Histological evolution from primary lung adenocarcinoma harboring EGFR mutation to high‐grade neuroendocrine carcinoma

Background Although patients with EGFR mutated lung adenocarcinoma benefit greatly from tyrosine kinase inhibitors ( TKI s), they inevitably develop acquired resistance after an average of 10–14 months of continuous treatment. Methods We retrospectively analyzed the clinical and histopathological data of eight patients with primary lung adenocarcinoma harboring EGFR mutations that transformed into high‐grade neuroendocrine carcinoma after TKI therapy. Morphology scanning for neuroendocrine differentiation and immunohistochemistry for neuroendocrine markers CD 56, chromogranin, and synaptophysin were performed on primary adenocarcinoma tissues and repeated biopsies. Mutations of EGFR exons 19–21 were reexamined using the amplification refractory mutation system. Results The carcinoma in seven patients transformed to small cell lung carcinoma; two of these patients enrolled in the AZD 9291 study after acquiring a T 790 M missense mutation. The carcinoma in one patient transformed to large cell neuroendocrine carcinoma. None of the eight primary tumors exhibited neuroendocrine morphologic features and only one surgical specimen displayed a weak stain for neuroendocrine marker synaptophysin. Drug resistant high‐grade neuroendocrine carcinomas retained their initial activating EGFR mutations. Conclusions Lung adenocarcinoma in eight patients transformed into high‐grade neuroendocrine carcinoma and retained the original activating EGFR mutations after targeted therapy by TKI s. Furthermore, the prognosis of the transformed carcinoma was worse than the original primary genetic and morphologic type.