title: Tyrosine kinase inhibitor-induced vasculopathy in clear cell renal cell carcinoma: an unrecognized antitumour mechanism.
abstract: OBJECTIVE
  To evaluate the pathological features of clear cell renal cell carcinoma (CCRCC) treated with tyrosine kinase inhibitors (TKIs), and to elucidate the mechanism of action of TKIs.
  
  
  RESULTS
  Twenty cases of CCRCC treated with TKIs (sorafenib or sunitinib) were retrospectively analysed: 16 were patients who had undergone radical nephrectomy after neoadjuvant TKI therapy, and four were autopsy cases of patients who received TKI treatment. All tumours had two distinct regions: one characterized by necrosis and/or degeneration, indicating antitumour activity; and the other characterized by no or few pathological changes, indicating the absence of antitumour activity. Vasculopathy of tumour vessels was observed in or adjacent to the necrotic or degenerative areas; a decreased density of endothelial cells was noted in the tumour vessels. Few or no changes of vasculopathy were observed in tumour vessels in the other CCRCC areas, indicating the absence or low levels of antitumour activity.
  
  
  CONCLUSIONS
  This is the first pathological report of vasculopathy in TKI-treated CCRCC cases. Our data suggest that TKIs initially induce vasculopathy in tumour vessels, and consequently cause reduction or diminution of blood supply to the CCRCCs, resulting in antitumour activity characterized by necrosis and hyalinization.
authors.affiliation: Department of Pathology, Nagoya Daini Red Cross Hospital, Nagoya, Japan.
authors.forename: Toyonori
authors.initials: T
authors.lastname: Tsuzuki
authors.forename: Naoto
authors.initials: N
authors.lastname: Sassa
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Shimoyama
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Morikawa
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Shiroki
authors.forename: Makoto
authors.initials: M
authors.lastname: Kuroda
authors.forename: Akitoshi
authors.initials: A
authors.lastname: Fukatsu
authors.forename: Kyoko
authors.initials: K
authors.lastname: Kuwahara
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yoshino
authors.forename: Ryohei
authors.initials: R
authors.lastname: Hattori
authors.forename: Momokazu
authors.initials: M
authors.lastname: Gotoh
mesh_terms: D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D009392:Nephrectomy; D009536:Niacinamide / Q000031:analogs & derivatives / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011758:Pyrroles / Q000627:therapeutic use; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D012189:Retrospective Studies; D000077157:Sorafenib; D000077210:Sunitinib
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D007211:Indoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D009536:Niacinamide; D000077157:Sorafenib; D011505:Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D000077210:Sunitinib
keywords: antitumour mechanism; clear cell renal cell carcinoma; tyrosine kinase inhibitor; vasculopathy