Tumor-infiltrating lymphocytes-based subtypes and genomic characteristics of EBV-associated lymphoepithelioma-like carcinoma

Tumor-infiltrating lymphocytes (TILs) offer a key for morphological diagnosis of lymphoepithelioma-like carcinoma (LELC) and are the foundation of oncoimmunology. To date, no reports have found a specific risk stratification value of TILs and related it to genomic variation in LELC. Based on the stromal TILs (str-TILs) ratio, we classified 105 Epstein-Barr virus (EBV)-associated LELC cases into two subtypes: patients with ≥60% str-TILs area ratio in tumor were classified as subtype I, and otherwise as subtype II. Subtype I patients had significantly better progression-free survival (PFS) and overall survival (OS). We also explored the genomic characteristics of EBV-associated LELC within different involved organs. We performed whole-exome sequencing for 51 patients with enough tissue and analyzed the genomic characteristics of EBV-associated LELC. Overall, EBV-associated LELCs were characterized by a low somatic mutation rate and copy number variations; the enriched genetic lesions affected RTK-RAS, PI3K, and cell cycle pathways. Moreover, EBV-associated LELCs from different organs were more similar to each other genetically as compared with other traditional carcinomas of the same sites-as evidenced by unsupervised clustering based on the quantitative data from both mutation signature and chromosomal aneuploidies. Notably, EBV-associated LELC patients with oncogenic driver alterations showed a worse prognosis compared with patients without such alterations. © 2022 The Pathological Society of Great Britain and Ireland.