Mixed phenotype hepatocellular carcinoma after transarterial chemoembolization and liver transplantation.

We investigated the phenotype of hepatocellular carcinoma (HCC) in livers removed during transplantation after local ablation therapy by transarterial chemoembolization (TACE). This study involved 80 HCC nodules (40 treated with TACE and 40 not treated with local ablation before transplantation) observed in 64 explanted livers and included clinicopathological evaluations as well as single and double immunohistochemistry and reverse-transcription polymerase chain reaction (RT-PCR) for cytokeratin 19 (CK19), epithelial cell adhesion molecule (EpCAM), neural cell adhesion molecule (NCAM), and CD133. HCCs with complete necrosis post-TACE without viable tumors were excluded from the analysis. Cholangiolar, glandular, or spindle cell areas suggestive of a mixed hepatocholangiocellular phenotype were seen in 14 post-TACE HCCs and in none of the non-TACE HCCs (P < 0.001). According to single-epitope immunohistochemistry of post-TACE HCCs, CD133, CK19, EpCAM, and NCAM were expressed in 14 (35%), 8 (20%), 12 (30%), and 8 (20%), respectively. Only EpCAM was detected in 4 non-TACE HCC cases (10%). RT-PCR experiments using tissues obtained by laser microdissection showed that 4 of 5 investigated post-TACE HCCs expressed at least 1 of the markers, which were coexpressed in 3 of 5 tumors, whereas CD133 and EpCAM were individually expressed in 2 non-TACE HCCs. Double immunostaining showed that CD133(+) cells frequently coexpressed CK19, EpCAM, or NCAM. Interestingly, the recurrence rate for patients with CD133(+) post-TACE HCC was significantly higher than the rate for patients with CD133(-) post-TACE HCC (P = 0.025). In conclusion, HCC with the combined hepatocholangiocellular phenotype appears to be more frequent in post-TACE HCC versus untreated HCC. Further studies are needed to investigate the potential relationships between TACE and HCC subpopulations with a chemoembolization-resistant phenotype and their clinical significance.