Pathology in Practice

Stacey L. Piotrowski From the Center for Laboratory Animal Medicine and Care, Health Science Center at Houston, MD Anderson Cancer Center, University of Texas, Houston, TX 77030
Department of Veterinary Medicine and Surgery, MD Anderson Cancer Center, University of Texas, Houston, TX 77030

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Mihai Gagea Department of Veterinary Medicine and Surgery, MD Anderson Cancer Center, University of Texas, Houston, TX 77030

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Steven Y. Huang Department of Experimental Radiation Oncology, MD Anderson Cancer Center, University of Texas, Houston, TX 77030

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Gunapala Shetty Department of Interventional Radiology, MD Anderson Cancer Center, University of Texas, Houston, TX 77030

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Lori R. Hill Department of Veterinary Medicine and Surgery, MD Anderson Cancer Center, University of Texas, Houston, TX 77030

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History

An approximately 5-year-old 6.61-kg (14.5-lb) captive-born sexually intact male rhesus macaque (Macaca mulatta) was evaluated because of a 2-day history of non–weight-bearing lameness of the right pelvic limb. The macaque was housed with another macaque at an academic research institution. Its previous clinical conditions included Shigella flexneri infection that was successfully treated with enrofloxacin. The macaque underwent appropriately approved experimental manipulations (including bilateral testicular cobalt irradiation) in an accredited facility.

During a routine experimental procedure, the macaque was sedated with an IM injection of ketamine in the right quadriceps femoris muscle followed by isoflurane anesthesia. There were no clinical abnormalities identified during the procedure, and recovery from anesthesia was unremarkable. The next day, right pelvic limb lameness was observed, and meloxicam injections were initiated as treatment. With no improvement in lameness after 2 days of meloxicam administration, the macaque was sedated for a thorough physical examination and radiography.

Clinical and Gross Findings

On physical examination, the macaque had no palpable fracture but had intermittent crepitus in the right stifle joint. Atrophy of all muscles of the right pelvic limb was noted. Radiography revealed flattening of the right femoral head and generalized osteopenia of the right femur, tibia, and fibula. Lameness did not improve with treatment; however, the macaque was perceived to be comfortable and in otherwise good clinical condition. Its participation in the research study was continued until its scheduled terminal tissue collection 5 months later; prior to euthanasia by IV injection of phenytoin-pentobarbital solution, radiography was repeated, and necropsy was subsequently performed.

Repeated radiography provided evidence of progressive atrophy of the right pelvic limb muscles and a greater degree of flattening of the right femoral head with associated osteopenia of the right femur, tibia, and fibula. At necropsy, the right hip joint had marked thickening of the articular capsule, complete loss and rupture of the ligament of the femoral head, abundant serosanguineous fluid in the hip joint, and a severely misshaped femoral head (Figure 1). The articular surfaces of the right femoral head and acetabulum were irregular and rough with extensive areas of cartilage erosions and pale red foci. On longitudinal cut section, the right femur had remodeling of the cancellous bone with loss of the surface cartilage and a markedly collapsed and misshaped femoral head. The compact cortical bone of the right femur was approximately half the thickness of that of the unaffected left femur.

Figure 1
Figure 1

Photographs of the right hip joint (A) and femurs (B) of a juvenile rhesus macaque (Macaca mulatta) that was evaluated because of right pelvic limb lameness. A—There is abundant serosanguineous fluid in the right hip joint, thickening of the articular capsule, loss of the ligament of the femoral head, and a misshapen femoral head. B—In longitudinal section, there is marked collapse, deformity, cancellous bone remodeling, and loss of cartilage on the head of the right femur (left side of the image), compared with the appearance of the left femur (right side of image).

Citation: Journal of the American Veterinary Medical Association 258, 2; 10.2460/javma.258.2.161

Histopathologic Findings

Sections of the right and left femurs and hip joints were examined histologically. There was necrosis of the cartilage, bone, and bone marrow of the entire head of the right femur (Figure 2). The amount of trabecular bone was notably reduced in comparison with that of the unaffected left femoral head. The trabecular spaces contained acellular eosinophilic proteinaceous material and cellular debris intermixed with a few small fragments of fractured trabecular bone. The osteocytes were missing from the lacunae of trabecular bone tissue, and no osteoblasts or osteoclasts were lining the surface of trabecular bone. The epiphyseal growth plate tissue structure was not present, in contrast to findings for the unaffected left femoral head. The articular surface of the right femoral head was completely eroded, and the exposed subchondral trabecular bone was covered by an irregular layer of eosinophilic proteinaceous acellular material composed of degenerated cartilage, bone dust, bone fragments, and cellular debris. The torn ligament of the femoral head (round ligament) had irregular margins and marked chronic lymphocytic inflammation with fibrosis and collagen deposition.

Figure 2
Figure 2

Photomicrographs of sections of the right femoral head region. A—Necrosis of the bone and bone marrow of the head of the right femur is delineated by the green outline. In contrast to the unaffected left femur (not shown), there is a marked decrease in the density and amount of trabecular bone and complete lack of an epiphyseal growth plate. The articular surface of the right femoral head is eroded and replaced by an irregular layer of eosinophilic proteinaceous acellular material composed of degenerated cartilage, bone dust, bone fragments, and cellular debris on the exposed subchondral trabecular bone. H&E stain; bar = 2 mm. B—The trabecular spaces of the right femoral head contain acellular, pale, eosinophilic, proteinaceous material and cellular debris intermixed with a few fibroblasts, macrophages, and small fragments of fractured bone. There are no osteocytes in the lacunae of trabecular bone and no osteoblasts or osteoclasts lining the surface of bone trabeculae. H&E stain; bar = 100 µm.

Citation: Journal of the American Veterinary Medical Association 258, 2; 10.2460/javma.258.2.161

The acetabular cavity of the right hip joint was enlarged and slightly misshapen, in comparison with the unaffected left hip joint (Figure 3). The articular surface of the right acetabulum was markedly eroded with exposure of subchondral trabecular bone. The joint capsule of the right hip joint was markedly thickened with abundant fibrous tissue, collagen deposition, and evidence of chronic inflammation.

Figure 3
Figure 3

Photomicrographs of sections of the right and left acetabulum. A—The acetabular cavity of the right hip joint is enlarged and slightly misshaped. The ligament has evidence of chronic lymphocytic inflammation and abundant fibrous tissue with collagen deposition. H&E stain; bar = 2 mm. Inset—The right acetabulum has marked erosion of the articular surface with exposure of subchondral trabecular bone. H&E stain; bar = 200 µm. B—The left acetabular cavity appears unaffected. H&E stain; bar = 2 mm. Inset—The left acetabulum has an apparently normal articular surface. H&E stain; bar = 200 µm.

Citation: Journal of the American Veterinary Medical Association 258, 2; 10.2460/javma.258.2.161

Morphologic Diagnosis and Case Summary

Morphologic diagnosis: necrosis of bone, bone marrow, and cartilage of the right femoral head; rupture of the ligament of the right femoral head; cartilage degeneration and erosion and loss of the articular surfaces of the right acetabulum and femoral head; and severe muscle atrophy of the right pelvic limb.

Case summary: Legg-Calvé-Perthes disease (LCPD) in a juvenile rhesus macaque.

Comments

For the rhesus macaque of the present report, the initial differential diagnosis for the right pelvic limb lameness was postinjection sciatic neuropathy, a previously documented condition that can develop in macaques after IM injection of ketamine for sedation.1 However, interpretation of radiographic views of the macaque's pelvis and pelvic limbs by a board-certified radiologist revealed flattening of the right femoral head, generalized osteopenia of the right pelvic limb, and widening of the right acetabular cavity. These findings were consistent with osteonecrosis or avascular necrosis of the right femoral head.2 Various risk factors and causes can lead to avascular necrosis of the femoral head.

Corticosteroid use is a common risk factor for osteonecrosis of the femoral head.2,3 Coagulopathies, such as sickle cell anemia, can be associated with avascular necrosis of the femoral head in people.2,3 However, according to medical records, the macaque of the present report never received corticosteroid treatment, and there was no documented evidence of coagulopathy. A severe episode of shigellosis and enterotoxemia could have caused disseminated intravascular coagulopathy, possible intravascular thromboembolism with infarction, and avascular necrosis of the femoral head of this macaque. However, because the clinical signs of lameness developed almost a year after the macaque's shigellosis, it was unlikely that femoral head necrosis was induced by shigellosis. Radiation can also be associated with avascular necrosis of the femoral head,4 and the macaque did undergo bilateral testicular radiation as part of an experimental protocol. However, the radiation was limited to the testicular area, and none of the other 17 macaques in the experimental cohort had any clinical signs of lameness. Moreover, the left femoral head of the macaque of the present report was unaffected; therefore, the radiation seemed less likely to be a contributing factor. Although other factors such as epiphyseal plate dysplasia (which usually affects both limbs) or trauma could not be completely ruled out,3,4 a diagnosis of LCPD was ultimately supported by both clinical and histopathologic findings, even though some expected changes, such as fibroplasia and granulation tissue, were not identified histologically in examined bone sections.

Legg-Calvé-Perthes disease is a spontaneous idiopathic aseptic osteochondrosis of the femur.3,5 It is characterized by avascular necrosis of the epiphysis, which impairs the ossification of the femoral head.3 The exact etiopathogenesis of LCPD is unknown; however, multiple theories, such as repetitive microtrauma, skeletal retardation, and vascular insufficiency, have been proposed.3,4,5,6 The usual presenting complaint in people is limping or lameness,5 which was the initial clinical sign for the macaque of the present report. The condition can be diagnosed with radiography or more advanced diagnostic imaging, such as MRI.3,4,5,6 With progression of the disease, osteoarthritis of the ipsilateral hip joint may develop,7 as evident in the case described in the present report. The macaque also had muscle atrophy of the affected limb, which is a common clinical sign in affected humans.8

There are both surgical and nonsurgical treatment options for LCPD.6 Conservative treatment includes medical management through the administration of NSAIDs and casting or bracing of the limb.3,5 For the macaque of the present report, conservative management was elected owing to the clinical stability of the condition and the relatively short experimental timeline. The most common surgical treatment option is femoral head ostectomy.5,6 This surgical procedure has previously been used successfully to treat rhesus macaques with LCPD or degenerative hip joint disease.9,10

To our knowledge, there are 2 reports9,11 of LCPD in a nonhuman primate: one case involved a 27-month-old rhesus macaque,9 and another case involved a 5-year-old lowland gorilla.11 The age of onset of LCPD in nonhuman primates appears to be similar to the age of onset in humans, with the disease being detected in children between 3 and 7 years of age.3 Legg-Calvé-Perthes disease also develops in other species such as dogs, particularly dogs of miniature breeds.12 In addition to spontaneous cases of LCPD in rats, pigs, and goats, those species have been used in experiments to model the condition and investigate treatment options for LCPD in humans.13,14,15

Acknowledgments

The authors declare that there were no conflicts of interest.

At the time of case workup, Dr. Piotrowski was supported by the NIH-funded Gulf Coast Consortium Veterinary Training Program in Comparative Medicine. Dr. Piotrowski is currently a fellow in the NIH Comparative Biomedical Scientist Training Program and is supported by the National Cancer Institute and the National Institute of Neurological Disorders and Stroke in partnership with Purdue University.

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