CPZ: A Highly Sensitive Diagnostic Biomarker for the Differentiation Between Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma, Particularly in Poorly Differentiated Hepatocellular Carcinoma.

Abstract

Carboxypeptidase Z (CPZ) is a newly identified member of the metallopeptidase family, primarily reported in rats; however, its distribution in normal human tissues and expression characteristics in tumor tissues remain unclear. This study uses high-throughput and mass production technology for tissue microarray (TMA) to perform immunohistochemical staining of CPZ, for the first time delineating its distribution and expression in normal tissues and various tumors throughout the body, to discuss its potential pathologic value. CPZ exhibited varying degrees of cytoplasmic positive expression in the normal hepatocytes, pancreatic islets, and gallbladder epithelium, with no expression observed in other normal tissues. The positive expression rates of CPZ in hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), metastatic liver tumors, and normal liver tissue were 90.8% (109/120), 27.7% (13/47), 0% (0/22), and 100% (81/81), respectively. The sensitivity and specificity for diagnosing HCC with any of the 3 markers (CPZ, arginase-1 (Arg-1), and hepatocyte paraffin antigen-1 (Hep Par-1)) positive were 96.7% (116/120) and 65.2% (45/69), respectively. The sensitivity and specificity for diagnosing HCC with all 3 markers positive were 70.8% (85/120) and 100% (69/69), respectively. The sensitivity and specificity for diagnosing HCC with both CPZ and Arg-1 positive were 79.2% (95/120) and 95.7% (66/69), respectively. The sensitivity and specificity for diagnosing HCC with both CPZ and Hep Par-1 positive were 76.7% (92/120) and 97.1% (67/69), respectively. The sensitivity and specificity for diagnosing HCC with both Arg-1 and Hep Par-1 positive were 72.5% (87/120) and 98.6% (68/69), respectively. The ROC curve indicated that the combined detection of CPZ, Arg-1, and Hep Par-1 had the best diagnostic value for HCC (AUC=0.939, P<0.001). However, for individual detection, CPZ had the highest AUC value among the 3 markers (AUC=0.908, P<0.001). CPZ was not observed to be positive in the majority of 897 cases of solid tumors. Utilizing the TMA repository, we propose for the first time that CPZ may serve as a useful adjunctive tool for the diagnosis or differential diagnosis of HCC in routine surgical pathology practice. CPZ shows a trend of superiority over Arg-1 and Hep Par-1, particularly in poorly differentiated HCC.