NKX2-1 gene variants in solid tumours: the spectrum of gene variants and potential impact in surgical pathology diagnosis

The NKX2-1 gene, located on chromosome 14, encodes thyroid transcription factor 1 (TTF1), essential for lung development and expressed in peripheral lung cells.1 TTF1 is found in approximately 75% of adenocarcinomas of pulmonary origin. TTF1 immunohistochemistry (IHC) staining is a key marker to determine tumour origin, especially in lung lesions.2 Typically, positive TTF1 IHC suggests a pulmonary origin, while negative results suggest an extrapulmonary origin. However, this diagnostic approach may be confounded by genetic alterations, such as NKX2-1 mutations, which can reduce or eliminate TTF1 expression even in pulmonary tumours. This study examines the frequency of NKX2-1 mutations in solid tumours and discusses the implications for interpreting negative TTF1 IHC results, particularly in non-mucinous pulmonary carcinomas. Despite their rarity, NKX2-1 mutations can significantly impact the accuracy of TTF1-based diagnostic algorithms, underscoring the need for careful interpretation in surgical pathology.