title: A practical method to determine the site of unknown primary in metastatic neuroendocrine tumors.
abstract: BACKGROUND
  The site of a primary neuroendocrine tumor (NET) tumor is unknown before treatment in approximately 20% of small bowel (SBNET) and pancreatic (PNET) cases despite extensive workup. It can be difficult to discern a PNET from an SBNET on hematoxylin and eosin stains, and thus, more focused diagnostic tests are required. Immunohistochemistry (IHC) and gene expression profiling are two methods used to identify the tissue of origin from biopsied metastases.
  
  
  METHODS
  Tissue microarrays were created from operative specimens and stained with up to seven antibodies used in the NET-specific IHC algorithm. Expression of four genes for differentiating between PNETs and SBNETs was determined by quantitative polymerase chain reaction and then used in a previously validated gene expression classifier (GEC) algorithm designed to determine the primary site from gastrointestinal NET metastases.
  
  
  RESULTS
  The accuracy of the IHC algorithm in identifying the primary tumor site from a set of 37 metastases was 89%, with only one incorrect call. Three other samples were indeterminate as the result of pan-negative staining. The GEC's accuracy in a set of 136 metastases was 94%. The algorithm identified the primary tumor site in all cases in which IHC failed.
  
  
  CONCLUSIONS
  Performing IHC, followed by GEC for indeterminate cases, identifies accurately the primary site in SBNET and PNET metastases in virtually all patients.
authors.affiliation: Department of General Surgery, University of Iowa Carver College of Medicine, Iowa City, IA.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Maxwell
authors.affiliation: Department of General Surgery, University of Iowa Carver College of Medicine, Iowa City, IA.
authors.forename: Scott K
authors.initials: SK
authors.lastname: Sherman
authors.affiliation: Department of Pathology, University of Pennsylvania, Philadelphia, PA.
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Stashek
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: O'Dorisio
authors.affiliation: Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Bellizzi
authors.affiliation: Department of General Surgery, University of Iowa Carver College of Medicine, Iowa City, IA. Electronic address: james-howe@uiowa.edu.
authors.forename: James R
authors.initials: JR
authors.lastname: Howe
mesh_terms: D000465:Algorithms; D001707:Biopsy, Needle; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D007414:Intestinal Neoplasms / Q000235:genetics / Q000556:secondary*; D007421:Intestine, Small; D008297:Male; D046228:Microarray Analysis; D009382:Neoplasms, Unknown Primary / Q000235:genetics / Q000473:pathology*; D018358:Neuroendocrine Tumors / Q000235:genetics* / Q000556:secondary*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000556:secondary*; D012189:Retrospective Studies; D012494:Sampling Studies; D012680:Sensitivity and Specificity