Altered Expression of Cell Cycle-Regulatory Tumor Suppressor Proteins in Neuroendocrine Lung tumors : Their Significance for the Differential Diagnosis

肺的神经内分泌肿瘤代表了广泛的表型和生物学上不同的实体。它们的组织病理学诊断，具有治疗和预后意义，有时可能是困难的，因为它们的重叠功能。我们先前已经证明，大细胞神经内分泌癌（LCNEC）和小细胞肺癌（SCLC）未能显示RB蛋白的阳性核染色（RB-），而典型和非典型类癌（TC和AC）显示核RB免疫染色（RB+）（Cagle，P.T.，等Am. J. Pathol.，150：393，1997）。在本研究中，通过免疫组织化学研究了一系列58个手术切除的肺肿瘤（其中33个肿瘤最初被诊断为SCLC，25个肿瘤被诊断为TC或AC）的RB和p16蛋白表达。他们还审查了他们的病理诊断盲RB和p16蛋白状态。19个肿瘤被诊断为TC，5个为AC，7个为LCNEC，27个为SCLC。7个LCNEC中有3个为RB+，而其他4个为RB-。相反，所有19个TC均为RB+，所有27个SCLC均为RB-。此外，五个AC中有两个是RB+，而其他三个是RB-。有趣的是，所有三个RB+ LCNEC和一个RB+ AC测试未能显示任何肿瘤细胞中p16蛋白的核染色（p16-），尽管一些正常基质细胞显示p16蛋白的核染色（p16+）作为阳性内部对照，表明这些肿瘤中p16功能丧失。值得注意的是，三个RB+ LCNEC最初被诊断为SCLC，并且其中一个RB-AC最初被认为是TC。除了TC之外，与不吸烟者和烟龄[小于或等于] 20的轻度吸烟者相比，烟龄大于20的重度吸烟者中肿瘤的患病率显著更高（P<0.01）。这些发现表明，所有SCLC和LCNEC都有p16：RB通路异常，至少某些AC也有异常，而TC中p16：RB通路正常。

Neuroendocrine neoplasms of the lung represent a wide spectrum of phenotypically and biologically distinct entities. Their histopathological diagnosis, which carries therapeutic and prognostic significance, may sometimes be difficult because of their overlapping features. We have previously demonstrated that large cell neuroendocrine carcinomas (LCNECs) and small cell lung cancers (SCLCs) failed to show positive nuclear staining of RB protein (RB-), while typical and atypical carcinoids (TCs and ACs) showed nuclear RB immunostaining (RB+) (Cagle, P.T., et al. Am. J.Pathol., 150 : 393, 1997). In the present study, a series of 58 surgically resected lung tumors, of which 33 tumors were initially diagnosed as SCLCs and 25 as TCs or ACs, were studied for RB and p16 protein expression by immunohistochemistry. They were also reviewed for their pathological diagnosis blinded to the RB and p16 protein status. Nineteen tumors were diagnosed as TCs, five as ACs, seven as LCNECs, and 27 as SCLCs. Three of seven LCNECs were RB+, while the other four were RB-. In contrast, all 19 TCs were RB+ and all 27 SCLCs were RB-. In addition, two of five ACs were RB+, while the other three were RB-. Interestingly, all three RB+ LCNECs and the one RB+ AC tested failed to show nuclear staining of p16 protein in any tumor cells (p16-), although some normal stromal cells showed nuclear staining of p16 protein (p16+) as positive internal controls, indicating loss of p16 function in these tumors. Of note, the three RB+ LCNECs were initially diagnosed as SCLCs and one of the RB- ACs was initially considered to be a TC.With the exception of TCs, tumors were significantly more prevalent in heavy smokers with pack years greater than 20 compared with nonsmokers and light smokers with pack years 【less than or equal】 20 (P<0.01). These findings suggest that all SCLCs and LCNECs have abnormalities in the p16 : RB pathway as do at least certain ACs, whereas the p16 : RB pathway is normal in TCs.