Urothelial cell intracytoplasmic inclusions after treatment of promyelocytic leukemia with arsenic trioxide

• Published in: Toxicological sciences Vol. 134; no. 2; pp. 271 - 275
• Main Authors: Wedel, Whitney R, Muirhead, David E, Arnold, Lora L, Dodmane, Puttappa R, Lele, Subodh M, Maness-Harris, Lori, Hoyt, Rose, Cohen, Samuel M
• Format: Journal Article
• Language: English
• Published: United States 01.08.2013
• Subjects: Adult; Aged; Arsenicals - pharmacology; Arsenicals - therapeutic use; Case-Control Studies; Female; Humans; Inclusion Bodies - metabolism; Leukemia, Promyelocytic, Acute - drug therapy; Leukemia, Promyelocytic, Acute - pathology; Male; Microscopy, Electron, Transmission; Microscopy, Fluorescence; Middle Aged; Oxides - pharmacology; Oxides - therapeutic use; Urothelium - drug effects; Urothelium - metabolism; Urothelium - pathology; urothelial cell; arsenic trioxide; bladder
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1093/toxsci/kft120

Intramitochondrial inclusions containing arsenite that occur within urothelial cells have been previously described in mice exposed to high concentrations of arsenic but not in rats. In epidemiology studies, similar urothelial cell inclusions have also been observed in the urine of humans exposed to high concentrations of arsenic in the drinking water; however, these inclusions were mistakenly identified as micronuclei. To further examine the urothelial cell inclusions that occur in inorganic arsenic-exposed humans, we evaluated two patients with a history of acute promyelocytic leukemia treated for disease relapse with a combination of all-trans retinoic acid and arsenic trioxide. Posttreatment examination of the patients' urine cytology specimens by light and electron microscopy demonstrated cytoplasmic inclusions in exfoliated superficial urothelial cells similar to those seen in mice. The inclusions were present in decreasing quantities at 3 and 7 months after completion of treatment. No comparable inclusions were detected in exfoliated urothelial cells in urine from six individuals not treated with arsenic trioxide. Based on the results of the examination by light and electron microscopy, we have determined that urothelial cell inclusions in the urine of humans previously identified as micronuclei are instead intracytoplasmic inclusions similar to those found in arsenic-treated mice.