ALK fusion small cell transformation of lung adenocarcinoma: A case report and literature review.

Patients with anaplastic lymphoma kinase (ALK) fusion lung adenocarcinoma may develop drug resistance after treatment with ALK-tyrosine kinase inhibitor (ALK-TKI), and the mechanisms of this resistance are not yet fully defined. The Affiliated Hospital of Zunyi Medical University admitted a patient who was resistant to ALK fusion after ALK-TKI treatment, leading to disease progression and subsequent biopsy indicating a transformation to small cell lung cancer in September 2021. The patient, a 54-year-old female, initially presented with symptoms of cough, sputum production, and chest pain for 4 months. Chest CT showed a neoplastic lesion in the posterior segment of the right upper lobe to right lower lobe with obstructive pneumonia, metastasis in the right lower lobe, increased and enlarged mediastinal and right hilar lymph nodes, and thickening of the right hilar soft tissue. Bronchoscopy and pathological biopsy confirmed the diagnosis of lung adenocarcinoma. The results of next-generation sequencing indicated that echinoderm microtubule associated protein like 4-anaplastic lymphoma kinase (EML4-ALK) fusion is associated with tumor protein 53 (TP53) and retinoblastoma 1 (RB1) gene mutations. The patient received second-generation ALK-TKI aletinib, achieving a progression-free survival of 11 months before disease progression suggested aletinib resistance. Subsequently, the third-generation ALK-TKI lorlatinib administered for one month without efficacy, resulting in rapid systemic disease progression. The neuron specific enolase (NSE) was significantly increased, and the patient developed new pleural, pericardial, intracranial, liver, and multiple bone metastases occurred in a short period. A second biopsy indicated small cell lung cancer. Modification of treatment regimen to chemotherapy combined with immunotherapy proved effective. The mechanisms of drug resistance of ALK-TKI treatment for advanced non-small cell lung cancer with ALK fusion are complex, and small cell transformation of pathological type is one such mechanism, although rare. Concurrent TP53 and RB1 gene mutations may be characteristic of this transformation. Elevated NSE can serve as a predictive serum marker for adenocarcinoma transforming to small cell carcinoma. Timely re-biopsy and selection of subsequent treatments based on different resistance mechanisms are crucial for comprehensive disease management.