Gd-EOB-DTPA-enhanced magnetic resonance imaging and alpha-fetoprotein predict prognosis of early-stage hepatocellular carcinoma.
The survival of patients with hepatocellular carcinoma (HCC) is often individually different even after surgery for early-stage tumors. Gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) has been introduced recently to evaluate hepatic lesions with regard to vascularity and the activity of the organic anion transporter OATP1B3. Here we report that Gd-EOB-DTPA-enhanced MRI (EOB-MRI) in combination with serum alpha-fetoprotein (AFP) status reflects the stem/maturational status of HCC with distinct biology and prognostic information. Gd-EOB-DTPA uptake in the hepatobiliary phase was observed in ∼15% of HCCs. This uptake correlated with low serum AFP levels, maintenance of hepatocyte function with the up-regulation of OATP1B3 and HNF4A expression, and good prognosis. By contrast, HCC showing reduced Gd-EOB-DTPA uptake with high serum AFP levels was associated with poor prognosis and the activation of the oncogene FOXM1. Knockdown of HNF4A in HCC cells showing Gd-EOB-DTPA uptake resulted in the increased expression of AFP and FOXM1 and the loss of OATP1B3 expression accompanied by morphological changes, enhanced tumorigenesis, and loss of Gd-EOB-DTPA uptake in vivo. HCC classification based on EOB-MRI and serum AFP levels predicted overall survival in a single-institution cohort (n=70), and its prognostic utility was validated independently in a multi-institution cohort of early-stage HCCs (n=109).


CONCLUSIONS
This noninvasive classification system is molecularly based on the stem/maturation status of HCCs and can be incorporated into current staging practices to improve management algorithms, especially in the early stage of disease.
Department of General Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan; Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan.
Taro
T
Yamashita
Azusa
A
Kitao
Osamu
O
Matsui
Takehiro
T
Hayashi
Kouki
K
Nio
Mitsumasa
M
Kondo
Naoki
N
Ohno
Tosiaki
T
Miyati
Hikari
H
Okada
Tatsuya
T
Yamashita
Eishiro
E
Mizukoshi
Masao
M
Honda
Yasuni
Y
Nakanuma
Hiroyuki
H
Takamura
Tetsuo
T
Ohta
Yasunari
Y
Nakamoto
Masakazu
M
Yamamoto
Tadatoshi
T
Takayama
Shigeki
S
Arii
XinWei
X
Wang
Shuichi
S
Kaneko
D000368:Aged; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D015331:Cohort Studies; D005260:Female; D019786:Gadolinium DTPA; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism; D006801:Humans; D007564:Japan / Q000453:epidemiology; D008099:Liver / Q000473:pathology*; D008113:Liver Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D008297:Male; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism; D011379:Prognosis; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D000509:alpha-Fetoproteins / Q000378:metabolism*
C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D029362:Organic Anion Transporters, Sodium-Independent; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D000509:alpha-Fetoproteins; C073590:gadolinium ethoxybenzyl DTPA; D019786:Gadolinium DTPA