JPC SYSTEMIC PATHOLOGY

MUSCULOSKELETAL SYSTEM

April 2025

M-N05

 

Signalment (JPC #3026261): 11-month-old male Rocky Mountain elk (Cervus elaphus nelsoni)

HISTORY: This elk presented for anorexia, lameness and thickening of all four distal limbs. Pulmonary nodules were diagnosed radiographically. Tuberculosis was suspected and the animal was euthanized.

HISTOPATHOLOGIC DESCRIPTION: Bone, metatarsus (per contributor): Diffusely extending perpendicularly from the cortical surface and markedly elevating the periosteum up to 12mm are numerous trabeculae of variably mature bone, delineated from the peripheral edge of the normal cortex by a basophilic line (resting line). The deep third of new bone extending from the pre-existing cortex is dense and composed of mature lamellar bone, forming well-organized osteons with low numbers of osteocytes within lacunae and minimal intertrabecular fibrovascular tissue. Peripheral trabeculae are composed of irregular woven bone with scalloped margins and numerous haphazardly arranged osteocytes within lacunae. Between trabeculae of woven bone there is absence of normal bone marrow, and trabeculae are separated by a moderate amount of loose fibrovascular tissue. Woven trabecular bone immediately subjacent to the periosteum is lined by osteoid seams and further lined by 1-2 cells layers of plump, reactive osteoblasts. The periosteum is expanded up to 1.5mm by abundant fibrous connective tissue.

Lung: Disrupting and replacing 70% of the section are multiple coalescing pyogranulomas up to 6 mm in diameter that compress surrounding tissue. Pyogranulomas are characterized by a large central region of abundant eosinophilic cellular and karyorrhectic debris (lytic necrosis) and numerous poorly staining to pale basophilic fungal hyphae. Necrotic centers are surrounded by a basophilic rim of degenerate neutrophils and necrotic debris, further surrounded by epithelioid macrophages, reactive fibroblasts, mature collagen (fibrosis), and few multinucleated giant cells. Multifocally surrounding pyogranulomas are few lymphocytes, plasma cells, eosinophils, and small caliber blood vessels that are often regularly spaced and interspersed with reactive fibroblasts (granulation tissue) and lined by plump endothelium (reactive). Fungal hyphae are 3-6µm wide and regularly septate with dichotomous, acute angle branching and parallel walls. Multifocally, occasional remaining alveoli contain eosinophilic fibrillar material and fluid (fibrin and edema) admixed with occasional neutrophils, macrophages, and rare multinucleated giant cells. Focally few bronchioles contain abundant fibrin, neutrophils, macrophages, and necrotic debris which replace bronchiolar epithelium. Diffusely, interlobular septa are expanded up to 3mm by fibrous connective tissue.

MORPHOLOGIC DIAGNOSIS: 1. Bone, metatarsus: Periosteal new bone formation (hyperostosis), diffuse, severe, Rocky Mountain elk (Cervus elaphus nelsoni), cervid.

2. Lung: Pyogranulomas, multiple, severe, with numerous fungal hyphae.

CONDITION: Hypertrophic osteopathy

SYNONYMS: Hypertrophic pulmonary osteoarthropathy; “Marie’s disease” or Marie-Bamberger’s disease

GENERAL DISCUSSION:

• Characterized by diffuse, periosteal new bone formation along the diaphysis and metaphysis of certain limb bones, without involving the joint (arthritis is not a component), frequently associated with neoplastic or chronic inflammatory lesions
• Occurs secondary to space occupying masses (i.e. neoplasms) or granulomatous lesions, most often in the thorax or, less commonly, the abdomen; often referred to as pulmonary hypertrophic osteopathy even though not always related to the pulmonary or thoracic area; can occur with:
  • Primary or secondary pulmonary neoplasms (most frequent in the dog); neoplasms of the thoracic wall
  • Granulomatous pleuritis (most often granulomatous thoracic lesions in horse)
  • Mycotic pneumonia
  • Granulomatous lymphadenitis of bronchial and mediastinal lymph nodes
  • Endocarditis
  • Patent ductus arteriosus; right to left (dogs)
  • Chronic bronchitis
  • Dirofilaria immitis
  • Esophageal granulomas and neoplasia induced by Spirocerca lupi
  • Botryoid rhabdomyosarcoma of the urinary bladder (young dogs)
  • Ovarian tumors (mares)
  • Renal carcinoma with pulmonary metastasis
• Reported in humans and domestic and wild animals, with the dog being the most commonly affected
• Only present in a minority of those with thoracic lesion, but higher incidence with some types than others (i.e. pulmonary metastasis from osteosarcoma more often associated than metastatic carcinoma)

PATHOGENESIS:

• Unknown; theories (none consistently fits clinical and experimental observations):
  • Neurogenic theory: Impulses originating in the thoracic lesion travel via the vagus nerve (stimulation of afferent visceral nerves) to the brainstem and initiate reflex vasodilation in the limbs, either by humoral or neural means
  • Humoral theory: Either the primary lesion produces a hormone or hormone-like substance or arteriovenous anastomoses in the primary lesion prevent catabolism of such a substance in the lung à the hormone then produces the secondary skeletal lesions
  • Vascular endothelial growth factor and platelet derived growth factor are released secondary to platelets within abnormal limb circulation and may contribute to bone lesions
  • Hypoxic theory: Reduced oxygenation of peripheral blood resulting from congenital or acquired arteriovenous shunts stimulates periosteal osteophyte production
• Lesions likely reflect the limited range of periosteal reaction to diverse stimuli
• Increased blood flow to the distal limbs is a consistent early change

TYPICAL CLINICAL FINDINGS:

• Pain on movement and palpation
• Bony proliferations of the distal limb bones, which then extend proximally
• Earliest radiographic lesions tend to affect the second and fifth metacarpal/tarsal bones
• Progressive, but may regress if the primary lesion is removed

TYPICAL GROSS FINDINGS:

• Marked thickening and deformity of the long bones, with a rough surface
• In the dog, the radius, ulna, tibia, metacarpals, and metatarsals are most frequently involved (sparing of proximal limbs and phalanges)

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Earliest changes are hyperemia (gross finding) and edema, with proliferation of highly vascular connective tissue in the periosteum; severe hemorrhage possible
• Osteoid is deposited on the existing cortical bone
• New trabecular bone forms perpendicular to the original cortex; with chronicity, original cortex is converted to trabecular bone by endosteal surface resorption
• Remodeling and formation of pseudocortices

ADDITIONAL DIAGNOSTIC TESTS:

• Thoracic radiographs may be useful in identifying an inciting lesion

DIFFERENTIAL DIAGNOSIS:

Gross (periosteal proliferative lesion)

• Hepatozoon americanum (M-P01): Very similar to hypertrophic pulmonary osteopathy histologically and grossly; but generally affects the proximal long bones before affecting the distal long bones and rarely affects the metacarpals, whereas hypertrophic (pulmonary) osteopathy generally affects the metacarpals and distal long bones before the more proximal bones and has a slower onset
• Craniomandibular osteopathy (M-M18): Skull/mandibular lesions, rarely affects long bones; bilateral, generally symmetrical proliferation of non-neoplastic periosteal new bone; typically young animals with open growth plates; West Highland white, Scottish, and Cairn terriers most commonly affected
• Periosteal osteosarcoma (M-N02): Generally unilateral
• Callus: Generally unilateral
• Osteofluorosis: Fluoride toxicosis in growing rabbits causes periosteal and endosteal hyperostosis of the mandibles and extremities

COMPARATIVE PATHOLOGY:

• Reported in a variety of animals; dog most commonly affected
• Red wolf: HO associated with metastatic osteosarcoma was attributed to a heartworm infestation
• Hypertrophic osteopathy sporadic in roe deer and other cervids and is associated with mycotic pneumonia (Aspergillus fumigatus) and other intrathoracic masses
• In humans, this disease is referred to as hypertrophic osteoarthropathy and occurs in 1-10% of patients with bronchogenic carcinoma; affects the same bones as in dogs, but causes arthritis in adjacent joints and clubbing of the digits
• Non-human primates: Hypertrophic osteoarthropathy is characterized by symmetrical subperiosteal new bone formation at the end of long bones in association with destructive chronic lung disease or lung tumors; reported in a chimpanzee, an orangutan, and a gibbon

REFERENCES:

1. Abee CR, Mansfield K, Tardif S, Morris T. Nonhuman Primates in Biomedical Research: Volume 2: Diseases. 2^nd San Diego, CA: Elsevier; 2012:666.
2. Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits. 4th ed. Ames, IA: Wiley Blackwell; 2016.
3. Craig LE, Dittmer KE, Thompson KG. Bones and joints. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Elsevier; 2016:92-94.
4. Howerth EW, Nemeth NM, Ryser-Degiorgis MP. Cervidae. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:165-166.
5. Keel MK, Terio KA, McAloose D. Canidae, Ursidae, and Ailuridae. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:238.
6. Olson EJ, Dykstra JA, Armstrong AR, Carlson CS. Bones, Joints, Tendons, and Ligaments. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:1051, 1074-1075.
7. Snyder L, Seelig D. Chapter 11: Urinary System. In: Raskin RE, Meyer DJ, & Boes KM eds. Canine and Feline Cytopathology: A Color Atlas and Interpretation Guide. 4th ed. St. Louis, MO: Elsevier; 2022:396-412.
8. Sula MM, Lane LV. The Urinary System. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:755,763.

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