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Annals of Surgical Oncology

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Genetic and Immunohistochemical Studies Investigating the Histogenesis of Neuroendocrine and Carcinomatous Components of Combined Neuroendocrine Carcinoma

Misaki Iijima M.D., Ph.D., Takehiko Yokobori M.D., Ph.D., Akira Mogi M.D., Ph.D., Kimihiro Shimizu M.D., Ph.D., Toshiki Yajima M.D., Ph.D., Takayuki Kosaka M.D., Ph.D., Yoichi Ohtaki M.D., Ph.D., Kai Obayashi M.D., Seshiru Nakazawa M.D., Ph.D., Navchaa Gombodorj M.D., Ph.D., Mariko Tsukagoshi M.D., Ph.D., Ken Shirabe M.D., Ph.D., Hiroyuki Kuwano M.D., Ph.D.
Endocrine Tumors
Volume 26, Issue 6 / June , 2019



Lung combined neuroendocrine carcinomas (NECs) comprise NEC and non-NEC components, such as adenocarcinoma and squamous cell carcinoma. Mutation of epidermal growth factor receptor (EGFR) often is observed in non-NEC but is very rare in sporadic NEC, which almost always has p53 mutation. Therefore, we hypothesized the following research concept: mutation analysis of EGFR and p53 in each component of combined NEC tissues can provide important information on whether such components originate from the same tumor cells or incidentally arise as collision cancers.


We compared the mutations of EGFR and p53 in laser-microdissected NEC and non-NEC from lungs of eight cases affected by combined NEC. We examined the expression of EGFR and NEC markers in the combined NECs by immunohistochemistry.


Five of eight cases of combined NEC had the same mutations of EGFR and/or p53 in both non-NEC and NEC. One case had EGFR mutation in only the non-NEC component, and two cases did not have these mutations. Replacement transformation was observed in borderline areas between non-NEC and NEC. The signal of activated EGFR in non-NEC with the same EGFR mutation was more intense than that in NEC components.


Our study suggests the mechanism behind the carcinogenesis of lung combined NEC, which is partially caused by the transformation from epithelial carcinoma of non-NEC to NEC.

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