Vertebral telangiectatic osteosarcoma in a dog

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Vertebral telangiectatic osteosarcoma in a dog G. Brellou, N. Papaioannou, M. Patsikas, Z. Polizopoulou, I. Vlemmas Abstract: Telangiectatic osteosarcoma (TOS) affecting the seventh cervical vertebra (C7) was diagnosed in a 4-year-old male dog with signs of locomotor dysfunction. Bone lysis and an extradural-extramedullary mass were observed in radiographs and occipital myelograms. The diagnosis was confirmed by histopathologic and immunohistochemical examination of the mass. The tumor was composed of large blood-filled cavities lined by anaplastic stromal cells (malignant osteoblasts). Around the cavities were characteristic tumor giant cells (‘‘bizarre cells’’). Immunohistochemically the tumor cells were positive for proliferating cell nuclear antigen. The lining cells of the cysts were negative for von Willebrand factor. The histologic findings in this case of TOS involving C7 were similar to those seen in other cases of TOS in dogs and in people. Immunohistochemistry was a useful tool for assessing malignancy and for ruling out other differential diagnoses. (Vet Clin Pathol. 2004;33:159–162) 2004 American Society for Veterinary Clinical Pathology

Key Words: Cervical vertebra, dog, immunohistochemistry, osteosarcoma, telangiectatic, TOS u

Osteosarcomas are malignant tumors arising from mesenchyme, in which the tumor cells produce osteoid or bone. They are the most common skeletal neoplasms in dogs1–4 and cats,5 comprising about 80% and 50% of skeletal tumors, respectively. Osteosarcomas are extremely heterogeneous tumors.6 In one early report it was said to be impossible to offer a histologic description that was characteristic of an osteosarcoma.7 Pathologists have proposed a variety of schemes to classify osteosarcomas into histopathologic subtypes. The American College of Surgeons in 1939 proposed the classification of osteogenic tumors into 5 groups, which have been well described by Ewing.8 The 5 designated groups were a) medullary and subperiosteal, b) telangiectatic (TOS), c) sclerosing, d) periosteal, and e) fibrosarcoma (medullary and subperiosteal). Canine osteosarcomas tend to be classified into histologic subtypes based on the quality and quantity of extracellular matrix (osteoblastic, chondroblastic,9,10 and fibroblastic11), the degree of differentiation (poorly differentiated or undifferentiated), the relative abundance of giant cells (giant-cell, giant-cell-rich, and osteoclast-rich12 subtypes), and the dominance of blood-filled cystic lesions (telangiectatic13–15). A sclerotic subtype also has been described in dogs.16,17 The classification of osteosarcomas in humans also includes small-cell, osteoblastoma-like, and malignant fibrous histiocytoma-like subtypes.12,18–24 Small cell osteogenic sarcoma has been reported in a dog.25 The purpose of this case report was to describe the histologic and immunohistochemical features of a TOS in the cervical vertebra of a dog and to emphasize the significance of

immunohistochemistry for assessing malignancy and differential diagnoses. A 4-year-old male Doberman Pinscher was presented to the Companion Animal Teaching Hospital, Aristotle University of Thessaloniki, because of progressively worsening locomotor dysfunction. Clinical examination revealed ataxia that evolved into asymmetric tetraparesis, with the right side being more severely affected. These clinical signs were compatible with ‘‘cervical syndrome.’’ Extensive bone lysis of the body and the pedicle of the seventh cervical vertebra (C7), more evident on the right side, was detected on plain radiographs. Results of occipital myelography revealed an extradural-extramedullary mass at the level of C7. No flow of contrast medium caudal to C7 was detected, probably due to obstruction of the subarachnoid space. The clinical and imaging findings were compatible with a neoplastic lesion in C7. The owner elected euthanasia due to the debilitated status of the dog. The dog was necropsied with the owner’s permission. Grossly, the right transverse process of C7 was thickened. A tumor extended from the right process of C7 and measured 0.7 3 1.8 cm. On cut surface, the mass was composed of a network of blood-filled spaces with near total loss of preexisting bone. Pressure applied to the thickened area of the vertebra yielded brown, liquid material. Tissue samples from the transverse processes and the body of C7 were routinely fixed in 10% buffered formalin, decalcified according to the formic acidsodium citrate method, and embedded in paraffin wax. Hematoxylin and eosin (H&E) and periodic acid–Schiff

From the Department of Veterinary Pathology (Brellou, Papaioannou, Vlemmas), the Clinic of Surgery (Patsikas), and the Clinic of Companion Animals (Polizopoulou), Faculty of Veterinary Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece. Corresponding author: I. Vlemmas ([email protected]). ª2004 American Society for Veterinary Clinical Pathology

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Figure 1. Blood-filled spaces lined by tumor cells in a telangiectatic osteosarcoma. H&E, 35 objective.

Figure 2. Anaplastic tumor cells line the cavernous spaces (arrows) and osteoclast-like multinucleated giant cells (arrowhead) are visible. H&E, 310 objective.

(PAS) stains were used for histologic examination. Single-labeling immunohistochemical studies by the avidin-biotin complex method were performed using primary monoclonal antibodies against proliferating cell nuclear antigen (PCNA; Oncogene, Paris, France), Ki67, p53 protein, and von Willebrand factor (factor VIIIrelated antigen) (DAKO, Glostrup, Denmark). Histologic sections of canine malignant mammary tumors (complex carcinoma) were used as positive controls.26 For negative controls, sections were incubated while omitting the first antibody. Many variably-sized blood-filled spaces were observed in the histologic sections of C7 (Figure 1). Cavernous spaces were lined by anaplastic malignant stromal cells (atypical tumor cells) with numerous mitotic figures (Figure 2). The atypical cells were either spindle-shaped or round, with hyperchromatic, pleomorphic nuclei. Around the cavities, osteoid and osteoclast-like multinucleated giant cells, some of which were bizarre, were observed. Most of the osteoclast-like giant cells contained abundant basophilic cytoplasm. The bizarre cells contained intracytoplasmic hyaline globules that were PAS-positive. The anaplastic stromal cells also stained positive with PAS. Cartilage formation was not observed. Immunohistochemically, the tumor mass was positive for PCNA, weakly positive for p53, and negative for Ki67. The anaplastic lining cells of the cavities were negative for von Willebrand factor, while endothelial cells were positive (Figure 3).

especially giant breeds27) and most frequently arise in distal long bones or proximal humerus or femur.28–30 The rare type of TOS was first described in 1854 by Paget.31 The term ‘‘malignant bone aneurysm,’’ instead of TOS, was originally coined in 1903 by Gaylord.32 In dogs, TOS rarely has been reported, in the tibia,33 scapula,13 mandible,13 and thoracic wall15; in one case, lesions were multifocal.28 The breed and the age of the dog in this case was in agreement with those of other studies,27 but to our knowledge, the location of TOS in C7 has not been reported previously. TOS also occurs in humans, usually in children and young adults, and has characteristic features of rapid growth, marked bone destruction, pathologic fractures, and gross polycystic


Figure 3. Immunohistochemical staining for von Willebrand factor. Tumor cells lining the cavities are negative (arrowhead) and endothelial cells (arrow) stain positive. Avidin-biotin complex, 3,39 diamino-benzidine chromogen, 35 objective.

Osteogenic sarcomas most often are diagnosed in largebreed dogs of middle age (mature males of large and

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Brellou, Papaioannou, Patsikas, Polizopoulou, Vlemmas

composition.33 On radiographic examination of TOS, lytic lesions are the prominent finding. On microscopic examination, pseudocystic lesions identified by radiography may not always be telangiectatic but may in fact be fibrosarcomatous or fibrohistiocytomatous osteogenic sarcomas.29 The major diagnostic criteria for TOS are lytic lesions of bone with no bone formation and the presence of many blood-filled spaces lined by large undifferentiated tumor cells. TOS is characterized by malignant osteoblasts that produce a minimum of osteoid.13 In the dog in this case, radiographic and histologic examination revealed the characteristic lesions described above. The osteoclastic-giant cells, which were PAS-positive for cytoplasmic hyaline globules, were termed ‘‘bizarre cells’’ in a case of ovarian sarcoma with histologic features of TOS in a human being.34 In that case, the bizarre cells also were PAS-positive; thus, the term ‘‘bizarre cells’’ may be used in cases of TOS or in sarcomas with histologic features of TOS in animals. Immunohistochemically, the tumor cells were positive for PCNA, a protein whose synthesis is markedly increased during the S phase of the cell cycle. Positive PCNA staining correlates with DNA synthesis and demonstrates a proliferative cell fraction. Immunohistochemical examination for p53 protein, the product of a tumor suppressor gene thought to regulate the proliferation of normal cells, may be used as an additional diagnostic and prognostic indicator for osseous tumors.34 In this case, immunohistochemical staining for p53 protein was weakly positive. This result was in agreement with the literature, which suggests that telangiectatic osteosarcomas have a lower p53 index than osteosarcomas belonging to other histopathologic subtypes, reinforcing the perception that they are distinct clinicopathologic entities.35 The negative results for Ki-67 staining may have been attributable, in part, to the decalcification process. It is important to differentiate TOS from hemangiosarcoma,33,34 hemangioma, aneurysmal bone cysts,30,33,34 giant cell tumors15,30,34 of bone, and metastatic carcinomas. Vascular spaces lined only by endothelial cells and the absence of osteoid in hemangiosarcoma are the key histologic features used to differentiate it from TOS.33 Additionally, negative staining for von Willebrand factor, which normally is present in endothelial cells, differentiates TOS from hemangiosarcoma.36 Hemangiomas lack features of malignancy as well as stain positive for von Willebrand factor. In this case, negative immunohistochemical staining of the lining cells of the cavities for von Willebrand factor indicated the tumor was nonangioblastic in origin.

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TOS also must be differentiated from aneurysmal bone cyst. On histologic examination, an aneurysmal bone cyst has dilated vascular spaces of various sizes engorged with blood and traversed by fibrous connective tissue septa. The fibroblastic stromal cells reveal no cellular aplasia or atypical mitoses. The dividing wall often contains abundant delicate lacy osteoid and is lined by osteoclastic giant cells.37 In comparison, the mesenchymal cells in TOS are exceptionally proliferative and there usually is soft tissue invasion, features not seen in typical bone cysts.36 Giant cell tumors are characterized by a very small amount of tumor osteoid and by multinucleated tumor giant cells, which comprise up to 35% of the cell population.27,38 The above characteristics were used in this dog to differentiate TOS from giant cell tumor. The giant cells in this case were fewer in number than would be expected in a giant cell tumor. Osteoid is not a histologic feature of malignancy, although it is derived from the tumor cells.27,38 The observation of osteoid primarily in trabeculae in the TOS in this case was in accordance with other cases in the literature. In conclusion, the histologic findings of this TOS involving C7 in a dog were similar to those seen in other cases of TOS in dogs and in people. Immunohistochemistry was a useful tool for assessing malignancy of the TOS and ruling out other differential diagnoses.

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