Incidences and Range of Spontaneous Findings in Control Cynomolgus Monkeys (Macaca fascicularis) Used in Toxicity Studies
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Toxicologic Pathology, 38: 642-657, 2010
Copyright # 2010 by The Author(s)
ISSN: 0192-6233 print / 1533-1601 online
DOI: 10.1177/0192623310368981
Incidences and Range of Spontaneous Findings in Control
Cynomolgus Monkeys (Macaca fascicularis) Used in Toxicity Studies
RONNIE CHAMANZA, HEIKE A. MARXFELD, ANA I. BLANCO, STUART W. NAYLOR, AND ALYS E. BRADLEY
Charles River Edinburgh, Tranent, EH33 2NE, Scotland, United Kingdom
ABSTRACT
The authors performed a retrospective study to determine the incidences and range of spontaneous pathology findings in control cynomolgus
monkeys. Data were collected from 570 monkeys (285 animals per sex), aged twelve to thirty-six months, from sixty regulatory studies evaluated
at our laboratory between 2003 and 2009. The most common finding overall was lymphoplasmacytic infiltrates observed in the following incidence:
liver (60.7%), kidneys (28.8%), heart (25.8%), salivary glands (21.2%), and stomach (12.1%). Inflammation also commonly occurred in the heart,
kidneys, lungs, and stomach. The most common degenerative changes were localized fatty change in the liver, myocardial degeneration, and miner-
alization and pigment deposits in various tissues. Parathyroid, thyroid, and pituitary cysts; ectopic thymus in the parathyroid or thyroid gland; acces-
sory spleen within the pancreas; and adrenohepatic fusion were among the most common congenital findings. Some incidental findings bearing
similarities to drug-induced lesions were also encountered in various organs. It is hoped that the results presented here and elsewhere could form
the groundwork for the creation of a reliable database of incidental pathology findings in laboratory nonhuman primates.
Keywords: cynomolgus; Macaca fascicularis; nonhuman primate; spontaneous pathology; incidental findings; toxicity studies.
INTRODUCTION strain and source of the animals used, housing and manage-
ment and variations in nomenclature and recording levels of
Nonhuman primates are increasingly being used as nonro-
the individual pathologists evaluating these studies. Such data
dent species in preclinical toxicology studies, mainly owing
also need to be updated regularly to reflect possible changes
to their close phylogenic relationship to humans and where
in these factors over time.
there is no alternative. Of the available species, the cynomolgus
The main aims of this study were to present and discuss
macaque has become the most widely used species, and they
summarized results from studies carried out at Charles River,
are widely available as purpose bred for laboratory use. How-
Edinburgh, of the range and incidences of the most common
ever, despite their common usage, specific information on the
spontaneous lesions of control cynomolgus macaques, and by
range and incidence of spontaneous background pathology
doing so help provide the basis for further work on organ/
findings in laboratory-raised young adult macaques is not read-
system-specific pathology of nonhuman primates. Presentation
ily available. Because some of these incidental findings may
of some less common or unusual findings, but of toxicological
resemble drug-induced findings and thus hinder the interpreta-
significance, since they can be confused with treatment related
tion of pathology results, it is important for the pathologist to
changes, was one of the main objectives of this study.
have available some reference material such as a historical con-
trol database or published literature with incidences, range, and
histopathological presentation of incidental findings in this MATERIALS AND METHODS
species. Both common incidental findings and findings likely Animals
to be confused with treatment-related lesions are important in
this regard. Tissue samples from a total of 570 cynomolgus macaques
Historical background pathology data are particularly (285 animals per sex) were obtained from control groups of
important in studies involving nonrodent species because sixty preclinical toxicological studies evaluated between
fewer numbers of animals are used, which can greatly 2003 and 2009. The animals were purpose bred for laboratory
increase the chance of some spontaneous finding occurring use and came from accredited suppliers (Bioculture, Mauritius;
only in treated animals and can lead to misinterpretation of Harlan, UK; Guanxi Grandforest Primate Company, China)
the finding as treatment effect. When compiling such data, from three geographical regions: Mauritius (more than 90%
consideration should be paid to some important factors that of the animals), China, and Vietnam. All control animals incor-
may affect the composition of the collected data such as the porated into the study were obtained from groups of animals
that had been sham dosed with an appropriate vehicle. The fol-
lowing vehicles or method of sham dosing were used: empty or
Address correspondence to: Ronnie Chamanza, Charles River Edinburgh, gelatin capsules for the oral capsule route, carboxymethylcellu-
Tranent, EH33 2NE, Scotland, United Kingdom; e-mail: ronnie.
chamanza@crl.com.
lose or drinking water for the oral gavage route, and phosphate-
Abbreviations: AHF, adreno-hepatic fusion; BALT, bronchial-associated buffered saline, physiologic saline, and acetic or citrate
lymphoid tissue; GALT, gut-associated lymphoid tissue. buffers for intravenous or subcutaneous injection routes of
642
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Vol. 38, No. 4, 2010 SPONTANEOUS FINDINGS IN CYNOMOLGUS MONKEYS 643
TABLE 1.—Number of studies per route of administration and supervision of a veterinary pathologist who was either present
the vehicle(s) used for each route in control animals. throughout the necropsy sessions or remained on call after
observing the commencement of the necropsy. Tissues were
Number of preserved in 10% neutral buffered formalin, embedded in
Route of studies
paraffin wax, sectioned to a 4–5 mm thickness, and stained with
administration (Total ¼ 60) Vehicle used
hematoxylin and eosin. They were examined histopathologi-
Oral gavage 23 Carboxymethylcellulose, drinking cally, and the findings were entered directly into a computer-
water
ized database (PLACES 2000 Instem, Apoloco Limited
IV bolus 17 Phosphate-buffered saline, acetate/
citrate buffers Systems, Plymouth Meeting, PA, USA).
Subcutaneous 7 Phosphate-buffered saline, acetate/
citrate buffers Study Design
Discontinuous 7 Physiological saline
IV infusion Data were collected retrospectively from control groups of
Continuous 2 Physiological saline cynomolgus monkey studies evaluated over a period of six
IV infusion years (2003-2009). From this pool of information, studies to
Inhalation 2 Air
be incorporated into the present investigation were selected
Oral capsule 2 Empty or gelatin capsules
based on the following criteria:
(a) At least one control or untreated group (controlled
administration. For inhalation studies, animals from only the studies)
air control groups were used. The total number of studies for (b) Equal numbers of male and female animals, with a
each route of administration and the main type of vehicle(s) minimum of three animals per sex per group
used for the particular method of administration are shown in (c) GLP-compliant toxicological studies with evalua-
Table 1. tion of a full tissue list
All animals were between twelve and thirty-six months of
age and had body weights ranging between 1.6 and 2.5 kg. Study material including histological incidence tables, individ-
They were housed in groups of two or three animals of the same ual animal data listings, and a few selected glass slides were
sex and dose group in custom-designed U.K. Home Office– retrieved from the archives and analyzed for pathology findings
compliant primate cages (Chapter 14, section 21, UK Animals under each body and organ system. Data were available from
[Scientific Procedures] Act of 1986). The temperature and sixty controlled studies, with three to eight animals per sex per
humidity were automatically controlled at 21 C + 4 C and study, giving a total of 570 control animals. A limited number
55% + 10%, respectively, with a minimum of fifteen air of slides with lesions of interest were re-evaluated by a quali-
changes per hour. An automatic light cycle of 7:00 AM–7:00 fied veterinary pathologist.
PM (twelve-hour cycle) was maintained. Each individual gang
pen had drinking water and food hoppers, and animals were fed
a commercial primate diet (Mazuri diet, Special Diet Service RESULTS
Ltd, Witham, Essex, England). Twice-weekly fruit supple- Common Histopathology Findings
ments were also offered to all animals.
All studies were conducted in accordance with the UK Tables 2-7 present the most common histopathological find-
Animals (Scientific Procedures) Act 1986, which conforms to ings by organ system and the prevalence (range) of each find-
the European Convention for the Protection of Vertebrate ing per control group of three to eight animals. A few
Animals Used for Experimental and Other Scientific Purposes uncommon spontaneous findings of toxicological or clinical
(Strasbourg, Council of Europe). significance are also included. Findings were graded on a scale
All animals in the study were serologically tested and confirmed of 1 to 5 represented by minimal, mild, moderate, marked, and
free of the following viral diseases during quarantine: simian severe, respectively.
immunodeficiency virus (SIV), Cercopithecine herpesvirus 1 (B Inflammation and mononuclear inflammatory cell infiltrates
virus), simian retroviruses type D, rabies, simian T-cell leukemia were the most commonly recorded pathological processes in
virus (STLV), measles, and filoviruses. Tuberculin tests; other bac- most tissues and were considered to represent different stages
teriology screening tests for Shigella, Yersinia, and Salmonella; of the same pathological continuum by most pathologists, even
and parasitological screening (including malaria smears) were car- though umbrella terms were rarely applied for the two pro-
ried out on arrival at the test facility. cesses. They were most commonly recorded in the liver, kid-
neys, heart, salivary glands, lungs, and stomach. In general,
inflammatory cell infiltrations were characterized by intersti-
Pathological Evaluation
tial accumulation of lymphocytes and plasma cells in varying
Animals were humanely euthanized by intravenous injec- proportions (lymphoplasmacytic), with little or no evidence
tion with sodium pentobarbitone and exsanguinated via of damage to parenchymal tissue such as renal tubules, gastric
femoral veins. A detailed necropsy was performed under the glands, cardiac myocytes, or hepatocytes. Moderate grades of
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644 CHAMANZA ET AL. TOXICOLOGIC PATHOLOGY
TABLE 2.—Histological findings in the lung, heart, and aorta of TABLE 3.—Histological findings of the liver, gall bladder,
control cynomolgus monkeys (Macaca fascicularis) and their exocrine pancreas, and salivary glands of control cynomolgus
corresponding incidences across sixty studies (285 animals monkeys (Macaca fascicularis) and their corresponding
per sex). incidences across sixty studies (285 animals per sex).
Number of cases Number of cases
a b a
Organ (n ) / Findings Male Female Total (%) Range (%) Organ (n ) / Findings Male Female Total (%) Range (%)b
Lung (55) Liver (58)
Inflammatory cell infiltration 28 27 55 (9.6) 0 – 100 Inflammatory cell foci 166 180 346 (60.7) 0 – 100
Interstitial inflammation 22 14 36 (6.3) 0 – 37.5 Diffuse hepatocyte vacuolation/ 18 17 35 (6.1) 0 – 60
Alveolar macrophage 16 16 32 (5.6) 0 – 40 lipidosis
accumulation Tension lipidosis/focal lipidosis 7 26 33 (5.8) 0– 50
Pigment deposits 16 10 26 (4.6) 0– 100 Glycogen vacuolation 14 18 32 (5.6) 0– 100
Focal pleural fibrosis/pleuritis 16 9 25 (4.4) 0– 50 Focal necrosis/single cell necrosis 11 11 22 (3.9) 0– 37.5
Foreign body granuloma 8 9 17 (3.0) 0– 37.5 Subcapsular hemorrhage/fibrosis 11 9 20 (3.5) 0– 37.5
Hyperplasia of BALT 7 10 17 (3.0) 0– 37.5 Bile duct hyperplasia/periportal 7 4 11 (1.9) 0– 20
Bronchiolitis 5 8 13 (2.3) 0– 12.5 fibrosis
Emboli 7 5 12 (2.1) 0– 12.5 Pigment 5 6 11 (1.9) 0 – 50
Vasculitis/vascular degeneration 5 4 9 (1.6) 0– 40 Ectopic adrenal gland 0 2 2 (0.4) 0 – 12.5
Heart (50) Gall bladder (16)
Inflammatory cell foci 67 80 147 (25.8) 0 – 100 Inflammatory cell infiltrations 5 4 9 (1.6) 0 – 20
Focal myocarditis 22 14 36 (6.3) 0 – 66.7 Exocrine Pancreas (30)
Myocardial degeneration/fibrosis 19 13 32 (5.6) 0 – 66.7 Inflammatory cell infiltrations 19 17 36 (6.3) 0 – 66.7
Karyomegaly 8 8 16 (2.8) 0 – 50 Acinar cell atrophy/duct cell 9 4 13 (2.3) 0 – 12.5
Mucinous change 6 7 13 (2.3) 0 – 20 hyperplasia
Endocardiosis 6 4 10 (1.8) 0 –12.5 Acinar cell degranulation 4 4 8 (1.4) 0 – 50
Coronary intimal thickening 5 5 10 (1.8) 0 – 25 Accessory spleen 5 2 7 (1.2) 0 – 12.5
Arteritis/periarteritis 3 4 7 (1.2) 0 – 25 Submaxillary Salivary gland (49)
Mineralization – 3 3 (0.5) 0 – 12.5 Inflammatory cell infiltrations 50 71 121 (21.2) 0 – 100
Squamous/epithelial cysts or 1 2 3 (0.5) 0 – 12.5 Inflammation 7 4 11 (1.9) 0 – 40
plaques Parotid salivary gland (17) (43c)
Aorta (20) Inflammatory cell infiltration 30 46 76 (13.3) 0 – 100
Mucinous change 7 8 15 (2.6) 0 – 40 Inflammation 14 18 32 (5.6) 0 – 50
Intimal thickening/degeneration 4 5 9 (1.6) 0 – 12.5 Mineralized duct contents 8 6 14 (2.5) 0 –50
Mineralization 3 2 5 (0.9) 0 – 12.5
a
Number of studies with a recorded finding in the organ.
a b
Number of studies with a recorded finding in the organ. Determined only in studies with five to eight animals per group.
b c
Determined only in studies with five to eight animals per group. Refers to number of studies in which the organ was evaluated.
moderate focal myocarditis (Figure 1a) were present in more
lymphoplasmacytic infiltration were common in organs such as than a quarter of the animals, and occasionally, 100% of control
salivary glands, esophagus, stomach, urinary bladder, lungs, animals in a study were affected. Focal inflammatory cell infil-
and kidneys. They were often associated with lymphoid trates were mainly composed of uniform and bland aggregates
nodules or follicles around salivary gland ducts, small arteries of lymphoplasmacytic cells with little or no associated damage
in the urinary bladder, and bronchi and blood vessels in the to the cardiac myocytes, whereas myocarditis was character-
lungs. Inflammation was recorded when there was evidence ized by some pathologic change to cardiac myocytes such as
of degeneration and necrosis of parenchymal tissues in associ- necrosis, karyomegaly, or fibrin deposition. The inflammatory
ation with minimal to moderate inflammatory cell infiltrates, cell infiltrate associated with focal myocarditis was usually of a
usually of a mixed nature, or when other obvious signs of mixed nature and included granulocytes and macrophages in
inflammation such as edema and fibrin depositions were pres- addition to lymphoplasmacytic cells.
ent. Nevertheless, the distinction between the two processes, These inflammatory lesions were rarely observed in deeper
which often occurred simultaneously in most organs, was not parts of the myocardium, as they were mostly confined to sub-
always clear, particularly in the heart. endocardial or subepicardial/epicardial areas, including the
epicardial fat, and showed no differences in distribution of
lesions between the apex and the base of the heart. Simulta-
Findings by Organ System
neous occurrence of myocarditis and focal lymphoplasmacytic
Cardiovascular and Respiratory Systems: The incidence and cell infiltrates in the same heart were common. Focal or multi-
range of spontaneous findings of the heart in control cynomol- focal myocarditis was also occasionally observed within the
gus macaques are presented in Table 2. As the results indicate, same hearts with other changes such as myocardial fibrosis at
incidental findings occur commonly in the heart. Minimal to the papillary muscle, hemorrhage, or myocardial degeneration
mild idiopathic inflammatory cell infiltrates and minimal to with karyomegaly.
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Vol. 38, No. 4, 2010 SPONTANEOUS FINDINGS IN CYNOMOLGUS MONKEYS 645
TABLE 4.—Histological findings of the stomach, small TABLE 5.—Histological findings of the urinary, reproductive,
intestines, large intestines, esophagus, and tongue of control and endocrine systems of control cynomolgus monkeys
cynomolgus monkeys (Macaca fascicularis) and their corre- (Macaca fascicularis) and their corresponding incidences
sponding incidences across sixty studies (285 animals per sex). across sixty studies (285 animals per sex).
Number of cases Number of cases
a b a
Organ (n ) / Findings Male Female Total (%) Range (%) Organ (n ) / Findings Male Female Total (%) Range (%)b
Stomach (46) Kidney (56)
Gastritis 35 35 70 (12.3) 0– 100 Inflammatory cell infiltrations 87 77 164 (28.8) 0– 100
Inflammatory cell infiltration 36 33 69 (12.1) 0– 100 Interstitial nephritis 27 29 56 (9.8) 0– 100
Lymphoid hyperplasia 10 6 16 (2.8) 0– 50 Mineral deposits/mineralization 6 9 15 (2.6) 0– 37.5
Parasitic granuloma 8 7 15 (2.6) 0– 75 Glomerulonephritis/sclerosis 6 5 11 (1.9) 0– 37.5
Focal muscle atrophy/ 6 6 12 (2.1) 0– 12.5 Tubular degeneration/ 5 4 9 (1.6) –
degeneration regeneration
Gastric infarction/necrosis 1 2 3 (0.5) – Urinary bladder (19)
Small intestine (20) Inflammatory cell foci 12 15 27 (4.7) 0 – 66.7
Inflammatory cell infiltration 9 6 15 (2.6) 0 – 37.5 Focal mineralization, adventitial 6 0 6 (1.2) 0 – 12.5
Pigmented macrophage, lamina 11 4 15 (2.6) 0 – 50 remnants
propria Cystitis/eosinophilic cystitis 3 3 6 (1.2) 0 – 12.5
Inflammation 5 2 7 (1.2) 0– 12.5 Testis (5)
Lacteal ectasia/edema 5 2 7 (1.2) 0– 37.5 Hypoplasia, seminiferous tubules 4 – 4 (1.4) 0 – 40
Diffuse goblet cell hyperplasia 3 4 7 (1.2) 0– 66.7 Inflammatory cell foci 1 – 1 (0.4) –
Diverticulum/glandular 3 2 5 (0.9) 0– 12.5 Epididymis (3)
herniation Inflammatory cell foci/ 6 – 6 (2.1) 0 – 33.3
Large intestine (24) inflammation
Balantidium in the lumen 68 46 114 (20.0) 0– 100 Arteritis/periarteritis 5 – 5 (1.8) 0 –16.6
Inflammatory cell infiltrations 16 16 32 (5.6) 0– 50 Prostate (15)
Syncytial cells, GALT 9 11 20 (3.5) 0– 75 Inflammatory cell infiltrates 9 – 9 (3.2) 0 – 66.7
Inflammation/colitis 8 4 12 (2.1) 0– 37.5 Ovary (43)*
Vasculitis/perivasculitis 5 6 11 (1.9) 0– 37.5 Cysts (follicular/paraovarian/rete – 25 25 (8.8) 0 – 66.7
Glandular microherniation 4 4 8 (1.4) 0– 33.3 ovarii)
Parasitic granuloma/fibrosis/ 2 3 5 (0.9) 0– 12.5 Mineralized atretic follicles – 20 20 (7.0) 0 – 66.7
mineralization Thyroid gland (39)
Esophagus (15) Ectopic thymus 31 33 64 (11.2) 0– 83.3
Inflammatory cell infiltrations 11 8 19 (3.3) 0 – 60 Cysts/ultimobranchial cysts 22 13 35 (6.1) 0– 100
Focal muscle atrophy/ 8 9 17 (3.0) 0 – 14.2 Dilated/cystic follicles 13 5 18 (3.2) 0– 100
degeneration Lymphocytic thyroiditis 1 3 4 (0.7) 0– 16.6
Tongue (19) Adrenal gland (19)
Inflammation/subepithelial 15 7 22 (3.9) 0 – 50 Mineralization 5 3 8 (1.4) 0 – 50
myositis Cortical cell vacuolation 2 6 8 (1.4) 0 – 40
Inflammatory cell foci 9 3 12 (2.1) 0 – 37.5 Pigment 2 3 5 (0.9) 0–16.6
Adrenohepatic fusion/adhesion 2 3 5 (0.9) 0 – 37.5
a
Number of studies with a recorded finding in the organ. Parathyroid gland (22)
b
Determined only in studies with five to eight animals per group. Ectopic thymus 10 6 16 (2.8) 0 – 20
Congenital cysts 10 5 15 (2.6) 0 – 20
Idiopathic myocardial degeneration or cardiomyopathy was Pituitary (10)
recorded in a few studies but with a moderately high prevalence Inflammatory cell foci 4 2 6 (1.1) 0 – 33.3
in those studies in which it occurred. The finding was charac- Cysts 6 0 6 (1.1) 0 – 40
terized by minimal to moderate localized to extensive degen- Focal anterior pituitary cell 2 4 6 (1.1) 0 –12.5
hypertrophy
eration or necrosis of cardiac myocytes with mild to marked
hypertrophy, karyomegaly, and vacuolation of cardiac myofi- a
Number of studies with a recorded finding in the organ.
b
bers (Figure 1b), with or without minimal inflammation or Determined only in studies with five to eight animals per group.
fibrosis. In earlier lesions, only vacuolation of cardiac myofi-
bers and karyomegaly with increased nuclear basophilia were decreasing order, the apex, the interventricular septum (just
present, whereas in more advanced cases, inflammation and below the atrioventricular valves), the papillary muscle, and
fibrosis or mineralization were present (Figure 1c). In some the subendocardial areas of both ventricles. Acute hemorrhagic
rare and severe cases of cardiomyopathy, the hypertrophic car- necrosis or fibrosis at the papillary muscle, resembling
diac myofibers could occasionally be observed to contain large ischemic lesions observed with b-agonists and other cardioac-
intracytoplasmic eosinophilic granules and intranuclear inclu- tive drugs (Greaves 2000), were also encountered in occasional
sions thought to represent invagination of the cytoplasm and its animals. There were more male animals with myocarditis and
organelles into the nucleus (Figure 1d). Areas of the heart most myocardial degeneration than females, but the difference was
commonly affected by myocardial degeneration were, in not statistically significant.
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646 CHAMANZA ET AL. TOXICOLOGIC PATHOLOGY
TABLE 6.—Histological findings of the hematopoietic and the TABLE 7.—Histological findings of the skin and the musculo-
lymphoid systems of control cynomolgus monkeys (Macaca skeletal and nervous systems of control cynomolgus monkeys
fascicularis) and their corresponding incidences across sixty (Macaca fascicularis) and their corresponding incidences
studies (285 animals per sex). across sixty studies (285 animals per sex).
Number of cases Number of cases
a b
Organ (n ) / Findings Male Female Total (%) Range (%) Total Range
Organ (na) / Findings Male Female (%) (%)b
Mesenteric lymph node (12)
Sinus histiocytosis 8 3 11 (1.9) 0 – 50 Skin (41)
Eosinophil infiltration 3 4 7 (1.2) 0 – 20 Dermatitis 14 17 31 (5.4) 0 –100
Lymphangiectasia 2 2 4 (0.7) 0 – 37.5 Hair follicular atrophy 5 7 12 (2.1) 0 – 50
Submandibular lymph node (9) Epidermal hyperplasia, penile 4 0 4 (1.4) 0 – 50
Pigmented macrophages 6 2 8 (1.4) 0 – 50 Brain (26)
Granulocytic infiltrates 3 3 6 (1.1) 0 – 20 Inflammatory cell foci, meningeal 7 7 14 (2.5) 0 – 50
Thymus (9) Pigment 7 5 12 (2.1) 0 – 50
Atrophy 4 6 10 (1.8) 0 – 66.7 Perivasculitis, meningeal 6 4 10 (1.8) 0 – 100
Cystic tubular hyperplasia 3 6 9 (1.6) 0 – 16.6 Perivascular cuffs 4 5 9 (1.6) 0 – 100
Myoid cells/muscle tissue 0 2 2 (0.4) – Mineralization, thalamus 5 4 9 (1.6) 0 – 50
Spleen (15) Focal gliosis/glial scar 2 3 5 (0.9) 0 – 40
Focal lymphoid follicular 18 16 34 (6.0) 0 – 50 Spinal cord (9)
hyperplasia Perivasculitis, meningeal 8 5 13 (2.3) 0 – 50
Capsular fibrosis 6 3 9 (1.6) 0 – 50 Sciatic nerve (9)
Hyalinized germinal centers 5 3 8 (1.4) 0 – 37.5 Inflammation, perineural 1 3 4 (0.7) 0 – 33.3
Perivasculitis 1 2 3 (0.5) 0 – 33.3
a
Number of studies with a recorded finding in the organ. Skeletal muscle (20)
b
Determined only in studies with five to eight animals per group. Inflammatory cell infiltrates 4 3 7 (1.2) 0 – 25
Histiocyte infiltration/vaccine 3 3 6 (1.1) 0 – 33.3
granuloma
Myositis 2 3 5 (0.9) 0 – 50
Some of the uncommon but important findings seen in the Bone (10)
Digital fractures 5 2 7 (1.2) 0 – 40
heart of cynomolgus monkeys such as congenital ectopic
Physeal lesions 3 2 5 (0.9) 0 – 12.5
epithelial and squamous cysts/plaques, arteritis/periarteritis,
mineralization, and valvular endocardiosis (Figure 1e) or muci- a
Number of studies with a recorded finding in the organ.
b
fication of the valves and subendocardial areas or the tunica Determined only in studies with five to eight animals per group.
intima of great vessels, are listed in Table 2.
Accumulation of mucopolysaccharides in the intima of the
aorta, subendocardial areas of the base of the heart, or coronary inflammation or focal subpleural fibrosis, focal foreign body
arteries without lipid accumulation was a common incidental granuloma, emboli, and lung pigment were some of the more
finding in animals. Another related finding observed uncom- common histopathology findings in the lungs. Focal foreign
monly in the coronary arteries, and to a lesser extent the aorta, body granulomas were associated with either inhalation of tiny
was focal thickening of the intima of the blood vessels with particles of food/plant material or with embolism. Hair emboli
fibrosis or mucin accumulation leading to formation of athero- were the most commonly encountered form of embolism and
sclerotic lesions and near-occlusion of the affected blood vessel were almost exclusively associated with the intravenous form
(Figure 1f). The atherosclerotic lesions and intimal thickening of drug delivery. With intravenous infusion studies, focal to
were formed by infiltration of the intima by smooth muscle multifocal pulmonary thrombi, diffuse interstitial pneumonia,
cells, mucins, and fibrous tissue with little or no foam cells pulmonary edema and periarteritis (Figure 2a), and localized
or extracellular lipids. broncho-pneumonia (associated with thrombi and infarction)
Compared with the heart, incidences of spontaneous find- were encountered at particularly high incidences, which often
ings in the lungs of cynomolgus macaques were not just less corresponded to the incidence and severity of thrombophlebitis
numerous but also of considerably lower severity and signifi- at the cannula tip.
cance. The most common findings were recorded at necropsy, Dark brown to black lung pigment was observed in alveolar
where focal adhesions between lung lobes or adherence to the macrophages with perivascular or peribronchial distribution
parietal pleura were common but of little or no clinical signifi- (Figure 2b), but it was not associated with lung mites (Pneumo-
cance. Lung adhesions observed at necropsy were not always nyssus sp.) or other pathological changes of the lung parench-
associated with histopathology findings, but at times focal yma. However, in some moderate to marked cases, most of
pleural or subpleural fibrosis and chronic pleuritis were which were noted at necropsy, the aggregates of pigment-
observed. Perivascular or peribronchial inflammatory cell infil- laden macrophages tended to form nodules that bulged into the
tration, peribronchial bronchial-associated lymphoid tissue alveolar space. Similar pigment deposits were also present in
(BALT) hyperplasia, minimal to mild focal interstitial bronchial lymph nodes in affected animals, and in the absence
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Vol. 38, No. 4, 2010 SPONTANEOUS FINDINGS IN CYNOMOLGUS MONKEYS 647
FIGURE 1.—Figure 1(a). Focal myocarditis with a predominantly plasmacytic infiltration (with moart cells and Russell bodies) in the subendocar-
dial region of the left ventricle of a young male cynomolgus monkey (Macaca fascicularis). H & E, 200. Figure 1(b). Mild focal myocardial
degeneration with hypertrophic cardiac myocytes, karyomegaly, cytoplasmic vacuolation, and inflammatory cell infiltrates at the right ventricular
apex of the heart. Young male cynomolgus monkey (Macaca fascicularis). H & E, 200. Figure 1(c). Fibrosis and mineralization at the papillary
muscle of a female cynomolgus monkey (Macaca fascicularis) with spontaneous cardiomyopathy. H & E, 50. Figure 1(d). Eosinophilic intra-
nuclear inclusion bodies in hypertrophic and karyomegalic myocardial fibers of the left ventricle of the heart in a young female cynomolgus
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FIGURE 2.—Figure 2(a). Mild interstitial inflammation with periarteritis and edema associated with continuous intravenous infusion in the lung of a
control female cynomolgus monkey (Macaca fascicularis). H & E, 100. Figure 2(b). Lung pigment (pneumoconiosis) in a young female cyno-
molgus monkey (Macaca fascicularis), characterized by peribronchial and perivascular accumulation of dark brown pigment in macrophages. H
& E, 200.
of mites or any associated damage to the lung parenchyma, a and Helicobacter heilmannii–like organisms were frequently
diagnosis of pneumoconiosis was considered for this pigment. seen both in gastritis cases and in normal-appearing sections,
even though investigative staining for bacterial identification
Digestive System: Common lesions encountered in the liver, was rarely performed.
gall bladder, pancreas, salivary glands, tongue, esophagus, and Acute gastritis, which occurred at a much lower incidence
gastrointestinal tract are shown in Tables 3 and 4. Mononuclear than chronic gastritis, was often characterized by hemorrhage,
cell infiltrates or inflammatory cell foci in the liver, salivary erosions, ulceration, or glandular micro-abscesses and occurred
glands, tongue, and esophagus; localized fatty change or ten- more commonly in the fundus/body of the stomach (Figure 3b).
sion lipidosis in the liver; and gastritis were among the most Other findings recorded at low incidences in the stomach
common lesions. include mucosal herniation and diverticuli, parasitic granulo-
Gastritis was one of the most commonly and consistently mas (mostly identified as Oesophagostomum species), and gas-
recorded findings, and incidences of 100% affected animals tric infarction. Gastric infarction was reported as a rare
were reported in nearly half of the studies. The majority of the incidental finding noted at necropsy as a pale or red focal area
lesions were subacute to chronic in nature, with moderate to affecting any part of the serosal surface of the stomach. On his-
marked grades being recorded more commonly in the gastric tology, there was evidence of vascular compromise character-
antrum than the fundic/body region. Chronic gastritis was char- ized by hemorrhage, necrosis, and fibrin deposition of the
acterized by mild to marked lymphoplasmacytic cell infiltra- submucosa and muscularis, with the mucosa largely unaffected
tion of the mucosa and submucosa, an increase in lymphoid (Figure 3c). As the animals were clinically normal until the
follicles and mucosal atrophy with attenuation of glandular scheduled time of kill, the cause and pathogenesis of this find-
epithelium, separation and scarcity of glands, and an accompa- ing were not determined.
nying increase in the lamina propria. In some severe cases, a Although the incidences of histopathology findings observed
few neutrophils or a mixture of cells within gastric glands in the intestine were much lower than those recorded for the sto-
(glandular micro-abscesses) and mucosal erosion were mach, findings in the intestine, especially the large intestine,
observed (Figure 3a). Lymphoplasmacytic infiltration of the were more clinically significant, with diarrhea being one of the
superficial layers of the mucosa and the formation of prominent most common and important clinical signs observed in control
lymphoid nodules associated with chronic gastritis were often animals or untreated, pretrial animals. Idiopathic or nonspecific
observed as white nodules at necropsy, but no clinical signs diarrhea occurred more commonly than diarrhea associated with
were reported in the majority of the cases. Helicobacter pylori an etiologic agent. Clinically significant diarrhea was usually
Figure 1 continued. monkey (Macaca fascicularis) that was killed prematurely owing to clinical signs of heart disease and that had marked dif-
fuse cardiomyopathy on histology. Inclusions are believed to derive from the invagination of the cytoplasmic organelles into the nucleus. H & E,
400. Figure 1(e). Valvular endocardiosis in a young male cynomolgus monkey (Macaca fascicularis) that had moderate diffuse cardiomyopathy
with fibrosis. H & E, 200. Figure 1(f). Intimal thickening of an intramural coronary artery in a clinically normal young female cynomolgus
monkey (Macaca fascicularis). H & E, 200.
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FIGURE 3.—Figure 3(a). Chronic gastritis with erosion and atrophy of the antral mucosa in a young male cynomolgus monkey (Macaca fascicu-
laris). Spiral-shaped bacteria (Helicobacter species) are visible on the luminal surface and within glands. H & E, 200. Figure 3(b). Gastritis of
the fundus/body of the stomach characterized by moderate mucosal erosion/ulceration, glandular microabscesses, and hemorrhage with a limited
inflammatory reaction in a young male cynomolgus monkey (Macaca fascicularis). H & E, 100. Figure 3(c). Marked gastric infarction of
the body of the stomach with extensive necrosis and hemorrhage of the submusosa and part of the muscularis, but an apparently normal mucosa.
Young female cynomolgus monkey (Macaca fascicularis). H & E, 100. Figure 3(d). Mild chronic colitis in a young female cynomolgus macaque
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associated with chronic colitis, characterized by mild to moderate sub- such as might occur during manipulation of the animals. Ten-
mucosal lymphocyte and plasma cell infiltration; a few neutrophils sion lipidosis, which was almost always associated with a
within dilated, shortened, or irregular crypts (crypt micro-abscesses); necropsy finding of pale focus adjacent to attachment sites of
attenuation of enterocytes; glandular micro-herniation; mucosal ligaments, was more common in females than in males ( p <
hemorrhage; and hyperplasia of mucosal epithelium with a reduction 0.05). Other minor findings such as diffuse vacuolation or lipi-
in numbers of goblet cells (Figure 3d). Frank ulceration was rarely dosis, glycogen accumulation, pigmentation in Kupffer cells,
encountered, but micro-ulcers and erosions caused by the rupture of and periportal fibrosis were variably recorded by the patholo-
crypt micro-abscesses were more common. The gross finding of focal gist, with some considering these findings ‘‘normal.’’ Congeni-
reddening of the mucosa, especially at the ileo-cecal junction, was the tal findings in the digestive tract included ectopic pancreatic
most commonly recorded necropsy finding associated with chronic tissue in the small intestine, accessory splenic tissue in the pan-
colitis. Histology analysis of samples collected from around the ileo- creas (which was almost always located at the tail of the organ
cecal junction revealed that a considerable proportion of chronic colitis or within the adipose tissue surrounding the tail); (Figure 3f),
cases also involved parts of the distal ileum. and ectopic adrenal tissue within the liver capsule.
Other intestinal findings were uncommon, but accumulation
of pigmented macrophages in the lamina propria of the small Urogenital and Endocrine Systems: Common lesions
intestines (mostly jejunum and ileum), Balantidium sections encountered in the urogenital and endocrine systems are out-
within the lumen or in the mucosa, edema, and glandular lined in Table 5. Minimal to moderate focal interstitial nephritis
micro-herniations unassociated with inflammation were vari- (Figure 4a) was the second most commonly encountered inflam-
ably recorded. Parasitic granulomas with or without sections matory lesion after inflammatory changes in the heart. It was
of nematode parasites in the walls of the intestines, isolated more commonly observed in the outer cortex or subcapsular
crypt micro-abscesses, cystic dilation of intestinal crypts and regions of the renal cortex and invariably involved surrounding
lacteal ectasia, and mucosal diverticuli were some of the rarer tubules or glomeruli. The inflammatory infiltrate associated
findings occasionally encountered in this system. Balantidium with interstitial nephritis were predominantly lymphoplasmacy-
protozoa were rarely seen invading the mucosa, except in those tic, with occasional intratubular polymorphonuclear cell infil-
cases where the animals had been subjected to some form of trates (tubulointerstitial nephritis). Tubular regeneration,
stress. Frequently, the parasite was seen seemingly gaining interstitial fibrosis, intra-epithelial pigment, and mineralization
access to the intestinal wall via glandular micro-herniation into were occasionally observed in association with chronic intersti-
the gut-associated lymphoid tissue (GALT) (Figure 3e). tial nephritis.
Cases of infection with some opportunistic pathogens such Glomerular lesions were uncommon but not rare and
as Campylobacter jejuni were very rare and occurred at a fre- included mild to moderate cases of both focal membranous and
quency of approximately one case per year, whereas Yersinia proliferative glomerulonephritis and glomerulosclerosis. How-
species were isolated in a single case of ulcerative colitis with ever, focal and chronic membranous or membranoproliferative
multiple abscesses in the liver and spleen. Two confirmed cases forms of glomerulonephritis with sclerosis were more com-
of Shigella were also reported in control animals in the six-year mon. The lesions were characterized by glomerular enlarge-
period investigated. ment, thickening of the Bowman’s capsule, hypercellularity
Foci of inflammatory cells within the liver parenchyma or in of the mesangium with narrowing or obliteration of capillary
the periportal areas was the most common finding recorded in lumen, and global or segmental deposition of periodic acid–
these studies. The finding was usually of a minimal severity Schiff (PAS)–positive eosinophilic material (Figure 4b). The
and was occasionally associated with negligible necrosis or degree of deposited eosinophilic material varied greatly from
apoptosis of a few hepatocytes. The cell type was predomi- minimal segmental deposition to marked global deposition of
nantly lymphoplasmacytic, and a few macrophages or neutro- collagen-like substances resembling collagenofibrotic nephro-
phils were encountered in cases of single-cell necrosis of pathy. Periglomerular or interstitial fibrosis in adjacent par-
adjacent hepatocytes or in the periportal or subcapsular areas. enchyma and glomerulocystic changes characterized by
No necropsy findings or clinical chemistry changes were asso- atrophy of glomerular tufts and dilation of Bowman’s capsule
ciated with this incidental finding. Minimal to moderate grades were other associated findings. There were no gross pathologi-
of focal subcapsular hemorrhage, inflammation, or fibrosis cal findings or systemic disease associated with the glomerular
were recorded with some frequency in the liver. The lesions changes, and no cases of generalized glomerulonephropathy
were usually associated with some necropsy findings such as were encountered.
pale or red foci on parietal surfaces of the liver and were thus Intracapsular ectopic adrenal cortical tissue attached to the
considered to represent areas of traumatic injury to the liver outer cortex of the kidney, cuboidal metaplasia of the parietal
Figure 3 continued. characterized by a predominantly mononuclear inflammatory cell infiltration into the lamina propria, crypt microabscesses,
and attenuation of enterocytes. H & E, 100. Figure 3(e). Balantidium colitis in a young male cynomolgus monkey (Macaca fascicularis) show-
ing parasites gaining access to the mucosa and submucosa via micro-herniation of glands into gastrointestinal lymphoid tissue. H & E, 100.
Figure 3(f). An acccessory spleen lying within pancreatic tissue at the tail end of the pancreas in a young male cynomolgus monkey (Macaca
fascicularis). H & E, 50.
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FIGURE 4.—Figure 4(a). Interstitial nephritis with lymphoplasmacytic cell infiltration and associated tubular damage in the outer cortex of the
kidney in a young female cynomolgus monkey (Macaca fascicularis). H & E, 100. Figure 4(b). Focal membranoproliferative glomerulone-
phritis with global and segmental glomerulosclerosis in a young and clinically normal male cynomolgus monkey (Macaca fascicularis). Fibrosis
of the Bowman’s capsule and glomerular enlargement are also present. H & E, 100. Figure 4(c). Adrenohepatic fusion in a young male cyno-
molgus monkey (Macaca fascicularis). Hepatic tissue (center) is wedged between the adrenal cortex (right) and the medulla (left) and therefore
appears to be completely enclosed within the adrenal gland. H & E, 100. Figure 4(d). Ectopic adrenal cortex attached to the subcapsular
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epithelium of the Bowman’s capsule, pigment within the perivascular distribution within the submucosa or the muscu-
epithelium of the medullary rays, intracytoplasmic pseudo- laris (Figure 4e). In some cases, these lymphocytic foci were
inclusions of the uroepithelium (including that of the urinary associated with a periarteritis of small- to medium-sized
bladder), and multinucleated cells of the renal medulla were arteries or cystitis. Cystitis was less commonly encountered
inconsistently recorded findings, and most pathologists consid- than inflammatory cell infiltration and was occasionally asso-
ered them to be either normal anatomic variations in this spe- ciated with perivascular infiltration by eosinophils (eosinophi-
cies or minor findings of little pathological significance. lic cystitis). Eosinophilic infiltration of the bladder usually
Ectopic thymus in the thyroid or parathyroid gland; thyroid, affected the entire wall, from the mucosa to the adventitia,
parathyroid or pituitary cysts; ovarian squamous cysts; adreno- without any evidence of parasitic infestation. Mineralization
hepatic fusion (Figure 4c) or adhesion; and foci of ectopic adre- of functional or vestigial arteries (thought to be remnants of
nal tissue in the liver (within the capsule) (Figure 4d), testes, umbilical arteries) was also commonly observed in the adven-
epididymides and prostate were some of the most common titia of the bladder (Figure 4f), with early stages of the lesions
congenital findings associated with the endocrine and urogen- presenting as focal degeneration, fibrosis, foreign body macro-
ital systems. There were twice as many congenital cysts of the phage accumulation, and pigmentation of arterial walls. The
thyroid gland, including ultimobranchial cysts and dilated/cys- significance of this finding was not established, and no associ-
tic thyroid follicles, in males compared to female animals ( p < ated necropsy findings were observed.
.05). Minimal to mild grades of lymphocytic thyroiditis were Owing to the sexual immaturity of the majority of the ani-
uncommonly recorded in a few animals, mostly females, and mals, reproductive tracts of both male and female animals were
were characterized by the diffuse formation of primary or sec- among the least affected organs, with very little pathology
ondary lymphoid follicles within the thyroid, surrounded by a recorded in the respective tissues. Occasionally, mild to mod-
few remaining and distended follicles with hypertrophic thyr- erate arteritis/periarteritis was observed in the epididymis,
oid follicular cells. Minimal to moderate grades of focal hyper- whereas inflammatory cell foci within the prostate were not
trophy of the anterior pituitary cells were not uncommon. uncommon. A single case of ectopic adrenal cortical tissue
Fusion between liver and right adrenal tissue, known as within the epididymis was also recorded. In the female repro-
adrenohepatic fusion (AHF), was observed much more com- ductive tract, the most common incidental findings were miner-
monly than adrenohepatic adhesion and was distinguished by alization in the ovary, ovarian cysts, squamous cysts within the
the lack of fibrous tissue between the two parenchymal tissues ovary, and ectopic ovarian follicles in the uterus, mesome-
in the former. Adrenohepatic fusion was not a very common trium, or other parts of the broad ligament of the uterus.
finding, although its prevalence within certain studies was
often high, affecting as many as three out of eight control ani- Hematopoietic and Lymphoid Systems: Mild to marked lym-
mals in such studies. The lesion was characterized by the pres- phoid follicular hyperplasia/prominent lymphoid follicles in
ence of hepatic tissue composed of normal-appearing the spleen was the most common finding in the hematopoietic
hepatocytes located mostly between the medulla and zona reti- and lymphoid systems. Hyperplastic follicles that resulted in
cularis, but occasionally in the cortex or hilar region of the right compression of adjacent tissue or bulging of the splenic capsule
adrenal gland. In some cases, the right adrenal gland was (Figure 5a) were often observed at necropsy as raised pale foci.
observed to be attached to the liver at necropsy, and the histo- Hyalinization of germinal centers (antigen-antibody complex
logical picture in such cases was suggestive of liver tissue material), fibrosis, and histiocytic accumulation in the center
growing into the adrenal gland, whereas in other cases in which of the prominent lymphoid follicles were other findings associ-
there were no associated necropsy findings, the hepatic tissue ated with lymphoid follicular hyperplasia in the spleen and
appeared to be completely enclosed within the adrenal capsule therefore usually not recorded separately. Other findings
on the routine longitudinal sections of the adrenal gland. The recorded in the spleen include focal capsular fibrosis, granulo-
most common finding in the adrenal glands, though, was focal cytic infiltration, pigment, and capsular hemorrhage/thrombi.
mineralization at the junction of the medulla and cortex (or In the thymus, atrophy, mineralization, and cystic tubules were
occasionally within the zona reticularis), which is believed to the few incidental findings encountered.
be caused by dystrophic calcification of remnants of the fetal Most lymph nodes had unremarkable findings, with the
adrenal cortex (Lowenstine 2003) and was considered to be exception of pigment deposits in the bronchial and, rarely, sub-
of no pathological significance. mandibular lymph nodes, granulocytic infiltrates in the
The urinary bladder was one of the organs with a moderately submandibular lymph nodes and histiocytosis in mesenteric
high number of incidental findings. The most common findings lymph nodes of animals with inflammatory lesions. A few
encountered in this organ were lymphocytic foci, usually with a cases of extramedullary hematopoiesis were recorded in
Figure 4 continued. surface of the liver in a young female cynomolgus monkey (Macaca fascicularis). All three zones of the cortex are repre-
sented, and the zona reticularis intermingles with hepatic tissue without intervening fibrous tissue. H & E, 100. Figure 4(e). Urinary bladder of a
young female cynomolgus macaque (Macaca fascicularis) showing perivascular lymphocytic cellular infiltration that tends to form lymphoid
nodules. H& E, 100. Figure 4(f). Mineralization of a nonpatent and thick-walled vascular structure (believed to be remnants of the umbilical
artery) in the adventitia of the urinary bladder of a young male cynomolgus macaque (Macaca fascicularis). H & E, 200.
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FIGURE 5.—Figure 5(a). Spleen of a young male cynomolgus monkey (Macaca fascicularis) showing marked lymphoid hyperplasia and coales-
cing of lymphoid follicles resulting in capsular bulging and compression. A small central pale area of lymphocytic necrosis, fibrosis, and macro-
phage accumulation can be visualized. Necropsy findings of raised pale foci were associated with this finding. H& E, 50. Figure 5(b). Lymphoid
tissue (GALT) of the large intestine with multinucleated lymphocytic syncytia resembling Warthin-Finkeldy giant cells of measles in a clinically
normal and healthy young male cynomolgus monkey (Macaca fascicularis). H & E, 200. Figure 5(c). Ulcerative inflammation and marked
(pseudocarcinomatous) hyperplasia of the mucosa of the penis in a young male cynomolgus macaque. H & E, 100. Figure 5(d). Squamous cell
carcinoma on the upper lip in a young female cynomolgus monkey (Macaca fascicularis). H & E, 200.
cutaneous-draining lymph nodes (local to injection sites) and Integument, Mammary Gland, and Musculoskeletal and
other internal nodes such as the lumbar and mediastinal lymph Nervous Systems: Common lesions of the skin, mammary
nodes. Lymphoid foci in the bone marrow were frequently gland, and the musculoskeletal and nervous systems are listed
observed and were usually associated with prominent lymphoid in Table 7. Most skin findings were traumatic injuries or treat-
foci in other sites such as the BALT of the larynx and lung, sali- ment site findings, and other lesions such as parasitic granulo-
vary glands, spleen, and urinary bladder and the GALT of the mas were very rare. However, in some male animals, a
intestines and stomach. Multinucleate lymphocytic syncytia pseudocarcinomatous hyperplasia of the prepuce and penile
resembling the Warthin-Finkeldy bodies associated with mucosa, characterized by marked to severe inflammation of the
measles virus were observed with some frequency in the BALT epidermis and tissues below it, hyperpigmentation and marked
of the larynx and the GALT of the large intestines (Figure 5b). epidermal hyperplasia with prominent rete pegs, was encoun-
No necrosis of lymphocytes was present within the lymphoid tered with some frequency (Figure 5c). The inflammatory cell
nodules, nor were viral inclusions present within the cells. The infiltrates were composed of a large proportion of eosinophils
cause of these syncytia in animals known to be free of measles and lymphoplasmacytic cells, and inflammation of the epider-
and other viral diseases is unknown. mis of the prepuce and the mucosa of the penis involved
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FIGURE 6.—Figure 6(a). Spontaneous perivasculitis or cuffing of a medium-sized vein in the meninges of the spinal cord of a young male cyno-
molgus monkey (Macaca fascicularis). H & E, 200. Figure 6(b). Mild gliosis, neuronal necrosis, neuronophagia, and perivascular cuffing in a
young female cynomolgus macaque (Macaca fascicularis) that showed no clinical neurological signs during life. H & E, 200. Figure 6(c).
Mineralized bodies distributed perivascularly in the globus pallidus of the brain of a young female cynomolgus monkey (Macaca fascicularis).
H & E, 400. Figure 6(d). Growth plate fracture of proximal tibia associated with focal metaphyseal retention (metaphyseal dysplasia) in a young
male cynomolgus monkey (Macaca fascicularis). H & E, 100.
ballooning degeneration of cells, vesiculation, and ulceration. lipofuschin pigment, and mineralized bodies in the basal gang-
Occasionally, similar inflammatory changes were observed lia were some of the most common findings. Perivascular and
on the tongue of affected animals, with similar eosinophilic meningeal melanin pigment (positive with Masson-Fontana
cellular infiltrates. Other skin and subcutis findings included stain) was often noted at necropsy as an intense blackening
fat necrosis of subcutaneous fat and fat within umbilical her- of large parts of the temporal lobe and was seen on histology
nias. Reducible umbilical hernias were a common necropsy to be perivascular in distribution and affecting only the cortical
finding, usually without a histological correlation. areas. Perivascular cuffs composed of lymphocytes were a
A squamous cell carcinoma of the inner part of the upper lip common finding observed mostly within the cerebellar pedun-
(Figure 5d) was the only neoplastic finding observed in the cle, periventricular areas, and around the vessels of the choroid
entire study. plexus.
In the central nervous system, the most commonly encoun- Deeply basophilic staining or dark purple mineralized bod-
tered lesions were centered around blood vessels. Perivascular ies were observed with some frequency in the various parts of
inflammatory cell infiltrates and perivasculitis in the meninges the basal ganglia such as the globus pallidus and the putamen
of the brain and spinal cord (Figure 6a), perivascular cuffs (Figure 6c). Smaller mineralized bodies were often perivascu-
within the brain (Figure 6b), perivascular melanin and lar in distribution and were associated with other changes in the
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perivascular space such as pigment accumulation or some Burnett 2003). In addition, a well-presented and extensive
small amorphous eosinophilic structures. Larger bodies were review of incidental findings and nonlesions in primates and
arranged in concentric onion ring circles that did not always their possible etiologies has also been published (Lowenstine
exhibit a proximity to blood vessels. Coronal sections passing 2003), and most of the findings discussed in this particular
through the mammillary bodies showed most mineralized paper were evident in our study. However this paper presents
areas, and the incidence of this finding was a direct function up-to-date results of incidences and prevalence of a wider
of the number of coronary sections taken, as dictated by the range of spontaneous findings by organ system and from a
study protocol. large population of laboratory-bred animals from a single
Focal gliosis with neuronal necrosis and neuronophagia, laboratory with consistent husbandry.
focal glial scars with pigmented microglial cells, and some The causes of a few of the more common findings such as
small spheroid bodies were some of the rare but unexpected gastritis, heart findings, and lymphoid hyperplasia in various
and unexplained incidental findings in the brain. Eye findings organs in laboratory primates remain unclear, but various etiol-
were extremely rare, and only inflammatory cell infiltration ogies have been proposed. Helicobacter species (H. pylori and
(lymphocytic) of the ciliary body, uvea, or conjunctiva was H. heilmannii–like organisms) are suspected of playing a cau-
ever recorded. sative role in gastritis (Reindel et al. 1999). However, the asso-
Lesions of the skeletal muscle were also rare and limited to ciation between these bacteria and clinically significant
focal myositis resulting from trauma; vaccine granulomas char- gastritis in most cases in this study was not conclusive. In fact,
acterized by an aggregate of large, foamy histiocytes within the most clinically apparent ulcerative gastritis cases with little
thigh muscle; and sarcocystis parasites found mostly within the inflammation present did not have evidence of bacterial organ-
tongue muscle and not associated with inflammation. Skeletal isms, whereas large numbers of bacteria could be seen in nor-
lesions were confined mostly to traumatic fractures and devel- mal stomach sections or sections with minimal to mild
opmental or idiopathic bone and cartilage abnormalities such inflammatory cell infiltrates, leading to the suggestion that
as physeal osteochondrosis or dyschondroplasia and metaphy- stress might have a role in some forms of gastritis in primates.
seal dysplasia consisting of foci of persistent hypertrophic Another intriguing finding in the stomach was idiopathic
chondrocytes. Some cases of metaphyseal dysplasia resem- gastric infarction. The causes of the few cases of this condition
bling rickets were often associated with growth plate (micro) encountered in this study were never established, but gastric
fractures (Figure 6d). infarction is reported in the literature to be associated with an
underlying clinical condition such as pancreatitis or cystitis
in cynomolgus monkeys (Fikes et al. 1996). However, in man,
DISCUSSION
gastric infarction is also known to occur in young children with
The main aims of this study were to investigate and outline no obvious explanation (Wanek et al. 1988).
the incidences of the most common background findings in The specific causes of spontaneous findings in the kidneys
control cynomolgus macaques used in preclinical toxicology of laboratory-bred animals are also not well documented. How-
studies and briefly describe some unusual and significant find- ever, in general, glomerulonephritis in nonhuman primates is
ings that may be confused with treatment-related findings. associated with infectious agents or conditions that cause
There are very few reports of this kind in the literature chronic antigen–antibody formation (Bennet et al. 1998). In
(Drevon-Gaillot et al. 2006; Ito et al. 1992; Lowenstine captive-bred animals, such conditions include long-term cathe-
2003; Shimoi et al. 1998). Most other published reports are terization or dental disease. Interstitial nephritis, on the other
based on studies in zoo or wild-caught primates or in older ani- hand, has not been associated with any etiological agent in nor-
mals (Bennett et al. 1998; Scott 1999), which predictably have mal, healthy, laboratory-bred animals. It was also reported to
a spectrum of pathological findings that is slightly different be the most frequently observed lesion at necropsy in zoo pri-
from that of laboratory-raised animals used in toxicological mates, but no possible cause was suggested (Bennet et al.
studies. 1998).
The findings in this study were generally consistent with the High incidences of inflammatory lesions of the heart have
incidence and occurrence of similar lesions described in the lit- been reported in cynomolgus monkeys, in which stress and the
erature. These findings include gastritis (Drevon-Gaillot et al. release of catecholamines were suggested as possible causes
2006; Scott 1999), interstitial nephritis (Bennet et al. 1998; (Chamanza et al. 2006). Catecholamine-induced stress was
Drevon-Gaillot et al. 2006), inflammatory lesions of the heart also considered to be the most likely cause of spontaneous car-
(Chamanza et al. 2006; Drevon-Gaillot et al. 2006; Keenan and diomyopathy in cynomolgus monkeys in a recent report (Zabka
Vidal 2006), inflammatory cell infiltrations in the liver (Foster et al. 2009). Findings such as hypertrophic cardiac myofibers,
2005; Ito et al. 1992), tension lipidosis of the liver (Drevon- karyomegaly, and vacuolation have been reproduced in a Rhe-
Gaillot et al. 2006), mineralization in the adrenal gland (Kast sus macaque (Macaca mulatta) with active angiomatous pheo-
et al. 1994; Majeed and Gopinath 1980), pneumoconiosis in the chromocytoma (Vogel and Fritz 2003) or injected with
lungs, pigment in the lamina propria of the small intestine catecholamines (Khullar et al. 1989). Repeated bouts of endo-
(Drevon-Gaillot et al. 2006; Scott 1999), and lung findings genous catecholamine release associated with captivity and
associated with continuous intravenous infusion (Lilbert and routine manipulation during toxicology studies is believed to
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