Expression profiling of receptor tyrosine kinases in high-grade neuroendocrine carcinoma of the lung: a comparative analysis with adenocarcinoma and squamous cell carcinoma

Abstract

Background As the comprehensive genomic analysis of small cell lung cancer (SCLC) progresses, novel treatments for this disease need to be explored. With attention to the direct connection between the receptor tyrosine kinases (RTKs) of tumor cells and the pharmacological effects of specific inhibitors, we systematically assessed the RTK expressions of high-grade neuroendocrine carcinomas of the lung [HGNECs, including SCLC and large cell neuroendocrine carcinoma (LCNEC)].Patients and methodsFifty-one LCNEC and 61 SCLC patients who underwent surgical resection were enrolled in this research. As a control group, 202 patients with adenocarcinomas (ADCs) and 122 patients with squamous cell carcinomas (SQCCs) were also analyzed. All the tumors were stained with antibodies for 10 RTKs: c-Kit, EGFR, IGF1R, KDR, ERBB2, FGFR1, c-Met, ALK, RET, and ROS1.ResultsThe LCNEC and SCLC patients exhibited similar clinicopathological characteristics. The IHC scores for each RTK were almost equivalent between the LCNEC and SCLC groups, but they were significantly different from those of the ADC or SQCC groups. In particular, c-Kit was the only RTK that was remarkably expressed in both LCNECs and SCLCs. On the other hand, about 20 % of the HGNEC tumors exhibited strongly positive RTK expression, and this rate was similar to those for the ADC and SQCC tumors. Intriguingly, strongly positive RTKs were almost mutually exclusive in individual tumors.ConclusionsCompared with ADC or SQCC, LCNEC and SCLC had similar expression profiles for the major RTKs. The exclusive c-Kit positivity observed among HGNECs suggests that c-Kit might be a distinctive RTK in HGNEC.Electronic supplementary materialThe online version of this article (doi:10.1007/s00432-015-1989-z) contains supplementary material, which is available to authorized users.

Anaplastic lymphoma kinase expression in small‐cell lung cancer

“…The intensity and proportion of ALK expression were different between individual tumours, and all ALK IHC‐positive tumours expressed ALK in some tumour cells, in contrast to strong and uniform expression in adenocarcinoma. The characteristics were those of SCLC with ALK expression as reported previously . There were two cases of combined small‐cell carcinoma and NSCLC in our cohort, in which positive reactions were observed only in the SCLC component, and not in the NSCLC component.…”

“…The characteristics were those of SCLC with ALK expression as reported previously. 20,[29][30][31][32] There were two cases of combined small-cell carcinoma and NSCLC in our cohort, in which positive reactions were observed only in the SCLC component, and not in the NSCLC component. This indicates the difference between NSCLC and SCLC in the mechanism of expression of ALK.…”

Genomic Profiling of Large-Cell Neuroendocrine Carcinoma of the Lung

“…S7 shows the relationship between RTK overexpression and genomic alterations in 51 resected LCNECs. The protein expression data for these LCNEC tumors are from our previous report (7). In this analysis, we saw no significant correlation between strong positivity for RTK expression and genomic alterations.…”

Insights into Novel Prognostic and Possible Predictive Biomarkers of Lung Neuroendocrine Tumors

“…Both LCNEC and SCLC had significantly higher immunohistochemical scores for c-KIT, IGF1R and KDR, and lower scores for ERBB2, FGFR1, c-MET and ROS1 compared with lung adenocarcinomas. In addition, LCNECs and SCLCs had significantly higher scores for c-KIT, KDR and RET and lower scores for EGFR and IGF1R when compared with squamous cell carcinoma (63). The RET tyrosine kinase receptor plays a key role in neuroendocrine development and RET mutations have been long known in patients with multiple endocrine neoplasia type 2 (MEN2) syndromes (64).…”

“…Expression of RTKs [c-KIT, insulin growth factor 1 receptor (IGF1R), kinase insert domain receptor (KDR), epidermal growth factor receptor (EGFR), erb-b2 receptor tyrosine kinase 2 (ERBB2), fibroblast growth factor receptor 1 (FGFR1), MET proto-oncogene; c-MET, ROS proto-oncogene 1 (ROS1) and ret proto-oncogene (RET)] was evaluated by immunohistochemical staining in a comparative study that included lung NETs, adenocarcinomas and squamous cell carcinomas (63). Of interest, no difference was noted among lung NET subtypes (LCNEC and SCLC) but significant differences in immunohistochemical score were noted between NETs and the other lung carcinomas under investigation (63). Both LCNEC and SCLC had significantly higher immunohistochemical scores for c-KIT, IGF1R and KDR, and lower scores for ERBB2, FGFR1, c-MET and ROS1 compared with lung adenocarcinomas.…”