Epstein-Barr Virus-Associated Pulmonary Carcinoma Proposing an Alternative Term and Expanding the Histologic Spectrum of Lymphoepithelioma-like Carcinoma of the Lung

Lymphoepithelioma-like carcinoma (LELC) of the lung is a rare Epstein-Barr virus (EBV)-associated carcinoma. It is histologically characterized by a syncytial growth pattern with marked lymphocytic infiltration that is indistinguishable from the histology observed in undifferentiated nasopharyngeal carcinomas. However, it has been noted that LELC can display nonclassic morphology and lack significant lymphocytic infiltration. In this study, we conducted a comprehensive clinicopathologic analysis of 61 patients with pulmonary LELC and performed automatic quantification of the lymphocytic infiltrate using the IHC Profiler software. We demonstrated that pulmonary LELCs have a morphologically continuous spectrum, ranging from classic poorly differentiated tumors with intense lymphocytic infiltration to nonclassic morphology with little lymphocytic infiltration. These EBV-associated tumors represent a distinct entity and usually occur in female and nonsmoking patients. Tumors with low lymphocytic infiltration can closely resemble nonkeratinizing squamous cell carcinoma and tend to be larger in size, have higher maximum standardized uptake values on radiography, and exhibit shorter times to recurrence than those with high lymphocytic infiltration. Through detailed pathologic examination, we observed several distinct morphologic features in pulmonary LELCs, including granulomatous inflammation, focal keratinization, spread through alveolar spaces, and lepidic spreading pattern. We also found that patients with tumors exhibiting granulomatous inflammation have favorable outcomes; however, spread through alveolar spaces did not significantly correlate with prognosis. As many of these LELCs do not resemble undifferentiated nasopharyngeal carcinoma or lymphoepithelioma, we propose using an alternative term, EBV-associated pulmonary carcinoma, to encompass the entire morphologic spectrum of this distinct disease entity.