A 29-year-old woman, with no history of smoking and unremarkable medical history, reported to our hospital with the chief complaint of respiratory distress. The patient was diagnosed with right pleural effusion and a tumor in her right lung (Figure 1a-c). Enhanced brain magnetic resonance imaging (MRI) revealed multiple brain metastases. Her previous physician had performed thoracentesis and examined the pleural fluid, but found no evidence of malignant cells, after which she was referred to our hospital. On her first visit, a second pleural effusion test was performed, but no malignant cells were detected. Bronchoscopy was performed on the fifth day. On transbronchial biopsy (TBB), malignant cells were detected using rapid on-site evaluation (ROSE), and genetic analysis was performed on fresh-frozen specimen using the AmoyDx Pan Lung Cancer PCR panel (Amoy) (Amoy Diagnostics). However, histopathological analysis performed on the eighth day showed insufficient tissue specimen, and transesophageal endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) was performed on the ninth day. A paraoesophageal lymph node lesion was collected, and a sufficient number of malignant cells were detected using ROSE, but several necrotic components were also found. On the 12th day, histopathological analysis revealed that the EUS-FNA specimen also did not yield a sufficient amount of tissue, and thoracoscopy was performed under local anesthesia on the same day. During thoracoscopy, pleural fluid was submitted for third examination, but no malignant cells were detected. However, sufficient tumor tissue samples were successfully obtained via thoracoscopy. The course of these biopsies is summarized in Figure 2. On the same day, EGFR L858R mutation was detected by Amoy, and treatment with EGFR-tyrosine kinase inhibitor was initiated. Immunohistochemistry was performed on bronchoscopy biopsy specimens, wherein the tissue samples were stained with a specific antibody against EGFR L858R, which confirmed the presence of tumor cells (Figure 3).