title: Atypical bronchopulmonary carcinoids show a tendency toward increased apoptotic and proliferative activity.
abstract: BACKGROUND
  Bronchopulmonary carcinoid tumors can be divided into typical and atypical carcinoids according to their histologic and clinical features. Atypical carcinoids tend to have less predictable biologic behavior and are associated with a worse prognosis than typical carcinoids. The authors examined apoptosis and the expression of apoptosis regulating proteins Bcl-2, Bax, Bak, and Mcl-1 in 21 typical and 10 atypical bronchopulmonary carcinoid tumors. To find features distinguishing the growth of these types of tumors, the expression of p53 protein and the proliferation marker Ki-67 were also investigated. Finally, the parameters were compared with clinical follow-up data.
  
  
  METHODS
  Thirty-one bronchopulmonary carcinoid tumors were examined by using in situ 3'-end labeling of DNA (TUNEL) for apoptosis and immunohistochemical staining methods for Bcl-2, Bax, Bak, Mcl-1, p53, and Ki-67 in formalin fixed, paraffin embedded tissue specimens.
  
  
  RESULTS
  The apoptotic indices (AIs) were low in general (mean 0.18%), but higher AIs (> 0.5%) were observed significantly more often in atypical than in typical carcinoids (P < 0.008) in association with shortened survival (P < 0. 008). No relation between apoptosis and Bcl-2, Bax, Bak, or Mcl-1 expression was found. Expression of p53 protein was detected in only three atypical carcinoids, which also had significantly higher AIs than p53 negative tumors (P < 0.03). Proliferation rates measured by Ki-67 index were unusually low; the highest proliferation rates were observed in atypical carcinoids. There was a positive correlation between AI and Ki-67 indices (P < 0.01).
  
  
  CONCLUSIONS
  This study suggests that the extent of apoptosis in bronchopulmonary carcinoid tumors is low. This, together with a low proliferation rate and an apparent absence of p53 mutation, enables a benign growth pattern. Some atypical carcinoids with enhanced apoptosis are associated with shortened survival, clearly deviating from typical carcinoids.
authors.affiliation: Department of Pathology, University of Oulu, Oulu, Finland.
authors.forename: K L
authors.initials: KL
authors.lastname: Laitinen
authors.forename: Y
authors.initials: Y
authors.lastname: Soini
authors.forename: J
authors.initials: J
authors.lastname: Mattila
authors.forename: P
authors.initials: P
authors.lastname: Pääkkö
mesh_terms: D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000096:biosynthesis; D001984:Bronchial Neoplasms / Q000378:metabolism / Q000473:pathology*; D002276:Carcinoid Tumor / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D002455:Cell Division; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein
chemical_list: C494772:BAK1 protein, human; C494826:BAX protein, human; D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein