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First biopsy specimens showing malignant cells with irregular papillary and tubular structures (A, haematoxylin and eosin staining, x100). Immunohistopathological analysis demonstrated positive staining for thyroid transcription factor 1 (TTF-1) (B, x400) and novel aspartic proteinase of the pepsin family (napsin A) (C, x400), which are markers of adenocarcinoma. Immunohistopathological analysis also demonstrated positive staining for synaptophysin, which suggests neuroendocrine differentiation (D, x400).
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Bronchoscopy revealed an adenocarcinoma (Fig. 1A-C) with an EGFR exon 19 deletion (E746-A750).
Second biopsy (after acquired epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) resistance developed) specimens showing diffuse proliferation of small- to intermediate-sized cells with scant cytoplasm and round to oval hyperchromatic nuclei. Immunohistopathological analysis demonstrated positive staining for synaptophysin (A, x400) and chromogranin (B, x400), which are markers of small-cell carcinoma.
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The obtained specimen harboured both SCLC transformation (Fig. 2A, B) with retention of the EGFR 19 deletion and the development of an EGFR T790M mutation.