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Life sciences · Journal article
Frontiers in Oncology · November 4, 2026
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Background Leptomeningeal metastasis (LM) is a severe complication of advanced non-small cell lung cancer (NSCLC). Conventional cerebrospinal fluid (CSF) cytology has limited sensitivity and often delays diagnosis. We report a case of LM molecularly supported by CSF next-generation sequencing (NGS) after three negative cytological examinations. NGS also revealed a potential bypass resistance alteration that informed subsequent treatment considerations. Case A 57-year-old female never-smoker had EGFR exon 21 p.L858R-mutant lung adenocarcinoma. After 18 months of first-line osimertinib (80 mg once daily), she developed progressive nausea, vomiting, and dizziness. Contrast-enhanced cranial magnetic resonance imaging (MRI) showed linear leptomeningeal enhancement. Lumbar puncture showed markedly elevated intracranial pressure (>300 mmH2O) and increased CSF protein. However, three CSF cytological examinations (including cell block sections) found no malignant cells. CSF NGS detected the EGFR p.L858R mutation identical to the primary tumor, together with CDK4 amplification. Integrated with the clinical and MRI presentation, these findings supported a diagnosis of probable LM and suggested cell-cycle bypass activation as a potential mechanism associated with osimertinib resistance. After intrathecal methotrexate plus continued oral osimertinib, her neurological symptoms improved markedly, and intracranial pressure returned to normal. The first seizure occurred on March 19, 2026, and MRI on April 8, 2026 confirmed new brain parenchymal metastases. Whole-brain radiotherapy with a local boost to the metastases, antiepileptic treatment, and continued osimertinib led to obvious shrinkage of the intracranial lesions. Grade 3 thrombocytopenia and severe malnutrition occurred during multimodal therapy and improved with supportive care. At the last follow-up, the patient was clinically stable with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 1. Conclusions CSF NGS can overcome the diagnostic bottleneck of cytology-negative LM. It can also identify potential resistance alterations and actionable targets (such as CDK4/6 inhibitors) at the same time, providing direction for subsequent targeted strategies. As part of multimodal therapy, intrathecal chemotherapy combined with an EGFR tyrosine kinase inhibitor (TKI) can contribute to disease control in the CSF compartment, whereas parenchymal progression still requires salvage radiotherapy. Cumulative hematological and nutritional toxicity should be monitored during sequential multimodal therapy.