Radiology 2012; 265:780–789 Departments of Radiology Kanazawa University Graduate School of Medical Science Azusa Kitao, MD et al. R3 Kwon Young Ho

 Gadoxetic acid–enhanced MR  new imaging modality with high accuracy for diagnosing HCCs  hepatobiliary phase  HCCs  hypointensity (compared with background liver) preArterial phase 20 min delayed phase3min delayed phase

Magnetic Resonance Imaging 29 (2011) 83–90 preArterial phase 20 min delayed phase 3min delayed phase

 6%–15% of hypervascular HCC  iso- or hyperintensity  due to overexpression of organic anion transporting polypeptide 8 (OATP8) Radiology 2010; 256:817–826

HCC Signal intensity on hepatobiliary phase OATP8 (+) (-) hepatocyte nuclear factor Tumor marker AFP (L-3) PIVKA-II Histologic degree and prognosis ? ?

Materials and Methods- Patients  207 consecutive patients who had 233 HCCs  surgically resected at our institution and six affiliated institutions - April 2008 to September 2011  Excluded pts.  more than one HCC (12 pts with 31 nodules)  previous treatment (3 pts with 10 nodules)  not have MR imaging (9 pts with nine nodules)  hypovascular in arterial phase (3 pts with three nodules)

Analysis of SI on Gadoxetic Acid–enhanced MR Images  By two abdominal imaging radiologists  SI of the tumor and surrounding background liver  Average size of ROI  mm 2 ± (range, 61–6167 mm 2 ). Hypointense HCC (tumor SI/background SI< 1.0) Hyperntense HCC (tumor SI/background SI> 1.0)

Histologic Diagnosis  H-E staining carried out in all 180 liver specimens  compared hypointense HCCs and hyperintense HCCs Regard to histologic features Macroscopic growth patterns indistinct margin, simple nodular, extranodular growth, and multinodular patterns Differentiation grade well, moderately, and poorly differentiated Proliferation pattern trabecular, pseudoglandular, scirrhous, and compact pattern Fibrous capsule invasion, portal vein invasion and hepatic vein invasion

Immunohistochemical Analysis of AFP, PIVKA-II, and OATP8  Two abdominal imaging radiologists  intensity of the AFP and PIVKAII expression on tumor cytoplasm  intensity of OATP8 expression on tumor cellular membranes  analyzed the average grades of the two investigators AFP and PIVKAII expression grade 0no expression grade 1weak expression grade 2moderate expression grade 3strong expression intensity of OATP8 expression grade 0no expression grade 1decreased expression grade 2equivalent expression grade 3increased expression

Recurrence and Survival Rates in Patients with HCC  Compared the two groups for recurrence and survival  including all local recurrence and intrahepatic and extrahepatic metastasis  Follow-up length  727 days ± 365 (range, 22–1293 days)

moderately differentiated HCC with trabecular proliferation pattern moderately differentiated HCC with fat deposition serum AFP level, 23 mg/L; AFP-L3, 5.8%; PIVKA-II 30,mAU/mL OATP8 AFP PIVKA-II serum AFP level, mg/L; AFP-L3, 48.7%; PIVKA-II, 7924 mAU/mL

Results

P =.039 P =.07 P <.001 P =.003P =.026P =.004

Results

Discussion  We suspect that the molecular regulatory mechanism  some common channels  OATP8 expression ∝ 1/ AFP or PIVKA-II expression  Several prior reports  suggested that transcription factor hepatocyte nuclear factors control both OATP8 and AFP expression  However, many pts  low AFP and PIVKA-II expression in hypointense HCCs  OATP8, AFP, and PIVKA-II - several direct and indirect regulatory mechanisms

Discussion  Molecular classification of subtypes of HCCs  Yamashita et al  classified on the basis of expression of AFP and epithelial cell adhesion molecule (stem cell marker)  AFP-(+) and epithelial cell adhesion molecule–(+) HCCs  stem and progenitor cell features with invasive character and poor prognosis  compared with negative  mature hepatocyte-like features with relatively good px.  resembled hyperintense HCCs  Surmised origin of hyperintense HCC  mature hepatocyte-like cells

CONCLUSION  Hyperintense HCCs on hepatobiliary phase images  Significantly higher differentiation grades, less frequent portal vein invasion, and lower recurrence rates  Significantly lower expression of AFP and PIVKA-II  Particular form of hypervascular HCC with biologically less aggressive features than those of hypointense HCCs