Tyrosine kinase inhibitor-induced vasculopathy in clear cell renal cell carcinoma: an unrecognized antitumour mechanism

• Published in: Histopathology 2014-03, Vol.64 (4), p.484-493
• Main Authors: Tsuzuki, Toyonori, Sassa, Naoto, Shimoyama, Yoshie, Morikawa, Takamitsu, Shiroki, Ryoichi, Kuroda, Makoto, Fukatsu, Akitoshi, Kuwahara, Kyoko, Yoshino, Yasushi, Hattori, Ryohei, Gotoh, Momokazu
• Format: Article
• Language: English
• Subjects: Aged; Angiogenesis Inhibitors - therapeutic use; Antineoplastic Agents - therapeutic use; antitumour mechanism; Carcinoma, Renal Cell - blood supply; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - pathology; clear cell renal cell carcinoma; Female; Humans; Indoles - therapeutic use; Kidney Neoplasms - blood supply; Kidney Neoplasms - drug therapy; Kidney Neoplasms - pathology; Male; Medical research; Middle Aged; Neoadjuvant Therapy; Neovascularization, Pathologic - drug therapy; Nephrectomy; Niacinamide - analogs & derivatives; Niacinamide - therapeutic use; Phenylurea Compounds - therapeutic use; Protein Kinase Inhibitors - therapeutic use; Protein-Tyrosine Kinases - antagonists & inhibitors; Pyrroles - therapeutic use; Receptors, Vascular Endothelial Growth Factor - antagonists & inhibitors; Retrospective Studies; tyrosine kinase inhibitor; vasculopathy
• ISSN: 0309-0167; 1365-2559
• DOI: 10.1111/his.12277

Aims 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. Methods and 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.