Panels of Immunohistochemical Markers Help Determine Primary Sites of Metastatic Adenocarcinoma

Abstract

Context.—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. Design.—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.

Carcinoma of Unknown Primary Origin: Application of Immunohistochemistry

“…However, Su et al and Bayrak et al showed that CDX2 is not a good predictor of the lower GI origin because it could be positive in all GI tract origin cases (17,18). CDX2 positivity in in different studies ranged from 18% to more than 70% in gastric cancers (17,15,22,24) and Vang et al showed CDX2 expression in 74 % of metastatic gastric cancers to the ovary (25). Special AT-rich sequence-binding protein 2(SATB2) was positive in our lower GI cases.…”

“…CK19 was positive in all patients and GATA3 was positive in 12.5%. showed that IHC predicted the primary origin of metastatic tumors in 64%, 66%, 67%, and 65% of cases, respectively, that are approximately in the same range (92,12,93,94). Also, in another previous study by Weiss et al, in 69% of cases, the origin site was diagnosed by an IHC study (5).…”

“…CDX2 was positive in 95.5% of cases of lower GI and 50% of upper GI origin carcinomas. Previous studies showed that CDX2 could be positive in more than 90% of colorectal cancer (1,13,14,15,16). However, Su et al and Bayrak et al showed that CDX2 is not a good predictor of the lower GI origin because it could be positive in all GI tract origin cases (17,18).…”

Tumor origin detection with tissue-specific miRNA and DNA methylation markers

“…However, there are still several tissues such as Bile Duct, Esophagus and Uterus, are inherently hard to classify correctly and are often poorly differentiated or dedifferentiated, these three tissues were also reported with a quite low prediction accuracy in other machine-learning methods, such as the method proposed by Rolf et el (Søkilde, et al, 2014). The testing accuracy of these three tissues in our miRNA-based classifier reach respectively about 79.66% and 72.55%, which are not good as other tissues but still better than some other methods, such as the IHC markers method Park et al (Park, et al, 2007) proposed which can be used to identify the cholangiocarcinoma (Bile Duct) wich a quite low accuracy (28%).…”

Patterns of Immunohistochemistry Utilization in Metastases to the Liver

“…To date, there are very few studies that suggest a simple systematic approach when dealing with metastatic tumors in the liver. 19 Our study showed the need for clear guidelines/recommendations on how to appropriately apply IHC when evaluating liver tumors, incorporating some of the clinical variables discussed in this audit. In most cases, the pathologist is presented with limited material such as a needle biopsy or fine needle aspiration, and therefore, a sequential and/or algorithmic approach is crucial when selecting the appropriate panel.…”