Genetic alterations in early-stage pulmonary large cell neuroendocrine carcinoma.
BACKGROUND
Small cell lung carcinoma (SCLC) and pulmonary large cell neuroendocrine carcinoma (LCNEC) are high-grade malignant neuroendocrine tumors. Histologic differentiation between SCLC and LCNEC is difficult in some cases and to the authors' knowledge, genetic alterations associated with LCNEC have not been identified. Therefore, the authors studied genetic alterations found in LCNEC and compared them with those of SCLC and classic large cell carcinoma (CLCC).


METHODS
Twenty-two patients with UICC TNM Stage I LCNEC, 12 patients with Stage I CLCC, and 11 patients with SCLC with limited disease were studied. All tumors were resected completely. Loss of heterozygosity (LOH) of the tumor cells was detected using fluorescent primers. Methylation status of the p16 gene and expression of the p53 protein, retinoblastoma protein, and p16 protein were evaluated immunohistochemically.


RESULTS
LOH at TP53 and 13q14 was observed in most patients. The prevalence of LOH at D3S1295, D3S1234, and D5S407 was significantly higher in patients with LCNEC and SCLC than in patients with CLCC. The prevalence of LOH at D5S422 was higher in patients with CLCC and in patients with SCLC than in patients with LCNEC. Expression of the p16 protein was observed more frequently in SCLC than in CLCC or LCNEC. Hypermethylation of the p16 gene was observed more frequently in LCNEC than in SCLC. Patients with allelic losses at D3S1234 and D10S1686 had poorer prognoses compared with patients without allelic losses at these sites.


CONCLUSIONS
Genetic alterations of LCNEC were akin to those of SCLC. However, allelic losses at 5q and abnormalities in the p16 gene may differentiate LCNEC from SCLC.
Hiroshima
Kenzo
K
Department of Basic Pathology, Graduate School of Medicine, Chiba University, Chiba, Japan. kenzo@faculty.chiba-u.jp
Iyoda
Akira
A
Shibuya
Kiyoshi
K
Haga
Yukiko
Y
Toyozaki
Tetsuya
T
Iizasa
Toshihiko
T
Nakayama
Toshinori
T
Fujisawa
Takehiko
T
Ohwada
Hidemi
H
D018287:Carcinoma, Large Cell / Q000235:genetics* / Q000401:mortality; D018278:Carcinoma, Neuroendocrine / Q000235:genetics* / Q000401:mortality; D018288:Carcinoma, Small Cell / Q000235:genetics / Q000401:mortality; D019175:DNA Methylation; D003937:Diagnosis, Differential; D019942:Genes, p16 / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000235:genetics*; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D016160:Retinoblastoma Protein / Q000096:biosynthesis; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53