Hiroshima Kenzo, Iyoda Akira, Shibuya Kiyoshi, Haga Yukiko, Toyozaki Tetsuya, Iizasa Toshihiko, Nakayama Toshinori, Fujisawa Takehiko, Ohwada Hidemi
Department of Basic Pathology, Graduate School of Medicine, Chiba University, Chiba, Japan.
Cancer. 2004 Mar 15;100(6):1190-8. doi: 10.1002/cncr.20108.
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).
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.
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.
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.
小细胞肺癌（SCLC）和肺大细胞神经内分泌癌（LCNEC）是高级别恶性神经内分泌肿瘤。在某些情况下，SCLC和LCNEC的组织学鉴别困难，据作者所知，与LCNEC相关的基因改变尚未被确定。因此，作者研究了LCNEC中发现的基因改变，并将其与SCLC和经典大细胞癌（CLCC）的基因改变进行比较。
研究了22例国际抗癌联盟（UICC）TNM I期LCNEC患者、12例I期CLCC患者和11例局限期SCLC患者。所有肿瘤均完整切除。使用荧光引物检测肿瘤细胞的杂合性缺失（LOH）。免疫组织化学评估p16基因的甲基化状态以及p53蛋白、视网膜母细胞瘤蛋白和p16蛋白的表达。
大多数患者观察到TP53和13q14的LOH。LCNEC和SCLC患者中D3S1295、D3S1234和D5S407的LOH发生率显著高于CLCC患者。CLCC患者和SCLC患者中D5S422的LOH发生率高于LCNEC患者。SCLC中p16蛋白的表达比CLCC或LCNEC更常见。LCNEC中p16基因的高甲基化比SCLC更常见。与在这些位点没有等位基因缺失的患者相比，D3S1234和D10S1686存在等位基因缺失的患者预后较差。
LCNEC的基因改变与SCLC相似。然而，5q的等位基因缺失和p16基因异常可能使LCNEC与SCLC相鉴别。
