves the skeletal system, ES can also arise in extraosseous soft tissues, including the retroperitoneum, thoracic wall, paravertebral region, and extremities. Primary pulmonary involvement by Ewing sarcoma is exceedingly uncommon, with fewer than 60 cases documented in the literature over the past decade. Aim: The objective of this study was to analyze the clinicopathological characteristics of primary pulmonary Ewing sarcoma cases diagnosed at our institution, supplemented by a comprehensive review of the existing literature. Materials and methods: A retrospective study was undertaken to evaluate cases of primary pulmonary Ewing sarcoma (ES) diagnosed at the Department of OncoPathology, MPMMCC, Varanasi, from January 2019 to July 2024. Thirteen histopathologically confirmed cases were identified. Comprehensive demographic and clinical data were retrieved from institutional medical records. Detailed analyses of histomorphological features, and immunohistochemical profiles, and molecular alterations was done. Longitudinal follow-up data were analyzed to assess patient survival and clinical outcomes. Results: The median age of the study cohort was 24 years, ranging from 8 to 63 years. A male predominance was observed, with 69.23% of cases (n=9) occurring in males and 30.76% (n=4) in females. The majority of tumors (92.3%) measured greater than 10 cm in maximum dimension, a finding that was statistically significant (p = 0.001). Immunohistochemically, NKX2.2, FLI-1, and CD99 demonstrated consistent and robust expression across most cases, serving as reliable diagnostic markers. Four out of six patients show EWSR-1 fusion in cytogenetics study. All patients underwent systemic chemotherapy, with one case subsequently managed with surgical resection. Additionally, three patients received adjuvant radiotherapy. Disease progression was documented in three out of thirteen patients. The mean progression-free survival (PFS) was estimated at 19 months (95% confidence interval [CI]: 12.9-26.1 months), while the mean overall survival (OS) was calculated at 13 months (95% CI: 9.7-23.0 months). Conclusion: Primary pulmonary Ewing sarcoma should be considered in the differential diagnosis of large pulmonary masses, particularly in the absence of a detectable extrathoracic primary lesion and after the exclusion of more common differential diagnoses. Definitive diagnosis relies on histopathological examination supported by immunohistochemistry, with cytogenetic and molecular analyses such as detection of EWSR1 gene rearrangement playing a critical role in confirming the diagnosis. Optimal patient management necessitates a multidisciplinary team approach to ensure early detection and improved therapeutic outcomes. Supplementary Information: The online version contains supplementary material available at 10.1007/s13193-025-02480-9.