title: Mechanistic background and clinical applications of indocyanine green fluorescence imaging of hepatocellular carcinoma.
abstract: BACKGROUND
  Although clinical applications of intraoperative fluorescence imaging of liver cancer using indocyanine green (ICG) have begun, the mechanistic background of ICG accumulation in the cancerous tissues remains unclear.
  
  
  METHODS
  In 170 patients with hepatocellular carcinoma cells (HCC), the liver surfaces and resected specimens were intraoperatively examined by using a near-infrared fluorescence imaging system after preoperative administration of ICG (0.5 mg/kg i.v.). Microscopic examinations, gene expression profile analysis, and immunohistochemical staining were performed for HCCs, which showed ICG fluorescence in the cancerous tissues (cancerous-type fluorescence), and HCCs showed fluorescence only in the surrounding non-cancerous liver parenchyma (rim-type fluorescence).
  
  
  RESULTS
  ICG fluorescence imaging enabled identification of 273 of 276 (99%) HCCs in the resected specimens. HCCs showed that cancerous-type fluorescence was associated with higher cancer cell differentiation as compared with rim-type HCCs (P < 0.001). Fluorescence microscopy identified the presence of ICG in the canalicular side of the cancer cell cytoplasm, and pseudoglands of the HCCs showed a cancerous-type fluorescence pattern. The ratio of the gene and protein expression levels in the cancerous to non-cancerous tissues for Na(+)/taurocholate cotransporting polypeptide (NTCP) and organic anion-transporting polypeptide 8 (OATP8), which are associated with portal uptake of ICG by hepatocytes that tended to be higher in the HCCs that showed cancerous-type fluorescence than in those that showed rim-type fluorescence.
  
  
  CONCLUSIONS
  Preserved portal uptake of ICG in differentiated HCC cells by NTCP and OATP8 with concomitant biliary excretion disorders causes accumulation of ICG in the cancerous tissues after preoperative intravenous administration. This enables highly sensitive identification of HCC by intraoperative ICG fluorescence imaging.
authors.affiliation: Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, University of Tokyo, Tokyo, Japan.
authors.forename: Takeaki
authors.initials: T
authors.lastname: Ishizawa
authors.forename: Koichi
authors.initials: K
authors.lastname: Masuda
authors.forename: Yasuteru
authors.initials: Y
authors.lastname: Urano
authors.forename: Yoshikuni
authors.initials: Y
authors.lastname: Kawaguchi
authors.forename: Shouichi
authors.initials: S
authors.lastname: Satou
authors.forename: Junichi
authors.initials: J
authors.lastname: Kaneko
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Hasegawa
authors.forename: Junji
authors.initials: J
authors.lastname: Shibahara
authors.forename: Masashi
authors.initials: M
authors.lastname: Fukayama
authors.forename: Shingo
authors.initials: S
authors.lastname: Tsuji
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Midorikawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.forename: Norihiro
authors.initials: N
authors.lastname: Kokudo
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D003287:Contrast Media; D003952:Diagnostic Imaging; D005453:Fluorescence; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007124:Immunoenzyme Techniques; D007208:Indocyanine Green; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D008856:Microscopy, Fluorescence; D016343:Monitoring, Intraoperative; D029363:Organic Anion Transporters, Sodium-Dependent / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism; D011300:Preoperative Care; D011379:Prognosis; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D027981:Symporters / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D003287:Contrast Media; D029363:Organic Anion Transporters, Sodium-Dependent; D029362:Organic Anion Transporters, Sodium-Independent; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D027981:Symporters; C071908:sodium-bile acid cotransporter; D007208:Indocyanine Green