Challenges in Diagnosis of Lepidic Subtype in Lung Cancer According to W.H.O Classification: A Case Report

Background Lepidic adenocarcinoma of the lung often presents with atypical radiological patterns mimicking pneumonia, posing significant diagnostic challenges, particularly from small cytology samples. This can lead to delayed diagnosis and advanced-stage presentation. Case presentation A 57-year-old non-smoking female presented with a persistent cough, massive sputum production, and diffuse bilateral pulmonary lesions on computed tomography scan, resembling pneumonia. The patient’s condition rapidly deteriorated into acute respiratory failure unresponsive to antibiotics. A sputum cell block confirmed lung adenocarcinoma (CK7+, TTF-1+). Liquid biopsy via Next-Generation Sequencing (NGS) identified an EGFR L858R mutation (VAF 80%). First-line Osimertinib induced a dramatic clinical and radiological response within days. However, disease progression occurred after 9 months. A repeat biopsy and NGS re-evaluation revealed a persistent L858R mutation with an increased VAF (89%), without secondary resistance mutations (T790M, C797S) or bypass alterations, suggesting non-genetic resistance mechanisms. Conclusion This case underscores the critical difficulty of diagnosing lepidic-patterned tumors in an oncological emergency. It highlights the necessity of a multidisciplinary approach, combining cytology, radiology, and early molecular testing as a surrogate for traditional histopathology to guide urgent targeted therapy.