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., beta-adrenergic stimulation) that may target brown fat adipocytes.
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ABSTRACT: In humans, hibernoma is a very rare, benign neoplasm of brown adipose tissue (BAT) that typically occurs at subcutaneous locations and is successfully treated by surgical excision. No single cause has been accepted to explain these very rare human tumors. In contrast, spontaneous hibernoma in rats is rare, often malignant, usually occurs in the thoracic or abdominal cavity, and metastases are common. In recent years, there has been an increased incidence of spontaneous hibernomas in rat carcinogenicity studies, but overall the occurrence remains relatively low and highly variable across studies. There have only been four reported examples of pharmaceutical-induced hibernoma in rat carcinogenicity studies. These include phentolamine, an alpha-adrenergic antagonist; varenicline, a nicotine partial agonist; tofacitinib, a Janus kinase (JAK) inhibitor; and hydromorphone, an opiod analgesic. Potential non-genotoxic mechanisms that may contribute to the pathogenesis of BAT activation/proliferation and/or subsequent hibernoma development in rats include: (1) physiological stimuli, (2) sympathetic stimulation, (3) peroxisome proliferator-activated receptor (PPAR) agonism, and/or (4) interference or inhibition of JAK/Signal Transducer and Activator of Transcription (JAK/STAT) signaling. The evaluation of an apparent increase of hibernoma in rats from 2-year carcinogenicity studies of novel pharmaceutical therapeutics and its relevance to human safety risk assessment is complex. One should consider: the genotoxicity of the test article, dose/exposure and safety margins, and pathophysiologic and morphologic differences and similarities of hibernoma between rats and humans. Hibernomas observed to date in carcinogenicity studies of pharmaceutical agents do not appear to be relevant for human risk at therapeutic dosages.Toxicology and Applied Pharmacology 10/2013; · 3.98 Impact Factor
Article: Subconjunctival hibernoma in a dog.[Show abstract] [Hide abstract]
ABSTRACT: A 10-year-old, castrated male, German Shepherd mixed-breed dog was presented to Kansas State University Veterinary Health Center for evaluation of a subconjunctival swelling in the ventral fornix of the left orbit. The owner elected to pursue excision of the mass 2 years after initial consultation following a sudden change in the size and color of the lesion. An excisional biopsy was performed, and the mass along with its associated capsule were submitted to the Comparative Ocular Pathology Laboratory of Wisconsin for histopathologic evaluation, which confirmed the diagnosis of a hibernoma. Fourteen months following excision, the patient showed no evidence of tumor regrowth.Veterinary Ophthalmology 11/2013; · 0.96 Impact Factor
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ABSTRACT: Uncoupling proteins (UCPs) are a family of inner mitochondrial membrane proteins whose function is to allow the re-entry of protons to the mitochondrial matrix, by dissipating the proton gradient and, subsequently, decreasing membrane potential and production of reactive oxygen species (ROS). Due to their pivotal role in the intersection between energy efficiency and oxidative stress, UCPs are being investigated for a potential role in cancer. In this review we compile the latest evidence showing a link between uncoupling and the carcinogenic process, paying special attention to their involvement in cancer initiation, progression and drug chemoresistance.Cancers. 01/2010; 2(2):567-591.
The online version of this article can be found at:
2009 37: 547 originally published online 22 April 2009Toxicol Pathol
B. Lawrence, Dawn G. Goodman, Brett H. Saladino, David G. Peters and George A. Parker
Richard H. Bruner, Meliton N. Novilla, Catherine A. Picut, Jeannie B. Kirkpatrick, Thomas P. O'Neill, Kathryn L. Scully, Wade
Spontaneous Hibernomas in Sprague-Dawley Rats
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Spontaneous Hibernomas in Sprague-Dawley Rats
RICHARD H. BRUNER,1MELITON N. NOVILLA,1CATHERINE A. PICUT,1JEANNIE B. KIRKPATRICK,2THOMAS P. O’NEILL,2
KATHRYN L. SCULLY,1WADE B. LAWRENCE,3DAWN G. GOODMAN,3BRETT H. SALADINO,3DAVID G. PETERS,3AND
GEORGE A. PARKER1
1Biotechnics, LLC, Hillsborough, North Carolina, USA
2WIL Research Laboratories, LLC, Ashland, Ohio, USA
3Covance Laboratories, Inc., Madison, Wisconsin, USA
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.
hibernoma; Sprague-Dawley rats; brown fat; carcinogenesis bioassay; UCP-1; brown adipose.
Hibernomas are rare neoplasms that originate in brown adi-
pose tissue (BAT) of both humans and animals. Brown adipose
tissue is a specialized adipose tissue whose primary function is
to provide nonshivering thermogenesis during periods of cold-
induced stress (Cannon and Nedergaard 2004; Iatropoulos and
Williams 2004). Brown adipose tissue is especially critical for
thermal maintenance in neonates, where it is abundantly pres-
ent in deposits within the abdominal and thoracic cavities as
well as in subcutaneous tissue of the interscapular regions
(Figure 1A). In rodents, BAT deposits normally persist in
multiple locations throughout life.
During routine necropsy procedures associated with three
Good Laboratory Practices–compliant, proprietary, chronic toxi-
city/carcinogenesis studies conducted at two separate research
laboratories, twenty-nine benign and thirty-three malignant
hibernomas were observed in a total population of 1760 Spra-
gue-Dawley rats (combined incidence of 3.5%). This rate of pre-
valence markedly exceeded historical incidence values for the
conducting laboratories, and for values reported in the open liter-
ature and in compilations reported by government agencies and
observation that hibernomas in all three studies were randomly
distributedamongall test article–treatedand controlgroups,sug-
gesting that therewasnocausal relationshipwith thetest articles.
Precise causative factors for the increase in hibernomas were not
identified. The marked increase over historical control values,
however, indicated that greater numbers of hibernomas may be
expected in future carcinogenesis bioassays with Sprague-
Dawleyrats. Theaim of this article is toinform pathologists,tox-
icologists, and allied biomedical scientists that, for undetermined
reasons, hibernomas have apparently become rather common,
spontaneous neoplasms in aging Sprague-Dawley rats.
MATERIALS AND METHODS
All three studies reported in this article were proprietary
that the precise nature of the respective test article(s) remain con-
fidential. Two studies (hereafter identified as Studies A and B)
were conducted at WIL Research Laboratories, LLC, Ashland,
Ohio, and the third study (Study C) was conducted at Covance
Laboratories, Madison, Wisconsin. All studies were conducted
in facilities accredited by the Association for the Assessment and
compliance with the U. S. Food and Drug Administration’s Good
Laboratory Practice regulations, the National Institutes of Health
Guide for the Care and Use of Laboratory Animals, and the Ani-
mal Welfare Act. Environmental conditions, including food and
water intake, were not considered to be influential in hibernoma
Address correspondence to: Richard H. Bruner, Biotechnics LLC, 310
Millstone Drive, Hillsborough, NC 27278, USA; e-mail: rbruner@biotechnics-
Competing Interests: No competing interests have been declared by the
Abbreviations: BAT, brown adipose tissue; Std, standard ration; TAA, Test
Article A; TAB, Test Article B; UCP1, uncoupling protein 1.
Toxicologic Pathology, 37: 547-552, 2009
Copyright # 2009 by The Author(s)
ISSN: 0192-6233 print / 1533-1601 online
development, and all other forms of neoplasia and reactive or
degenerative diseases observed in each study were within normal
background limits for Sprague-Dawley rats.
Study A was a twenty-four-month dietary study of two
potential food additives, either alone or in combination. Other
than dietary ingredients, no vehicle was required. This study
included 380 male and female rats (760 total) assigned to six
dietary test groups plus a control group that was fed a standard
ration. Rats included in this study were obtained from Charles
River’s breeding facility in Raleigh, North Carolina.
Study B was a twenty-four-month oral carcinogenicity study
including 240 male and female rats (480 total) assigned to three
test article was deionized water. Rats in this study were obtained
Study Cwas a scheduled 104-week oral gavage carcinogeni-
city and toxicokinetic study involving 260 male and female
(520 total) rats assigned to three test article–treated groups and
one control group. The vehicle for the test article was 2% (w/v)
Tween 80 in 1% (w/v) aqueous carboxymethylcellulose in
reverse-osmosis water. Males were terminated at ninety-eight
weeks when survivors in the high-dose group reached twenty
animals. Rats in this study were obtained from Charles River’s
breeding facility in Portage, Michigan.
cessing, and microscopic examination of a complete set of organs
sequently determined to be hibernomas were usually collected as
solitary, soft tissue masses with varying external profiles (nodular
patible with tumors of brown fat origin, select tumors were stained
immunohistochemically for the presence of uncoupling protein 1
ymal tumors that may have vacuolated cytoplasm (e.g.,
liposarcomas). The primary antibody was a rabbit polyclonal to
UCP1 obtained from Abcam (Cambridge, MA). The secondary
antibody was a biotin-SP–conjugated AffiniPure F(ab’)2 fragment
goat anti- rabbit IgG (HþL) purchased from Jackson Immuno
(West Grove, PA). The negative control was an IgG protein–
CA). The ABC Vector Rabbit Elite kit (Vector Labs, Burlingame,
CA) was incubatedonthe tissue for thirtyminutespriortostaining
with DAB. This kit was obtained from Dako (Carpinteria, CA).
Histologically, collected masses were determined to be
either benign or malignant hibernomas originating from brown
fat adipocytes. Benign tumors were characterized by expanding
populations of round to oval cells that were encapsulated and
subdivided into irregular clusters by fibrous strands of varying
thickness. Proliferating cells were well differentiated and dis-
played modest amounts of eosinophilic, foamy to multivacuo-
lated cytoplasm along with central nuclei that exhibited low
mitotic activity (Figures 1C and 1D). Malignant tumors often
were locally invasive and displayed more pleomorphic cell
increased mitotic activity (Figure 1E). Vascular invasion was
sometimes observed, with embolic clusters of tumor cells
reaching pulmonary blood vessels (Figure 1F).
In Study A, hibernomas were observed in 10/380 males
(2.6%) and in 4/380 females (1.1%). All hibernomas were
observed grossly as masses originating in the thoracic cavity,
where they often circumscribed the aorta and/or compressed
the lungs or mediastinal structures. Twelve tumors were con-
sidered to be benign; however, two (one male and one female)
displayed malignant features. Metastases to distant sites were
not observed. Of the ten males with hibernomas, eight were
either found dead or euthanized in extremis between study days
378 and 732, and the cause of death was uniformly attributed to
expanding hibernoma in the thoracic cavity. Of the four
females with hibernomas, all were found dead or euthanized
in extremis between study days 593 and 722; however, hiber-
noma was considered to be the cause of death in only one ani-
mal. Treatment-based incidence values for hibernomas
observed in Study A are presented in Table 1.
In Study B, hibernomas were observed in 15/240 males
(6.3%) and 10/240 females (4.2%). Most hibernomas were
observed grossly as masses originating in the thoracic cavity;
however, in two males the abdominal cavity was determined
to be the primary site, and in one male, the hibernoma appeared
to develop in the subcutaneous fat near the mammary gland. In
the females, all hibernomas appeared to originate in the thor-
acic cavity. Sixteen tumors were considered to be benign (eight
males and eight females), and nine were malignant (seven
males and two females). Metastases to the lungs (intravascular
emboli) were observed in one male and one female, and
metastasis to the adrenal gland was noted with one male. Of the
fifteen males with hibernomas, twelve were either found dead
or euthanized in extremis between study days 269 and 727.
Hibernomas were considered to be the cause of death foreleven
of the males and six of the females. Treatment-based incidence
values for hibernomas observed in Study B are presented in
In Study C, hibernomas were observed in 13/260 males
(5.0%) and 10/260 females (3.8%). Although brown fat of the
interscapular region was a protocol-required tissue, all hiberno-
mas were collected grossly as masses in the thoracic or abdom-
inal cavities or in the mammary gland region. In relative
contrast to studies A and B, twenty-two of twenty-three hiber-
nomas in Study C were regarded as malignant. Eighteen tumors
(seventeen malignant and one benign) were present in the thor-
acic cavity, whereas five additional malignant tumors were
observed in the abdominal cavity (one) or in the mammary
548BRUNER ET AL.TOXICOLOGIC PATHOLOGY
FIGURE 1.—(A) Abundant subcutaneous deposits of normal brown fat (arrows) stained immunohistochemically for uncoupling protein 1 in a neo-
natal rat, ?4. (B) Hibernoma cells exhibit positive immunohistochemical staining for UCP1, a unique protein that is expressed in brown fat adi-
pocytes, ?200. (C) Benign, expansile hibernoma juxtaposed to the thoracic aorta, ?20. (D) Benign hibernoma cells display multivacuolated
cytoplasm with central nuclei and low mitotic activity, ?200. (E) Malignant hibernomas with pleomorphic brown fat adipocytes that exhibit
increased mitotic activity, ?200. (F) Embolus of neoplastic hibernoma cells in a pulmonary artery, ?100.
Vol. 37, No. 4, 2009 HIBERNOMAS IN SPRAGUE-DAWLEY RATS549
gland region (four). Metastatic lesions were identified for six
primary malignant tumors. Malignant hibernoma was regarded
as the cause of death for seventeen rats that were either found
dead or euthanized in extremis between study day 264 and the
terminal necropsy (day 684 for males and days 728–734 for
In all three studies, hibernomas were slightly more prevalent
in males, and most tumors originated in the thoracic cavity.
When compared with Studies A and B, malignant hibernomas
were strikingly more common in Study C. Reasons for this
trend were not apparent; however, Study C was completed
approximately two years following the completion of Studies
A and B, and rats assigned to Study C were obtained from
Charles River’s breeding facility in Portage, Michigan, rather
than the facility in Raleigh, North Carolina. Essentially all
hibernoma diagnoses were based on grossly apparent masses
that were collected at necropsy from the thoracic or abdominal
cavities or the mammary gland region. In this regard, it is pos-
sible that some small hibernomas escaped gross detection and
were not processed for microscopic examination. Microscopic
findings in other tissues collected at necropsy from all three
studies were generally consistent with common, spontaneous
changes observed in aging Sprague-Dawley rats, and no
neoplasms were observed that were considered to be test arti-
cle–related. All studies (A, B, and C) were accompanied by
companion, long-term mouse studies with the same test arti-
cle(s) using similar exposure regimens. Hibernomas were not
observed in the mouse studies.
Incidence rates for hibernomas in these three studies greatly
exceeded historical values for the two conducting laboratories
and values reported by the National Toxicology Program
(NTP), NIEHS, and other commercial laboratories. Search of
the NTP tumor database identified a total of nine hibernomas
in rats and two in mice assigned, respectively, to 213 rat studies
(92,296 rats) and 201 mouse studies (91,366 mice). For both
species, the incidence was < 0.001%. Although most of the
NTP studies involved Fischer-344 (F-344) rats and B6C3F1
mice, six of the nine hibernomas were reported in Osborne-
Mendel rats assigned to two different studies that were
completed during the early phases of the NTP carcinogenesis
Hibernomas were not reported in a compilation of sponta-
neous neoplasms reported by Charles River Laboratories in
March 2004. This survey included nontreated control
Crl:CD(SD) rats representing thirty-one studies (104 weeks)
conducted in eight different testing facilities in the United
States, Europe, Canada, and Japan between 1989 and 2002.
In twelve of these studies, rats were confirmed to be from
Crl:CD(SD) colonies produced under the International Genetic
Standard (IGS) breeding system that was designed to stabilize
the degree of genetic diversity among colonies of Crl:CD(SD)
rats on a worldwide basis.
In a similar compilation of spontaneous neoplasms in con-
trol Crl:CD BR rats assigned to thirty-six different studies that
were conducted prior to February 1989, Charles River reported
one hibernoma in the thoracic cavity of a male. In addition to
the Charles River compilations, Al Zubaidy and Finn (1983),
Coleman (1980), and Stefanski (1987) reported small numbers
of hibernomas as incidental findings in the thoracic cavity of
TABLE 1.—Incidence of hibernomas observed in Study A.
Number of rats/group
50 5050 50 50 6565
4.5% Std5.5% TAA4.5% TAA
TAA and TAB
TAA ad lib
TAB ad lib
Number of rats/group
505050 5050 65 65
4.5% Std 5.5% TAA4.5% TAA
TAA and TAB
TAA ad lib
TAB ad lib
Abbreviations: ad lib, ad libitum; Std, standard ration; TAA, Test Article A; TAB, Test Article B.
TABLE 2.—Incidence of hibernomas observed in Study B.
Control Low Mid High Control Low Mid High
550BRUNER ET AL.TOXICOLOGIC PATHOLOGY
rats assigned to three unrelated studies. Two possible excep-
tions were noted in reports by Poulet et al. (2004) and by Brees
et al. (2008). In Poulet’s report, eleven hibernomas were
observed in a population of 520 Sprague-Dawley [Crl:CD
BR] rats (260/sex) assigned to a two-year carcinogenesis study
of phentolamine mesylate (an a-adrenergic antagonist) admi-
nistered at daily doses of 10, 50, and 150 mg/kg. In this study,
three males and one female given 10 mg/kg, four males given
50 mg/kg, and three males given 150 mg/kg displayed hiber-
nomas in either the thoracic cavity or in retroperitoneal
(abdominal) locations. In the report by Brees, hibernomas were
observed in the mediastinum of three male rats administered
high doses of varenicline (a partial nicotinic agonist) during a
two-year carcinogenesis study (unpublished data). Although
there was no distinct dose relationship for the hibernomas
observed in these two studies, phentolamine mesylate and var-
enicline could not be entirely ruled out as carcinogens because
hibernomas were restricted to treated animals only and were
considered to represent a rare form of neoplasia. In both stud-
ies, other forms of neoplasia were within historical control val-
ues for the performing laboratory. Furthermore, there were no
significant histopathological findings in a reported twenty-six-
week p53 mouse bioassay of phentolamine mesylate at doses
up to 150 mg/kg (Wenk 1998).
In humans, hibernomas have been described as rare neo-
plasms that occur most commonly in adults, with a mean age
of 38.0 years and an age range of 2–75 years. In a review of
170 cases from the Armed Forces Institute of Pathology,
ninety-nine tumors were observed in men and seventy-one in
women. The most common anatomic locations were thigh
(n ¼ 50), shoulder (n ¼ 20), back (n ¼ 17), neck (n ¼ 16), chest
(n ¼ 11), arm (n ¼ 11), and retroperitoneum (n ¼ 10) (Furlong
et al. 2001). Additional sites where hibernomas have been
reported include the forehead, axilla, and interscapular regions
(Baskurt et al. 2004; Chen et al. 1998; Chitoku et al. 1998; Lay
et al. 2000; Wilhelm et al. 1993). No association with drugs or
xenobiotic chemicals has been reported for hibernomas in
humans; however, in a report by Lele et al. (2002), two hiber-
nomas in human females were associated with an overexpres-
sion of p53 protein. In this report, the authors also noted that
hibernomas in transgenic mice have been reported to contain
simian virus (SV40)–transforming genes linked to the adipo-
cytes’ specific regulatory region, and that the SV40 large T
antigen can bind with and inactivate several tumor suppressor
genes, including p53. They further speculate that functional
inactivation of the p53 protein product may be important in the
development of hibernomas in humans.
Although brown fat appears to be relatively unimportant in
adult humans, it is critical in laboratory rodents that have higher
basal metabolic rates and substantially greater surface-to-body-
mass ratios. In rodents, brown fat deposits in the thoracic and
abdominal cavities and in the subcutaneous tissue are richly sup-
plied with adrenergic stimulation from the sympathetic trunks.
During periods of cold-induced stress, hypothalamic signaling
via sympathetic nerves releases norepinephrine, which binds to
receptors onbrown adipocytes, resultingina cascade ofintracel-
lular signals that activate lipoprotein lipase with the subsequent
liberation of free fatty acids. In brown adipocytes, the metabo-
lism of fatty acids is largely regulated by a unique protein UCP1
that is present along the inner mitochondrial membrane. This
from ADP phosphorylation and promotes the dissipation of
oxidation energy as heat. The ability of brown adipocytes to
efficiently convert fatty acids into energy is enhanced by the
large number of cytoplasmic mitochondria (Geloen et al.
1990; Nedergaard et al. 2001). In this connection, it has been
estimated that approximately 50% of the metabolic energy of
a rat at room temperature is supplied by brown fat sources. Iron
associated with mitochondrial respiratory chain cytochrome
enzymes contributes to the tinctorial quality of brown fat.
Despite the importance of BAT in thermoregulation and
metabolic homeostasisof laboratoryrodents, this tissue has been
largely ignored during the histopathological evaluation of ani-
mals assigned to preclinical drug safety and efficacy bioassays.
In part, this omission has resulted because brown fat exists as
irregular, widely disseminated deposits that complicate uniform
collection and organ weighing procedures. Additionally, distinct
morphologic changes are seldom recognized grossly or micro-
selectivelytargeted byxenobiotics are not functionally operative
in brown adipocytes. More recently, however, several classes of
new or investigational drugs have emerged that may target
peroxisome proliferators–activated receptor agonists (for dia-
betes and atherosclerosis), adrenergic agonists (norepinephrine),
fat-soluble environmental chemicals such as DDT and poly-
chlorinated biphenyls have the potential for altering the metabo-
lism of brown fat adipocytes. Based on increasing knowledge of
the pathophysiology of brown fat and the apparent increase in
hibernomas in recent studies, it would appear prudent to expand
the collection and examination of brown fat deposits in future
rodent carcinogenesis bioassays.
The overall incidence of hibernomas in Sprague-Dawley
rats assigned to three carcinogenesis bioassays with unrelated,
proprietary test articles greatly exceeded historical control
values for the testing laboratories and background incidence
TABLE 3.—Incidence of hibernomas observed in Study C.
65 6565 6565 65 6565
Control Low Mid High Control Low Mid High
Vol. 37, No. 4, 2009 HIBERNOMAS IN SPRAGUE-DAWLEY RATS 551
values reported in the open literature. Tumors were slightly
more prevalent in males, and most originated in brown fat of
the thoracic cavity. In Study A, fourteen hibernomas (twelve
benign and two malignant) were observed in total of 760 ani-
mals (380/sex). In Study B, twenty-five hibernomas (sixteen
benign and nine malignant) were observed in 480 rats (240/
sex), and in Study C, twenty-three hibernomas (one benign and
twenty-two malignant) were noted in 520 rats (260/sex). In
each study, tumors were randomly distributed among test arti-
cle–treated and control groups, and none was considered to be
test article–related. Furthermore, test article–related carcino-
genesis was not observed in other organs in any study, and
there was no evidence of hibernomas in companion mouse
studies. Collectively, pathologic findings in these three studies
strongly suggested that hibernomas represented spontaneous
neoplasms unrelated to respective test articles, and that genetic
and/or environmental factors should be considered as likely
causes. Results also suggest that increased numbers of hiberno-
mas can be expected in future carcinogenesis studies with
Sprague-Dawley rats, and that brown fat should receive greater
attention in future safety and efficacy studies.
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Brees, D. J., Elwell, M. R., Tingley III, F. D., Sands, S. B., Jakowski, A. B.,
Shen, A. C., Hon Cai, J., and Finkelstein, M. B. (2008). Pharmacological
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Chen, D. Y., Wang, C. M., and Chan, H. L. (1998). Hibernoma. Case report and
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Chitoku, S., Kawai, S., Watabe, Y., Nishitani, M., Fujimoto, K., Otsuka, H.,
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