Hepatocellular carcinoma: hepatocyte-selective enhancement at gadoxetic acid-enhanced MR imaging--correlation with expression of sinusoidal and canalicular transporters and bile accumulation.
OBJECTIVE
To investigate the mechanism of enhancement of hepatocellular carcinoma (HCC) on gadoxetic acid-enhanced hepatobiliary phase magnetic resonance (MR) images and to characterize HCC thus enhanced.


METHODS
This retrospective study was approved by the institutional review board, and patient informed consent for research use of the resected specimen was obtained. MR images in 25 patients (20 men, five women; mean age, 68 years; range, 49-82 years) with 27 resected hypervascular HCCs (one well, 13 moderately, 13 poorly differentiated) that demonstrated hepatocyte-selective enhancement on gadoxetic acid-enhanced MR images, were quantitatively studied, and findings were correlated with results of immunohistochemical staining for a sinusoidal transporter, organic anion transporting polypeptide (OATP) 1B1 (OATP1B1) and/or OATP1B3 (OATP1B1 and/or -1B3), and a canalicular transporter, multidrug resistance-associated protein 2 (MRP2), and also with bile accumulation in tumors. Statistical analysis was performed with the Student t test and Scheffé post hoc test.


RESULTS
Combined with positive OATP1B1 and/or -1B3 expression (O+), two patterns of MRP2 expression contributed to high enhancement: decreased expression (M-, n = 3) and increased expression at the luminal membrane of pseudoglands (M+[P], n = 3). Nodules without OATP1B1 and/or -1B3 expression (O-, n = 13) and nodules with O+ associated with increased MRP2 expression only at the canaliculi (M+[C], n = 8) induced significantly lower enhancement than those with the two expression patterns described before (O+/M- group vs O- group, P = .002; O+/M- group vs O+/M+[C] group, P = .047; O+/M+[P] group vs O- group, P < .001; O+/M+[P] group vs O+/M+[C] group, P < .001). Nodules with bile pigment (n = 12) showed significantly higher enhancement (P = .004); all five nodules (one well differentiated HCC, four moderately differentiated HCCs), which were enhanced more than adjacent liver parenchyma, contained bile pigment.


CONCLUSIONS
High hepatocyte-selective enhancement is induced by expression patterns of transporters, which may result in accumulation of gadoxetic acid in cytoplasm of tumor cells or in lumina of pseudoglands. An HCC with gadoxetic acid enhancement is characterized by bile accumulation in tumors.
Tsuboyama
Takahiro
T
Department of Radiology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. t-tsuboyama@radiol.med.osaka-u.ac.jp
Onishi
Hiromitsu
H
Kim
Tonsok
T
Akita
Hirofumi
H
Hori
Masatoshi
M
Tatsumi
Mitsuaki
M
Nakamoto
Atsushi
A
Nagano
Hiroaki
H
Matsuura
Nariaki
N
Wakasa
Kenichi
K
Tomoda
Kaname
K
D000368:Aged; D000369:Aged, 80 and over; D001646:Bile; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D003287:Contrast Media; D005260:Female; D019786:Gadolinium DTPA; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D027362:Organic Anion Transport Protein 1 / Q000378:metabolism*; D012189:Retrospective Studies
D003287:Contrast Media; D019786:Gadolinium DTPA; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027362:Organic Anion Transport Protein 1; C073590:gadolinium ethoxybenzyl DTPA