De novo pulmonary small cell carcinomas and large cell neuroendocrine carcinomas harboring EGFR mutations: Lack of response to EGFR inhibitors

Abstract

Introduction: Epidermal growth factor receptor (EGFR) mutations are present in 10-20% of all non-small-cell lung cancers and predict for response to EGFR tyrosine kinase inhibitors (TKIs). However, the incidence of these mutations and their ability to predict response to TKIs in high-grade pulmonary neuroendocrine carcinomas [i.e. small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC)] is unknown.

Methods: The presence of EGFR mutations, clinicopathologic and anti-cancer therapy response data were retrospectively compiled and analyzed from a cohort of 608 patients-lung tumors to identify EGFR mutated high-grade pulmonary neuroendocrine carcinomas. We identified 126 EGFR-mutated (21.8% of 578 successful genotyped cases) lung cancers and only 2 (1.6%) were high-grade neuroendocrine carcinomas.

Results: Case one was of a 63 year-old white never smoker woman with extensive stage SCLC harboring EGFR-delL747_P753insS but without EGFR protein expression. After progression on carboplatin/etoposide, the patient was treated with erlotinib and developed progressive disease with a survival <3 months from start of erlotinib. Case two was of a 73 year-old Asian 30 pack-year smoker man with metastatic LCNEC harboring EGFR-delL747_P753insQS and also lacking EGFR protein expression. The patient received first line therapy with erlotinib and had progressive disease with a survival of 4 months.

Conclusions: The lack of response to EGFR TKIs in EGFR mutated de novo SCLC and LCNEC reported here may indicate that tumor differentiation affects tumor dependency on EGFR as a driver oncogene.

Keywords: EGFR; Erlotinib; Large cell neuroendocrine carcinoma; Mutation; Never-smoker; Progression; Resistance; Small cell lung cancer.

Figure 1

Small cell carcinoma. A: Transbronchial needle aspiration of the right upper lobe lung mass demonstrates poorly differentiated tumor cells with scant cytoplasm, nuclear molding, and finely granular neuroendocrine-type chromatin, present in a background of tumor necrosis (ThinPrep, Papanicolaou stain, 1000x original magnification). B: Transbronchial biopsy of the right upper lobe mass highlights the prominent nuclear molding of the poorly differentiated tumor cells with frequent mitotic figures and tumor necrosis (Hematoxylin and Eosin stain, 600x objective original magnification). C: Immunohistochemical staining demonstrates strong cytoplasmic expression of the neuroendocrine marker synaptophysin (600x original magnification). The tumor was also positive for TTF-1 and chromogranin, negative for p63, and a Mib-1/Ki-67 proliferation marker was positive in >90% of tumor cells (not shown), all consistent with small cell carcinoma. D: Immunohistochemical staining for EGFR demonstrates essentially no detectible cytoplasmic expression of EGFR (600x original magnification).

Figure 2

Large cell neuroendocrine carcinoma. A: Ultrasound guided percutaneous core needle biopsy of the abdominal nodule demonstrates poorly differentiated tumor cells growing in solid nests and cords with moderate amounts of eosinophilic cytoplasm, round to oval nuclei with prominent nucleoli, some nuclear molding, and scattered single cell necrosis (Hematoxylin and eosin stain, 60x objective original magnification); no areas of glandular or squamous differentiation were identified. B: Immunohistochemical staining demonstrates strong diffuse cytoplasmic positivity for the neuroendocrine marker CD56 (600x original magnification). The tumor cells were also diffusely positive for synaptophysin, TTF-1, and cytokeratin 7; negative for chromogranin, cytokeratin 20; and a Mib-1/Ki-67 proliferation marker was positive in >50% of tumor cells (not shown). In this small biopsy specimen, the findings are consistent with metastatic pulmonary large cell neuroendocrine carcinoma.