Panels of immunohistochemical markers help determine primary sites of metastatic adenocarcinoma.
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.
Park
Seog-Yun
SY
Department of Pathology, Seoul National University College of Medicine and Cancer Research Institute, 28 Yongon-dong, Chongno-gu, Seoul 110-744, South Korea.
Kim
Baek-Hee
BH
Kim
Jung-Ho
JH
Lee
Sun
S
Kang
Gyeong Hoon
GH
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
D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins