title: Panels of immunohistochemical markers help determine primary sites of metastatic adenocarcinoma.
abstract: BACKGROUND
  Although identification of the primary tumor in patients with metastatic adenocarcinoma has a profound clinical impact, diagnosing the organ of origin is frequently difficult. Because none of the individual immunohistochemical markers used for tissue identification are both site specific and site sensitive, multiple markers are needed to improve the prediction of primary sites.
  
  
  OBJECTIVE
  To develop an effective approach to immunohistochemically evaluate metastatic adenocarcinoma for the assignment of a likely primary site of origin.
  
  
  METHODS
  Expression profiles of CDX2, cytokeratin (CK) 7, CK20, thyroid transcription factor 1 (TTF-1), carcinoembryonic antigen (CEA), MUC2, MUC5AC, SMAD4, estrogen receptor (ER), and gross cystic disease fluid protein 15 (GCDFP-15) were generated in adenocarcinomas from 7 primary sites, followed by construction of a decision tree and design of multiple-marker panels. Expression of these markers was evaluated immunohistochemically in 314 primary adenocarcinomas (50 cases each of colorectal, gastric, lung, pancreatic, bile duct, and breast, and 14 cases of ovarian origin) using the tissue array method. Results were validated using 60 cases of metastatic adenocarcinoma with known primaries.
  
  
  RESULTS
  Organ-specific immunostaining profiles using multiple markers provided high sensitivity, specificity, and positive predictive value in detecting primary adenocarcinomas, as follows: colorectal, TTF-1-/CDX2+/CK7-/CK20+ or TTF-1-/CDX2+/CK7-/CK20-/(CEA+ or MUC2+); ovarian, CK7+/MUC5AC+/TTF-1-/CDX2-/CEA-/GCDFP-15-; breast, GCDFP-15+/TTF-1-/CDX2-/CK7+/CK20- or ER+/ TTF-1-/CDX2-/CK20-/CEA-/MUC5AC-; lung, TTF-1+ or TTF-1-/CDX2-/CK7+/CK20-/GCDFP-15-/ER-/CEA-/ MUC5AC-; pancreaticobiliary, TTF-1-/CDX2-/CK7+/ CEA+/MUC5AC+; and stomach, TTF-1-/CDX2+/CK7+/ CK20-. Overall, these combined phenotypes correctly predicted the tester samples (metastatic adenocarcinomas with known primaries) in 75% of cases.
  
  
  CONCLUSIONS
  Determination of tissue-specific immunostaining profiles is valuable in the diagnostic differentiation of metastatic adenocarcinomas from seven common primary sites and should help to correctly predict the organ of primary tumor origin.
authors.affiliation: Department of Pathology, Seoul National University College of Medicine and Cancer Research Institute, 28 Yongon-dong, Chongno-gu, Seoul 110-744, South Korea.
authors.forename: Seog-Yun
authors.initials: SY
authors.lastname: Park
authors.forename: Baek-Hee
authors.initials: BH
authors.lastname: Kim
authors.forename: Jung-Ho
authors.initials: JH
authors.lastname: Kim
authors.forename: Sun
authors.initials: S
authors.lastname: Lee
authors.forename: Gyeong Hoon
authors.initials: GH
authors.lastname: Kang
mesh_terms: D000230:Adenocarcinoma / Q000737:chemistry* / Q000556:secondary*; D014408:Biomarkers, Tumor / Q000032:analysis*; D003663:Decision Trees; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques / Q000379:methods*; D009363:Neoplasm Proteins / Q000032:analysis*; D009382:Neoplasms, Unknown Primary / Q000737:chemistry / Q000175:diagnosis; D011237:Predictive Value of Tests; D012680:Sensitivity and Specificity; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins