Lung adenocarcinomas with isolated TP53 mutation: A comprehensive clinical, cytopathologic and molecular characterization

Background: TP53 mutation is present in about 50.8% of lung adenocarcinomas, frequently in combination with other genetic alterations. However, a rare subset harbors the TP53 mutation alone.Methods: Next-generation sequencing was performed in 840 lung adenocarcinomas diagnosed by fine needle aspiration. Fourteen cases (1.7%) showed isolated TP53 alteration and were subjected to a comprehensive analysis.Results: The average age at diagnosis was 65 years (range 48-79); 9 males and 5 females. All were smokers with an average pack-year of 41 (range 10-70). Nine had metastases, mostly in the brain (n = 2) and pleura (n = 2). After a follow-up period of up to 102 months, 9 died, 4 were alive with disease, and 1 was lost to follow-up. The median survival was 13 months. Most tumors exhibited poor differentiation, composed of solid sheets with moderate to severe atypia, increased mitotic activity, and necrotic background. Half were positive for TTF-1 and showed p53 overexpression. PD-L1 was positive in 6 cases. Most alterations were missense mutations in exons 5-8, and this mutation type was associated with p53 overexpression. Tumors with combined missense mutation and truncated protein had higher PD-L1 expression and significantly shorter overall survival, along with a trend towards an increase in tumor mutational burden (TMB). CEBPA deletion of undetermined significance was the most common copy number alteration.Conclusion: Isolated TP53 mutation was seen in association with smoking, high-grade cytomorphologic features, adverse prognosis, and recurrent CEBPA deletions. These tumors tend to have strong PD-L1 expression and high TMB, suggesting potential benefit from immune checkpoint inhibitors. Hence, the recognition of this molecular group has prognostic and therapeutic implications.