Human safety risk assessment of lymph node angiomas observed in 2-year carcinogenicity studies in rats

Evaluation of potential activity of luseogliflozin on vascular proliferation in the mesenteric lymph node with or without vascular tumors in Sprague-Dawley rats in a carcinogenicity study

“…The incidence of lymph node angioma is known to vary markedly over time and appears to be higher in some other rat strains than in the Crl:CD strain 1 , 2 , and a broader range of angiomatous lesions may occur in lymph nodes. It has been reported that mesenteric lymph node angiomas occur more commonly and at a higher incidence in male rats, with the incidence varying from rare to common in Sprague-Dawley rats (0%–8.6%) 2 , 16 , and these benign angiomas in different strains have always been more common in male rats than in female rats 1 , 2 , 23 , 24 . Tennekes et al reported that changes in tumor incidence over time in male Sprague-Dawley rats were primarily caused by genetic drift 25 .…”

“…Hemangioma in humans is a pathological condition, and it can be difficult to distinguish whether the lesion is a true tumor or tissue malformation (hamartoma) 26 . Such tumors are not believed to become malignant 2 , 9 . Hemangiosarcoma in humans represents the formation of an irregular vascular lumen consisting of large and small cells or the proliferation of atypical endothelial cells in the form of a mass.…”

“…It is a highly malignant pathological condition with the papillary protrusion of tumor cells into the vascular lumen 27 . Furthermore, in humans, hemangioma appears more commonly on the surface of the head and neck region and liver 27 , and lymph node angioma (lymphangioma and hemangioma) is extremely rare 2 . The incidence of hemangiosarcoma has recently been estimated to be 0.00021% 28 .…”

“…Vascular tumors of the mesenteric lymph nodes are generally regarded as uncommon in Sprague-Dawley rats. However, the spontaneous incidence of lymph node vascular tumors in Sprague-Dawley male rats can vary over time, and these tumors occur more commonly and with a higher incidence in male rats, with the incidence varying from rare to common 1 , 2 . In studies performed from 1983 to 2001, historical data compiled from the Registry of Industrial Toxicology Animal-Data (RITA, unpublished data) shows that the incidence ranged from 0% to 6% 2 .…”

“…However, the spontaneous incidence of lymph node vascular tumors in Sprague-Dawley male rats can vary over time, and these tumors occur more commonly and with a higher incidence in male rats, with the incidence varying from rare to common 1 , 2 . In studies performed from 1983 to 2001, historical data compiled from the Registry of Industrial Toxicology Animal-Data (RITA, unpublished data) shows that the incidence ranged from 0% to 6% 2 . When the incidences of vascular tumors of lymph nodes are increased compared with those in control rats in carcinogenicity studies, it is important to perform additional risk assessment of tumorigenicity for humans to explore the possible vascular proliferation potential of the test agents.…”