Granulocyte colony-stimulating factor-producing lung squamous cell carcinoma positive for an uncommon EGFR Exon 20 S768I mutation: a case report

Granulocyte colony-stimulating factor (G-CSF) lung carcinoma is a rare and highly aggressive clinical entity characterized by persistent neutrophilia, high fever, and poor prognosis. Although the lung is a common primary site, the co-occurrence of G-CSF production and epidermal growth factor receptor ( EGFR ) mutations is extremely rare, particularly in squamous cell carcinoma (SCC). A 79-year-old Asian man, a former smoker, presented with an 80 mm mass in the left upper lobe and was diagnosed with a G-CSF-producing lung SCC (cT4N2bM0, cStage IIIB). Genetic testing identified a minor mutation and high programmed death ligand 1 (PD-L1) expression (tumor proportion score: TPS 65%). Despite an initial partial response to concurrent chemoradiotherapy, the disease progressed rapidly during maintenance durvalumab therapy, with a marked secondary increase in serum G-CSF and interleukin 6 (IL-6) levels. Subsequent lines of therapy, including docetaxel and the EGFR-tyrosine kinase inhibitors (TKIs) afatinib and osimertinib, provided only transient or limited clinical benefits. The patient eventually succumbed to tumor progression 22 months after the initial diagnosis. To the best of our knowledge, this is the first English-language report of a G-CSF-producing lung SCC harboring an EGFR S768I mutation. The present findings suggest that the inflammatory and immunosuppressive tumor microenvironment associated with G-CSF and IL-6 production may contribute to resistance against both immune checkpoint inhibitors and EGFR-TKIs, even when targetable mutations are present. Although driver mutations are rare in G-CSF-producing lung carcinoma, their presence may not guarantee a good response to targeted therapies. This case underscores the need for careful treatment selection and highlights the importance of further research into the mechanisms of treatment resistance in this intractable phenotype.