title: Differential retinoblastoma and p16(INK4A) protein expression in neuroendocrine tumors of the lung.
abstract: BACKGROUND
  Neuroendocrine neoplasms of the lung represent a wide spectrum of phenotypically and biologically distinct entities. Their histopathologic diagnosis, which carries therapeutic and prognostic significance, may sometimes be difficult because of their overlapping features. We previously demonstrated that large cell neuroendocrine carcinomas (LCNECs) and small cell lung carcinomas (SCLCs) failed to show positive nuclear staining of RB protein (RB-), whereas typical and atypical carcinoids (TCs and ACs) showed nuclear RB immunostaining (RB+).
  
  
  METHODS
  In the current 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 pathologic diagnosis; the reviewers were blinded to the RB and p16 protein status.
  
  
  RESULTS
  Nineteen tumors were diagnosed as TCs, 5 as ACs, 7 as LCNECs, and 27 as SCLCs. Three of seven LCNECs were RB+, whereas 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+, whereas the other three were RB-. Interestingly, all 3 RB+ LCNECs and the 1 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. It is also noteworthy that the three RB+ LCNECs were initially diagnosed as SCLCs and one of the RB- ACs was initially considered a TC. With the exception of TCs, tumors were significantly more prevalent among heavy smokers with >20 pack-years compared with nonsmokers and light smokers with < or = 20 pack-years (P < 0.01).
  
  
  CONCLUSIONS
  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.
authors.affiliation: First Department of Medicine, Hokkaido University School of Medicine, Sapporo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Dosaka-Akita
authors.forename: P T
authors.initials: PT
authors.lastname: Cagle
authors.forename: H
authors.initials: H
authors.lastname: Hiroumi
authors.forename: M
authors.initials: M
authors.lastname: Fujita
authors.forename: M
authors.initials: M
authors.lastname: Yamashita
authors.forename: A
authors.initials: A
authors.lastname: Sharma
authors.forename: Y
authors.initials: Y
authors.lastname: Kawakami
authors.forename: W F
authors.initials: WF
authors.lastname: Benedict
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002276:Carcinoid Tumor / Q000235:genetics / Q000473:pathology; D018278:Carcinoma, Neuroendocrine / Q000235:genetics / Q000473:pathology; D018288:Carcinoma, Small Cell / Q000235:genetics / Q000473:pathology; D002467:Cell Nucleus / Q000648:ultrastructure; D004396:Coloring Agents; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000235:genetics / Q000473:pathology*; D016160:Retinoblastoma Protein / Q000032:analysis* / Q000235:genetics; D016037:Single-Blind Method; D012907:Smoking / Q000235:genetics / Q000473:pathology
chemical_list: D004396:Coloring Agents; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016160:Retinoblastoma Protein