title: Tumour cell proliferation (Ki-67) in non-small cell lung cancer: a critical reappraisal of its prognostic role.
abstract: BACKGROUND
  Uncontrolled proliferation is a hallmark of malignant tumour growth. Its prognostic role in non-small cell lung cancer (NSCLC) has been investigated in numerous studies with controversial results. We aimed to resolve these controversies by assessing the Ki-67 proliferation index (PI) in three large, independent NSCLC cohorts.
  
  
  METHODS
  Proliferation index was retrospectively analysed by immunohistochemistry in a cohort of 1065 NSCLC and correlated with clinicopathological data including outcome and therapy. RESULTS were validated in two independent cohorts of 233 squamous cell carcinomas (SQCC) and 184 adenocarcinomas (ADC).
  
  
  RESULTS
  Proliferation index (overall mean: 40.7%) differed significantly according to histologic subtypes with SQCC showing a mean PI (52.8%) twice as high as ADC (25.8%). In ADC PI was tightly linked to growth patterns. In SQCC and ADC opposing effects of PI on overall (OS), disease-specific and disease-free survival were evident, in ADC high PI (optimised validated cut-off: 25%) was a stage-independent negative prognosticator (hazard ratio, HR OS: 1.56, P=0.004). This prognostic effect was largely attenuated by adjuvant radio-/chemotherapy. In SQCC high PI (optimised validated cut-off: 50%) was associated with better survival (HR OS: 0.65, P=0.007).
  
  
  CONCLUSIONS
  Our data demonstrate that PI is a clinically meaningful biomarker in NSCLC with entity-dependent cut-off values that allow reliable estimation of prognosis and may potentially stratify ADC patients for the need of adjuvant therapy.
authors: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors: A
authors: A
authors: Warth
authors: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors: J
authors: J
authors: Cortis
authors: Institute of Pathology, University Hospital Zürich, Zürich, Switzerland.
authors: A
authors: A
authors: Soltermann
authors: Translational Research Unit, Thoraxklinik at University Hospital Heidelberg, Heidelberg, Germany.
authors: M
authors: M
authors: Meister
authors: Institute of Pathology, Charité Berlin, Berlin, Germany.
authors: J
authors: J
authors: Budczies
authors: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors: A
authors: A
authors: Stenzinger
authors: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors: B
authors: B
authors: Goeppert
authors: Department of Thoracic Oncology, Thoraxklinik at University Hospital Heidelberg, Heidelberg, Germany.
authors: M
authors: M
authors: Thomas
authors: Department of Pneumology and Critical Care Medicine, Thoraxklinik at University Hospital Heidelberg, Heidelberg, Germany.
authors: F J F
authors: FJ
authors: Herth
authors: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors: P
authors: P
authors: Schirmacher
authors: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors: P A
authors: PA
authors: Schnabel
authors: Department of Thoracic Surgery, Thoraxklinik at University Hospital Heidelberg, Heidelberg, Germany.
authors: H
authors: H
authors: Hoffmann
authors: Department of Thoracic Surgery, Thoraxklinik at University Hospital Heidelberg, Heidelberg, Germany.
authors: H
authors: H
authors: Dienemann
authors: Translational Research Unit, Thoraxklinik at University Hospital Heidelberg, Heidelberg, Germany.
authors: T
authors: T
authors: Muley
authors: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors: W
authors: W
authors: Weichert
mesh_terms: D000230:Adenocarcinoma / Q000737:chemistry / Q000556:secondary* / Q000628:therapy; D002289:Carcinoma, Non-Small-Cell Lung / Q000737:chemistry / Q000556:secondary* / Q000628:therapy; D002294:Carcinoma, Squamous Cell / Q000737:chemistry / Q000556:secondary* / Q000628:therapy; D049109:Cell Proliferation; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000032:analysis*; D008175:Lung Neoplasms / Q000737:chemistry / Q000473:pathology* / Q000628:therapy; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011013:Pneumonectomy; D018714:Radiotherapy, Adjuvant; D012189:Retrospective Studies; D015996:Survival Rate
chemical_list: D019394:Ki-67 Antigen