Monique T. Kramer , BS, MS; Kenneth S. Latimer, DVM, PhD; Pauline M. Rakich, DVM, PhD; Royce E. Roberts, DVM, MS; Nicole C. Northrup, DVM; and Perry J. Bain, DVM, PhD
Class of 2003 (Kramer), Department of Pathology (Bain, Latimer), Athens Veterinary Diagnostic Laboratory (Rakich), Department of Anatomy and Radiology (Roberts), and Oncology Service, Department of Small Animal Medicine (Northrup), College of Veterinary Medicine, The University of Georgia, Athens, GA 30602-7388
Osteosarcoma (OSA) is a rapidly growing, destructive neoplasm of bone that accounts for 80% of all malignant bone tumors in dogs.9,10 Neoplasms of the skeleton are more common in dogs than in any other species. Primary bone tumors such as OSA are five times more common than metastatic skeletal neoplasms, and malignant tumors are more common than benign neoplasms.12
Breed, Age, and Sex Predisposition
Osteosarcoma is most common in giant and large breed dogs (90%) and is uncommon in small and medium breeds.13 Breeds especially predisposed to development of OSA include Saint Bernards, Rottweilers, Great Danes, Golden Retrievers, Irish setters, Doberman Pinschers, and Labrador retrievers. The mean age of occurrence is 7-1/2 years and incidence of OSA is slightly more common in males than females (1.2:1).10,13
Factors Influencing Tumor Development
Ionizing radiation, chemical carcinogens, foreign bodies (including metal implants, such as internal fixators, bullets, and bone transplants), and pre-existing skeletal abnormalities such as sites of healed fractures contribute to the development of OSA. In addition, there have been correlations with genetic predisposition to tumor development in certain family lines. Dogs with OSA have been found to have aberrations of the p53 tumor suppressor gene.11 In laboratory animals, both DNA viruses (polyomavirus and SV-40 virus) and RNA viruses (type C retroviruses) have been found to induce OSA.13
Sites of Origin and Metastasis
OSA can be found in both the appendicular and axial skeleton with the former being 3-4 times more common.10 This neoplasm originates most commonly in the metaphyses of the long bones of forelimbs, especially the distal radius and proximal humerus. These areas are especially active during skeletal development and predominate in weight bearing. OSA also can be found in the distal ulna, proximal and distal tibia, and femur. OSA usually arises in the medullary cavity, penetrates the cortex, and extends into the subperiosteum, causing the formation of a large soft tissue mass contiguous to the bone. Axial skeletal OSA is less common and can involve the ribs, vertebrae, and skull. Most neoplasms of the skull arise in the cranial vault, zygomatic arch, and jaw, but occasionally may originate within the nasal cavity. OSA originating in the skull is usually of the multilobular type and is observed more commonly in middle-aged dogs. Axial OSA is more common in females.9 Extraskeletal OSA is rare but may originate in the spleen, adrenal gland, eye, testicle, vagina, kidney, intestine, mesentery, liver, skin, and mammary gland.
OSA metastasizes primarily via hematogenous routes and rarely through lymphatics. The lung is the most common site for visceral metastases. Other metastatic sites include liver, kidneys, amputation stump, and, rarely, adjacent bones.
The most common clinical signs of OSA involving the appendicular skeleton are lameness, swelling, and pain. The considerable soft tissue swelling is predominantly due to edema and reactive fibroplasia caused by impaired circulation in the subcutaneous and intramuscular tissue proximal and distal to the tumor.
Congestion, edema, fibroplasia, and periosteal new bone formation accompany continued tumor expansion. Muscle atrophy of the affected limb may occur from disuse. Pathological fractures may occur later in the disease as the neoplasm weakens the cortical bone. Osteolytic neoplasms are larger, more aggressive, exhibit rapid growth, and cause pathological fractures. Neoplasms involving the skull and nasal cavity can result in neurological deficits, dyspnea, nasal obstruction, and a bloody to purulent nasal discharge.
Lymphadenopathy occasionally can be observed in sites distal to the tumor. Pulmonary metastases may be associated with the development of hypertrophic osteopathy where space occupying lesions of the lung incite subperiosteal formation of new bone. Lymph nodes draining the neoplastic site may become enlarged and firm following tumor mestastasis.
Radiographically, primary bone neoplasms have a lytic, productive, or mixed appearance. Characteristic radiographic findings in OSA include the sunburst pattern, Codmans triangle, irregular osteolysis that does not cross joint spaces, and variable degrees of periosteal new bone formation.
The sunburst appearance is the result of tumor extension, mineralization, and formation of periosteal spicules in the surrounding tissue (Figs. 1 and 2). OSA is poorly delimited radiographically because there is a wide zone of transition between abnormal and normal bone that lacks a sclerotic border at the margin of the lesion. Normal metaphyseal architecture is lost and the cortical shadow is partially or completely effaced.
|Figure 1. Osteosarcoma of the distal radius in a dog. The extent of the neoplasm is delineated by the arrows (dorsoventral radiograph).||Figure 2. Osteosarcoma of the distal radius in a dog. Codmans triangle is formed by the elevation of the periosteal reaction (arrows, lateral radiograph).|
Codmans triangle is the regular periosteal elevation on either side of the lesion that appears irregular and discontinuous (Fig. 2). Spicular or amorphous patterns of mineralized matrix may fill the breach in the periosteal response. The adjacent soft tissue swelling may show neoplastic invasion.
There is little correlation between the type of radiographic pattern and the biological age of the neoplasm or its degree of malignancy. Nuclear scintigraphy overestimates tumor margins but may provide a larger margin of safety when determining the site of proximal osteotomy during limb-salvage techniques.4
The radiographic differential diagnosis for proliferative and lytic bone lesions may include bony proliferation secondary to healing fractures as well as fungal and bacterial osteomyelitis.
Alkaline phosphatase activity may be within the reference interval or increased.2,3 Decreased total iron binding capacity and increased ferritin concentration may be observed.3 Serum concentrations of zinc, chromium, and iron also may be decreased. Dogs with OSA have decreased rates of protein synthesis, increased urinary nitrogen loss, and increased postoperative glucose flux.7 Concentration of prostaglandin E2 may be increased in dogs with OSA.8 Resting energy expenditure also has been found to be higher in dogs with OSA.8
Fine-needle aspirates of OSA contain mesenchymal cells that appear round, plump, or fusiform (Fig. 3). These cells are scattered singly or in small clusters. Individual neoplastic cells may display anisocytosis, anisokaryosis, karyomegaly, eccentrically located nuclei, large nucleoli, and basophilic, vacuolated cytoplasm with fine pink granules (Fig. 3). More well differentiated osteoblasts may have a plasmacytoid appearance (Fig. 4).
|Figure 3. Pleomorphic population of mesenchymal cells that are round, plump, or fusiform (dog, osteosarcoma, Wright stain).||Figure 4. Neoplastic cells exhibit anisocytosis and anisokaryosis. A few cells have a plasmacytoid appearance. A mitotic figure is present at the upper left of the image (dog, osteosarcoma, Wright-Leishman stain).|
Osteoclasts are large cells that are multinucleate (Fig. 5). Scattered mitoses also may be observed. Islands of osteoid may be observed within some clusters of neoplastic cells or within the background of the smear. Osteoid is amorphous to fibrillar and bright pink in Wrights-stained cytology specimens (Fig. 6).
|Figure 5. Osteoclasts are large cells that are multinucleate (dog, osteosarcoma, Wright-Leishman stain).||Figure 6. Pleomorphic population of neoplastic osteoblasts are surrounded by pink osteoid matrix (dog, osteosarcoma, Wright-Leishman stain).|
Biopsy is often necessary for the definitive diagnosis of OSA (Fig. 7). The biopsy can be obtained with a Jamshidi needle that removes a core of the osseous neoplasm. A core biopsy taken from the center of the lesion is preferred for preoperative diagnostic purposes. However, initial biopsies often reveal reactive bone and inflammation. Therefore, multiple core samples may be necessary for a definitive diagnosis. Most OSAs exhibit three common properties: 1) destruction of normal bony architecture, 2) stimulation of reactive bone production by endosteum and periosteum, and 3) deposition of osteoid. OSA may have a heterogeneous appearance histologically and have been classified as poorly differentiated, fibroblastic, osteoblastic, telangectatic, giant cell, or chondroblastic based upon the character of the neoplastic cell population and the type(s) of matrix produced.12 OSA also may have a combined or mixed appearance (e.g., a mixture of chondroid and osteoid matrix), but newer classification schems place these neoplasms within the osteoblastic subtype.
Figure 7. Poorly differentiated osteosarcoma with a homogeneous population of spindle cells, scattered mitoses, and a few pink deposits of osteoid (dog, osteosarcoma, hematoxylin and eosin stain).
Poorly differentiated and fibroblastic OSAs have a pleomorphic to fusiform cell population with minimal deposition of osteoid or production of bony spicules. Poorly differentiated OSA is a highly aggressive neoplasm. Fibroblastic OSA begins as a lytic tumor. Approximately 50% of these neoplasms transition onto a combined type as the neoplastic spindle cells begin to form matrix material. The fibroblastic type of OSA has the most favorable prognosis.
Osteoblastic OSA is characterized by anaplastic osteoblasts admixed with plump to spindle shaped osteogenic precursor cells. Evidence of osteoid deposition or formation of bony spicules is usually evident; however, these neoplasms occasionally may be lytic or non-productive.
Telangectatic OSA is a rare neoplasm characterized by variably sized blood-filled spaces that are lined by tumor cells rather than endothelial cells; mitoses are frequently observed. This form of OSA is lytic, destructive, and rapidly fatal. Telangectatic OSA exhibits rapid growth, widespread metastasis, and may be difficult to differentiate from hemangiosarcoma.
Giant cell OSA appear as expansive and lytic bone lesions. Histologically, they resemble non-productive osteoblastic OSA except that the neoplasm may contain large areas in which tumor giant cells predominate.
The combined or mixed type of OSA has no dominant matrix pattern. Tumor matrix usually consists of osteoid in combination with chondroid matrix and/or collagen fibers. This form of OSA is more common in dogs than any of the other subtypes.10 Chondroblastic OSA is characterized by a mesenchymal cell population that produces both osteoid and chondroid matrix.
Treatment of OSA can include surgery, chemotherapy, and radiation therapy. Survival without treatment is ~ 2-6 months.10 Amputation is palliative but rarely increases survival time. Chemotherapy administered after amputation helps to control metastatic disease and may increase survival time significantly. The most successful chemotherapy protocol is a combination of cisplatin and doxorubicin that is administered following amputation.
The clinical prognosis for OSA is variable. A poor prognosis is associated with high serum alkaline phosphatase activity, tumor extension into soft tissue, tumor origin in a hindlimb, and the presence of pulmonary metastases. The best prognosis is associated with the fibroblastic subtype of OSA that has the lowest grade of malignancy. Dogs between 7 and 10 years of age have greater survival times than younger and older dogs.9
1. Chun R, Kurzman ID, Couto CG, Klausner J, Henry C, MacEwen EG: Cisplatin and doxorubicin combination chemotherapy for the treatment of canine osteosarcoma: A pilot study. J Vet Intern Med 14:495-498, 2000.
2. Garzotto CK, Berg J, Hoffmann WE, Rand WM: Prognostic significance of serum alkaline phosphatase activity in canine appendicular osteosarcoma. J Vet Intern Med 14:587-592, 2000.
3. Kazmierski KJ, Ogilvie GK, Fettman MJ, Lana SE, Walton JA, Hansen RA, Richardson KL, Hamar DW, Bedwell CL, Andrews G, Chavey S: Serum zinc, chromium, and iron concentrations in dogs with lymphoma and osteosarcoma. J Vet Intern Med 15:585-588, 2001.
4. Leibman NF, Kuntz CA, Steyn PF, Fettman MJ, Powers BE, Withrow SJ, Dernell WS: Accuracy of radiography, nuclear scintigraphy and histopathology for determining the proximal extent of distal radius osteosarcoma in dogs. Vet Surg 30:240-245, 2001.
5. MacEwen EG, Kurzman ID: Canine osteosarcoma: amputation and chemotherapy. Vet Clin N Am Small Anim Pract 26:123-133, 1996.
6. Mahaffey EA: Cytology of the musculoskeletal System. In: Cowell RL, Tyler RD, Meinkoth JH (eds): Diagnostic Cytology and Hematology of the Dog and Cat, 2nd ed. St. Louis, Mosby Inc., 1999, pp. 120-124.
7. Mazzaferro EM, Hackett TB, Stein TP, Ogilvie GK, Wingfield WE, Walton J, Turner AS, Fettman MJ: Metabolic alterations in dogs with osteosarcoma. Am J Vet Res 62:1234-1239, 2001.
8. Mohammed SI, Coffman K, Glickman NW, Hayek MG, Waters DJ, Schlittler D, DeNicola DB, Knapp DW: Prostaglandin E2 concentrations in naturally occurring canine cancer. Prostaglandins, Leukotrienes, and Essential Fatty Acids 64:1-4, 2001.
9. Ogilvie GK: Bone tumors. In: Rosenthal R (ed): Veterinary Oncology Secrets. Philadelphia, Hanley and Belfus Inc., 2001, pp. 139-146.
10. Pool RR: Tumors of bone and cartilage. In: Moulton JE (ed.): Tumors in Domestic Animals. Berkley, University of California Press, 1990, pp. 157-230.
11. Setoguchi A, Sakai T, Okuda M, Minehata K, Yazawa M, Ishizaka T, Watari T, Nishimura R, Sasaki N, Hasegawa A, Tsujimoto H: Aberrations of the P53 tumor suppressor gene in various tumors in dogs. Am J Vet Res 62:433-439, 2001.
12. Slayter MV, Boosinger TR, Pool RR, Dämmerich K, Misdorp W, Larsen S: Histological Classification of Bone and Joint Tumors of Domestic Animals. American Registry of Pathology and the World Health Organization Collaborating Center for Comparative Oncology, Washington, D.C., Armed Forces Institute of Pathology, 1994.
13. Theilen GH, Madewell BR: Tumors of the skeleton. In: Theilen GH, Madewell BR (eds.): Veterinary Cancer Medicine. Philadelphia, Lea and Febiger, 1987, pp.471-493.