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

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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.