title: Neuroendocrine and biologic features of primary tumors and tissue in pulmonary large cell carcinomas.
abstract: BACKGROUND
  Because biological behavior in lung tumors with neuroendocrine differentiation is highly dependent on cell death (apoptosis) and angiogenesis, p21(waf1/cip1) and microvessel density have been targeted as potentially useful tumor markers. We sought to validate the importance of p21(waf1/cip1) and microvessel density and study their interrelationship, analyzing clinical factors, subclassifications, and tumor and stromal markers.
  
  
  METHODS
  We examined p21(waf1/cip1) and other markers in tissue from 61 patients with surgically excised large cell carcinomas. The amount of tumor staining for p21(waf1/cip1) and microvessel density was evaluated by immunohistochemistry and morphometry. The study outcome was survival time until death from recurrent lung cancer.
  
  
  RESULTS
  Multivariate Cox model analysis demonstrated that after surgical excision, histologic subtypes were significantly related to survival time (p = 0.02), but quantitative staining of the tumor for p21(waf1/cip1) and microvessel density added prognostic information and these variables were more strongly prognostic than histologic subtype (p = 0.00). Cut points at the median staining of 3.5% and 3.0% for p21(waf1/cip1) and microvessel density, respectively, divided patients into two groups with distinctive survival times. Patients with p21(waf1/cip1) staining of more than 3.5% and microvessel density staining of more than 3.0% had a median survival time of 14 months.
  
  
  CONCLUSIONS
  Tumor staining for p21(waf1/cip1) and microvessel density in resected large cell carcinomas and certain other types of lung tumors was strongly related to survival. Patients with more than 3.0% staining in their tumors were at high risk of death from lung cancer and may be an appropriate target for prospective studies of adjuvant chemotherapy after surgical resection.
authors.affiliation: Department of Pathology, University of São Paulo Medical School, São Paulo, Brazil.
authors.forename: Alexandre M
authors.initials: AM
authors.lastname: Ab' Saber
authors.forename: Ledo Mazzei
authors.initials: LM
authors.lastname: Massoni Neto
authors.forename: Cristina P
authors.initials: CP
authors.lastname: Bianchi
authors.forename: Bruno B
authors.initials: BB
authors.lastname: Ctenas
authors.forename: Edwin R
authors.initials: ER
authors.lastname: Parra
authors.forename: Esmeralda M
authors.initials: EM
authors.lastname: Eher
authors.forename: João Carlos
authors.initials: JC
authors.lastname: Pereira
authors.forename: Teresa
authors.initials: T
authors.lastname: Takagaki
authors.forename: Nise H
authors.initials: NH
authors.lastname: Yamaguchi
authors.forename: Vera L
authors.initials: VL
authors.lastname: Capelozzi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018287:Carcinoma, Large Cell / Q000737:chemistry / Q000401:mortality / Q000473:pathology*; D018278:Carcinoma, Neuroendocrine / Q000737:chemistry / Q000401:mortality / Q000473:pathology*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000032:analysis; D051546:Cyclooxygenase 2; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000032:analysis; D008175:Lung Neoplasms / Q000737:chemistry / Q000401:mortality / Q000473:pathology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D008565:Membrane Proteins; D008875:Middle Aged; D016016:Proportional Hazards Models; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis; D012189:Retrospective Studies; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D007527:Isoenzymes; D008565:Membrane Proteins; D016159:Tumor Suppressor Protein p53; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020780:Matrix Metalloproteinase 9