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Role of Chemotherapy and the Receptor Tyrosine Kinases KIT, PDGFR, PDGFRß, and Met in Large-Cell Neuroendocrine Carcinoma of the Lung

From the Integrated Department of Diagnostic and Laboratory Services and Legal Medicine, Section of Pathologic Anatomy, Respiratory Diseases Clinic, Department of Thoracic Surgery, University of Modena and Reggio Emilia, Modena; Operative Unit of Pathologic Anatomy and Pneumology, Hospital S. Maria Nuova, Reggio Emilia; Division of Oncology, Civic Hospital "Ramazzini," Carpi, Italy; and the Department of Pathology and L'Institut National de la Santé et de la Recherche Médicale U578, Centre Hospitalier Universitaire, Grenoble, France.

Address reprint requests to Giulio Rossi, MD, Integrated Department of Diagnostic and Laboratory Services and Legal Medicine, Section of Pathologic Anatomy, University of Modena and Reggio Emilia, via del Pozzo, 71-41100, Modena, Italy; e-mail: rossi.giulio{at}unimo.it

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 immunohistochemical expression and the mutational status of the receptor tyrosine kinases (RTKs) KIT, PDGFR, PDGFRß, 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, PDGFR in 60.2%, PDGFRß 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, PDGFRß, and Met in tumor cells suggests an important role of these RTKs in LCNEC, and these RTKs seem to be attractive therapeutic targets.

Supported by Ministero dell’Istruzione dell’Università e della Ricerca (Rome, Italy), Progetti di Ricerca di Interesse Nazionale 2004, and a grant of the "Associazione Angela Serra."

Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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