Role of chemotherapy and the receptor tyrosine kinases KIT, PDGFRalpha, PDGFRbeta, and Met in large-cell neuroendocrine carcinoma of the lung.
OBJECTIVE
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.


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, PDGFRalpha, PDGFRbeta, 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, PDGFRalpha in 60.2%, PDGFRbeta 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 (> or = 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).


CONCLUSIONS
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, PDGFRalpha, PDGFRbeta, and Met in tumor cells suggests an important role of these RTKs in LCNEC, and these RTKs seem to be attractive therapeutic targets.
Rossi
Giulio
G
Integrated Department of Diagnostic and Laboratory Services and Legal Medicine, Section of Pathologic Anatomy, Respiratory Disease Clinic, University of Modena and Reggio Emilia, via del Pozzo, 71-41100, Modena, Italy. rossi.giulio@unimo.it
Cavazza
Alberto
A
Marchioni
Alessandro
A
Longo
Lucia
L
Migaldi
Mario
M
Sartori
Giuliana
G
Bigiani
Nazzarena
N
Schirosi
Laura
L
Casali
Christian
C
Morandi
Uliano
U
Facciolongo
Nicola
N
Maiorana
Antonio
A
Bavieri
Mario
M
Fabbri
Leonardo M
LM
Brambilla
Elisabeth
E
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D018287:Carcinoma, Large Cell / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality; D018278:Carcinoma, Neuroendocrine / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality; D018288:Carcinoma, Small Cell / Q000188:drug therapy / Q000201:enzymology / Q000401:mortality; D002945:Cisplatin / Q000008:administration & dosage; D004252:DNA Mutational Analysis; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage; D016133:Polymerase Chain Reaction; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000096:biosynthesis / Q000235:genetics; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D016019:Survival Analysis; D015996:Survival Rate; D016896:Treatment Outcome; D000093542:Gemcitabine
D003841:Deoxycytidine; D016190:Carboplatin; D019009:Proto-Oncogene Proteins c-kit; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta; D017239:Paclitaxel; D002945:Cisplatin; D000093542:Gemcitabine