A case of large-cell neuroendocrine carcinoma harboring rare ALK fusion with initial response to the ALK inhibitor crizotinib and acquired F1174L mutation after resistance

A 51-year-old, male, non-smoker with a 3.4 cm mass in the right middle lobe was diagnosed with large cell neuroendocrine carcinoma (LCNEC). Fluorescence in situ hybridization revealed anaplastic lymphoma kinase (ALK) gene translocation, in agreement with the immunohistochemistry result obtained with use of ALK-Ventana. Radiographic examinations showed both bone and brain metastasis. After two cycles of chemotherapy consisting of etoposide and cisplatin, the patient achieved stable disease, and was subsequently switched to crizotinib. Both computed tomography and magnetic resonance imaging revealed partial response after 4 months of crizotinib, but progressed after treatment for 10 months, when several hard lymph nodes were palpable in the left supraclavicular fossa. Lymph node biopsy showed similar histology of tumor cells and targeted next-generation sequencing revealed ALK F1174L on exon 23 with two rare forms of ALK rearrangements. This case provides evidence of responsiveness of ALK inhibitors for a rare pattern of ALK-rearranged LCNEC, and suggests that F1174L, a common resistant mutation found in non-small-cell lung cancer, also causes crizotinib resistance in LCNEC.