Novel insights into immunohistochemical analysis of intrahepatic cholangiocarcinoma: ST6 N-acetylgalactosaminide alpha-2,6-sialyltransferase 1 (ST6GalNAc1) as a new marker for large duct type.

Intrahepatic cholangiocarcinoma (iCCA) is histologically classified into the small duct type (SDT) and large duct type (LDT), although their morphological differential diagnosis can be difficult. We aimed to identify new immunohistochemical markers to classify SDT and LDT with high sensitivity and specificity. We compared the gene expression profiles of SDT and LDT using cases obtained from our institution (n = 8) and The Cancer Genome Atlas database (n = 28). We selected the candidate molecules that were up-regulated in LDT, were minimally or not expressed in SDT, and had specific and available antibodies suitable for immunohistochemistry. We finally selected ST6 N-acetylgalactosaminide alpha-2,6-sialyltransferase 1 (ST6GalNAc1), Breast carcinoma amplified sequence-1 (BCAS-1), and Olfactomedin 4 (OLFM4), which were expressed in 100%, 100%, and 98.3% of 58 LDT cases, respectively. ST6GalNAc1 was expressed in 3.8% of 52 SDT cases, whereas BCAS-1 and OLFM4 were expressed in 48.1% and 34.6% of SDT cases, respectively. ST6GalNAc1 was also expressed in intraductal papillary neoplasm of the bile duct (100%, n = 17) and only the adenocarcinoma component corresponding to LDT among the combined hepatocellular-cholangiocarcinoma cases (100%), but not in hepatocellular carcinoma (n = 26). In small biopsy specimens, ST6GalNAc1 was expressed in 100% of LDT (n = 18) and 12.5% of SDT (n = 16) samples. ST6GalNAc1 expression was associated with significantly shorter overall survival (P = 0.012) and remained significant after adjustment for tumor subtype (hazard ratio 2.595; 95% confidence interval, 1.433-4.699; P = 0.002). ST6GalNAc1 is useful for iCCA subtype identification with high sensitivity and specificity, showing promise to become a more powerful tool when combined with other markers.