Role of chemotherapy and the receptor tyrosine kinases KIT, PDGFR alpha, PDGFR beta, and met in large-cell neuroendocrine carcinoma of the lung

Purpose Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is a relatively uncommon, high-grade neuroendocrine tumor sharing several features with small-cell lung carcinoma (SCLC) but currently considered as a variant of non-SCLC and accordingly treated with poor results. Little is known about the optimal therapy of LCNEC and the possible therapeutic molecular targets. Patients and Methods We reviewed 83 patients with pure pulmonary LCNEC. to investigate their clinicopathologic features, therapeutic strategy, and immunohistorchemical expression and the mutational status of the receptor tyrosine kinases (RTKs) KIT, PDGFR alpha, PDGFR beta, and Met. Results LCNEC histology predicted a dismal outcome (overall median survival, 17 months) even in stage I patients (5-year survival rate, 33%). LCNEC strongly expressed RTKs (KIT in 62.7% of patients, PDGFRa in 60.2%, PDGFR beta in 81.9%, and Met in 47%), but no mutations were detected in the exons encoding for the relevant juxtamembrane domains. Tumor stage and size (>= 3 cm) and Met expression were significantly correlated with survival. At univariate and multivariate analysis, SCLC-based chemotherapy (platinum-etoposide) was the most important variable correlating with survival, both in the adjuvant and metastatic settings (P < .0001). Conclusion Pulmonary LCNEC represents an aggressive tumor requiring multimodal treatment even for resectable stage I disease, and LCNEC seems to respond to adjuvant platinum-etoposide-based chemotherapy, Patients who received this therapy had the best survival rate. Despite our failure in finding mutational events in the tested RTKs, the strong expression of KIT, PDGFR alpha, PDGFR beta, and Met in tumor cells suggests an important role of these RTKs in LCNEC, and these RTKs seem to be attractive therapeutic targets.