title: Automated quantification of Ki-67 proliferative index of excised neuroendocrine tumors of the lung.
abstract: BACKGROUND
  The histopathologic distinction between typical carcinoid (TC) and atypical carcinoid (AC) of the lung is based largely on mitotic index. Ki-67 may aid in separation of these tumors, as well as the distinction from large cell neuroendocrine carcinoma (LCNEC).
  
  
  METHODS
  We identified 55 surgically resected primary neuroendocrine lung tumors (39 TC, 7 AC, 9 LCNEC) based on mitotic rate and histologic features. Ki-67 proliferative index based on automated image analysis, tumor necrosis, nodal metastases, local or distant recurrence, and survival were compared across groups.
  
  
  RESULTS
  The mean mitotic count and Ki-67 index for TC, AC, and LCNEC were 0.1 and 2.3%, 3.4 and 16.8%, and 56.1 and 81.3% respectively. The Ki-67 index did not overlap among groups, with ranges of 0-6.7% for TC, 9.9-25.7% for AC, and 63.2-91.9% for LCNEC. Nodal metastases were identified in 4/39 (10%) TC, 2/7 (22%) AC, and 2/8 (25%) LCNEC. There was no survival difference between TC and AC, but there was a significant survival difference between LCNEC and TC and AC combined (p<0.001). There was a step-wise increase in disease free survival with tumor grade: no TC recurred, 2/7 AC recurred or progressed (median interval 35.5 months), and all LCNEC recurred or progressed (median interval 10.1 months). No patient with TC or AC died of disease, compared to 7/8 LCNEC with follow-up data.
  
  
  CONCLUSIONS
  We conclude that Ki-67 index is a useful diagnostic marker for neuroendocrine tumors, with 7% a divider between AC and TC, and 50% a divider between LCNEC and AC. LCNEC is biologically different from AC and TC, with a much more aggressive course, and a high Ki-67 index.
  The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_174.
authors.forename: Sandy Z
authors.initials: SZ
authors.lastname: Liu
authors.forename: Paul N
authors.initials: PN
authors.lastname: Staats
authors.forename: Lindsay
authors.initials: L
authors.lastname: Goicochea
authors.forename: Borislav A
authors.initials: BA
authors.lastname: Alexiev
authors.forename: Nirav
authors.initials: N
authors.lastname: Shah
authors.forename: Renee
authors.initials: R
authors.lastname: Dixon
authors.affiliation: From the Departments of Pathology and Internal Medicine, University of Maryland, 22 S, Greene St, Baltimore 21201, USA. Allen.burke@gmail.com.
authors.forename: Allen P
authors.initials: AP
authors.lastname: Burke
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D002276:Carcinoid Tumor / Q000378:metabolism* / Q000473:pathology; D018287:Carcinoma, Large Cell / Q000378:metabolism* / Q000473:pathology; D018278:Carcinoma, Neuroendocrine / Q000473:pathology*; D018288:Carcinoma, Small Cell / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008940:Mitotic Index; D009364:Neoplasm Recurrence, Local; D018358:Neuroendocrine Tumors / Q000473:pathology*
chemical_list: D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen