Translational lung cancer research · 2025
TTF-1 and p40 co-expression defines a distinct subtype of non-small cell lung cancer with frequent TP53 mutations and FGFR pathway dysregulation.
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Braun Marcin, Sołek Julia, Stępień Grzegorz Jan, Masłowska Aleksandra Izabela, Kamecki Mateusz, Antosik Paulina, Jassem Jacek, Tomasik Bartłomiej, Kordek Radzisław
Аннотация
BACKGROUND: Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of cases. Accurate differentiation between adenocarcinoma (ADC) and squamous cell carcinoma (SCC) is critical for informing personalized therapies. Thyroid transcription factor-1 (TTF-1) and p40 are traditionally regarded as mutually exclusive markers of ADC and SCC, respectively. However, a subset of tumors exhibits co-expression of TTF-1 and p40, presenting diagnostic challenges and suggesting underlying biological distinctiveness. This study aimed to characterize the clinicopathological, molecular, and immunohistochemical features of NSCLCs co-expressing TTF-1 and p40, in order to clarify their biological and clinical significance.
METHODS: A retrospective analysis was performed on NSCLC cases diagnosed at the Central Clinical Hospital of the Medical University of Łódź between May 2021 and November 2022. Clinicopathological and survival data were collected. Tumors co-expressing TTF-1 and p40 underwent immunohistochemical evaluation and RNA/DNA-based next-generation sequencing (NGS).
RESULTS: Of 94 NSCLC cases analyzed, 18 (19.1%) demonstrated co-expression of TTF-1 and p40. These tumors were significantly more likely to exhibit solid growth patterns compared to control cases (P=0.03), but no significant difference in overall survival (OS) was observed (P=0.46). Among 17 samples subjected to NGS, genetic alterations were identified in 15 (88.2%) cases, with TP53 mutations in 11 (64.7%), KRAS in 4 (23.5%), FGFR1-3 in 4 (23.5%) and EGFR in 2 (11.8%) cases. Immunohistochemical analysis of 18 tumors revealed strong p63 and p53 expression in 11 (61.1%) and 13 (72.2%) cases, respectively. FGFR4 protein was abundantly expressed in 15 cases (83.3%, H-score >150), while elevated H-scores for FGFR1, FGFR2, and FGFR3 were observed in 10 (55.6%), 7 (38.9%), and 2 (11.1%) cases, respectively.
CONCLUSIONS: NSCLCs co-expressing TTF-1 and p40 appear to represent a biologically distinct and poorly differentiated subgroup, frequently associated with TP53 mutations and FGFR pathway alterations. These tumors may arise from basal reserve cells and undergo TP53-driven reprogramming, diverging from the classical pathways of ADC and SCC. Accordingly, they may be more appropriately classified as NSCLC, not otherwise specified (NOS), rather than strictly as ADC or SCC. Given their molecular complexity, broader genomic profiling may be warranted in these cases, even though current guidelines do not recommend routine molecular testing for SCC.
METHODS: A retrospective analysis was performed on NSCLC cases diagnosed at the Central Clinical Hospital of the Medical University of Łódź between May 2021 and November 2022. Clinicopathological and survival data were collected. Tumors co-expressing TTF-1 and p40 underwent immunohistochemical evaluation and RNA/DNA-based next-generation sequencing (NGS).
RESULTS: Of 94 NSCLC cases analyzed, 18 (19.1%) demonstrated co-expression of TTF-1 and p40. These tumors were significantly more likely to exhibit solid growth patterns compared to control cases (P=0.03), but no significant difference in overall survival (OS) was observed (P=0.46). Among 17 samples subjected to NGS, genetic alterations were identified in 15 (88.2%) cases, with TP53 mutations in 11 (64.7%), KRAS in 4 (23.5%), FGFR1-3 in 4 (23.5%) and EGFR in 2 (11.8%) cases. Immunohistochemical analysis of 18 tumors revealed strong p63 and p53 expression in 11 (61.1%) and 13 (72.2%) cases, respectively. FGFR4 protein was abundantly expressed in 15 cases (83.3%, H-score >150), while elevated H-scores for FGFR1, FGFR2, and FGFR3 were observed in 10 (55.6%), 7 (38.9%), and 2 (11.1%) cases, respectively.
CONCLUSIONS: NSCLCs co-expressing TTF-1 and p40 appear to represent a biologically distinct and poorly differentiated subgroup, frequently associated with TP53 mutations and FGFR pathway alterations. These tumors may arise from basal reserve cells and undergo TP53-driven reprogramming, diverging from the classical pathways of ADC and SCC. Accordingly, they may be more appropriately classified as NSCLC, not otherwise specified (NOS), rather than strictly as ADC or SCC. Given their molecular complexity, broader genomic profiling may be warranted in these cases, even though current guidelines do not recommend routine molecular testing for SCC.