Spontaneous Hibernomas in Sprague-Dawley Rats

Abstract

Hibernomas are rare neoplasms originating in brown adipose tissue of humans and other animal species, including laboratory animals. Background incidence values for these tumors in all common strains of laboratory rats are generally accepted as being <0.1%. Between April 2000 and April 2007, however, sixty-two hibernomas (an overall prevalence of 3.52%) were observed in a total of 1760 Sprague-Dawley rats assigned to three carcinogenesis bioassays at two separate research laboratories. All rats were obtained from Charles River's breeding facilities in either Portage, Michigan, or Raleigh, North Carolina. Tumors (twenty-nine benign and thirty-three malignant) were randomly distributed among test article-treated and control groups and were considered to be spontaneous. Most tumors originated in the thoracic cavity, and they were usually described as soft, mottled to tan masses with nodular to lobulated profiles. Immunohistochemical procedures for uncoupling protein 1 (UCP1) confirmed brown adipose tissue as the site of origin rather than white fat. The marked increase in hibernomas in our studies suggests that greater numbers of spontaneous hibernomas may be sporadically encountered in future carcinogenesis studies with Sprague-Dawley rats. The increased potential for hibernomas to arise as spontaneous neoplasms has important implications in studies involving peroxisome proliferators-activated receptor (PPAR) drugs, lipophilic environmental chemicals (e.g., polychlorinated biphenyls), and other molecules or physiologic processes (e.g., b-adrenergic stimulation) that may target brown fat adipocytes.

Clinical, Morphologic, and Immunohistochemical Features of Canine Orbital Hibernomas

“…8 A recent study described spontaneous hibernomas in aging Sprague-Dawley rats with a higher prevalence in males and the majority originating in the thoracic cavity. 2 The cause for the unusual location in the orbital region of the hibernomas described here is unknown. Speculation exists about the mechanism(s) of development of hibernomas.…”

“…The orbital hibernomas presented here consistently exhibited histologic, ultrastructural, and immunohistochemical features similar to those of hibernomas reported in a dog, rodents, and humans. 2,8,9,16,22,24,25 Potential differentials for the orbital neoplasms reported here include lipomatous neoplasms, rhabdomyomas, granular cell tumors, oncocytomas, and xanthogranulomas. Lipomas differ from hibernomas as they are less vascularized and resemble mature white adipose tissue with neoplastic cells having characteristic, large, cytoplasmic, lipid vacuoles that eccentrically displace the nucleus.…”

“…It was first described in humans by Merkel in 1906 as a ''pseudolipoma.'' 17 Hibernomas have been reported in laboratory rodents 2 and in humans. 8,9,12,16 The distinctive microscopic features of hibernomas include (1) lobules of closely apposed large polygonal cells and capillaries, (2) 3 principal cell types (granular eosinophilic, multivacuolated, and univacuolated), (3) investment of each tumor cell by the basal lamina, (4) an inverse relationship between lipid droplet size and the number of mitochondria per unit of cytoplasm, and (5) pleomorphic mitochondria with dense matrices or large, round mitochondria with transverse lamellar cristae.…”

Proliferative and Non-Proliferative Lesions of the Rat and Mouse Soft Tissue, Skeletal Muscle and Mesothelium

“…The foamy cytoplasm stains with oil red O. Electron microscopic study shows numerous mitochondria and small lipid droplets. They are rare tumors in all species including humans but they appear to be more commonly reported in rats ( 22 Coleman 1980; 1 Al Zubaidy and Finn 1983; 104 Stefanski et al 1987; 23 Coleman 1989; 14 Bruner et al 2009). A recent report has shown an increase in incidence in a colony of Sprague-Dawley rats ( 14 Bruner et al 2009).…”

Chordomas at High Prevalence in the Captive Population of the Endangered Perdido Key Beach Mouse (Peromyscus polionotus trissyllepsis)

“…1,3,9,32 Hibernomas are identified by immunohistochemistry for UCP1. 3,43 Brown fat from PKB mice used as a positive internal control exhibited intense cytoplasmic immunoreactivity, but metastases of chordomas in the lungs of PKB mice exhibited no UCP1 immunoreactivity. Unexpectedly, the ferret chordoma used as a negative control exhibited moderate cytoplasmic immunoreactivity for UCP1 around vacuoles; the reason for this is not clear.…”