A Comparison of Canine Giant Cell Tumor and Giant Cell Reparative Granuloma of Bone

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1 Vet. Pathol. 20: (1983) A Comparison of Canine Giant Cell Tumor and Giant Cell Reparative Granuloma of Bone F. J. TRIGO, C. W. LEATHERS, and D. F. BROBST Department of Veterinary Microbiology and Pathology, Washington Animal Disease Diagnostic Laboratory. and Department of Veterinary Clinical Medicine and Surgery, Washington State University, Pullman, Wash. Abstract. The clinical, radiographic. and pathologic features ofa canine giant cell tumor of bone are compared with those of a giant cell reparative granuloma of bone. The giant cell bone tumor usually emerges from the epiphysis of long bones as a rapidly developing lytic bone lesion without periosteal new bone formation. The giant cell reparative bone granuloma originates preferentially in flat bones on the skull and mandible as a result of traumaassociated intraosseous hemorrhage. with new bone formation and sclerosis. Histologically, the neoplastic giant cells are scattered diffusely throughout the tissue. in contrast to the inflammatory giant cells that accumulate at the periphery of hemorrhages or around bone spicules. This peripheral accumulation is accompanied by a prominent collagenous and reticulum stroma. The morphologic and histochemical features of the giant cells can not be used as reliable tools to differentiate these two conditions. Giant cell tumors of bone are relatively rare compared with other primary skeletal neoplasms in domestic animals (18, 21]. Most published descriptions are of single cases in dogs or cats [3, 6, 12, 15, 16,20,22,28]. The giant cell tumor in man is not common, yet it has morphological features that distinguish it from other bony lesions containing multinucleated giant cells [2, II, 26]. This neoplasm apparently arises from the mesenchymal cells of the bone marrow stroma [26] and develops almost exclusively in skeletally mature individuals [4, 7, 26]. On the other hand, giant cell reparative granuloma of bone is a reactive, non-neoplastic condition, commonly associated with a previous traumatic injury where intraosseous hemorrhage occurred (14]. It is reported commonly in flat bones of the skull in man [II, 14] and only rarely in dogs [9]. We describe a canine giant cell tumor of bone and a giant cell reparative granuloma of bone. Criteria are outlined for the differential diagnosis of these bony giant cell reactions. 215

2 216 Trigo, Leathers, and Brobst Materials and Methods One giant cell tumor of bone ("osteoclastoma") was identified among 132 canine primary skeletal neoplasms accessioned by the Washington Animal Disease Diagnostic Laboratory from January, 1977, to December, A canine giant cell reparative bone granuloma also was selected for comparison. Radiographs and a Wright's-stained needle aspirate from the neoplasm were available for examination. Paraffin sections of demineralized tissue from both dogs were stained with hematoxylin and eosin (HE), Masson's trichrome, Wilder's reticulum stain, periodic acid-schiff (PAS) before and after diastase (Sigma Laboratories, St. Louis, Mo.) digestion, or PAS-Alcian blue at ph 2.6. One-mm cubes from the formalin-fixed primary neoplasm were transferred to 2.5% glutaraldehyde in 0.1 M cacodylate buffer, post-fixed in osmium tetroxide, embedded in epon, sectioned, mounted on copper mesh grids, and examined with a Philips 200 electron microscope. Case I. Giant cell bone tumor Results Clinical history: An eight-year-old male golden retriever was presented to the WashingtonState University VeterinaryTeaching Hospital with a history oflameness in the left forelimb for two weeks. The dog was in good condition, but refused to bear any weight on the affected limb. A solid mass approximately 9 X 5 X 5 em was palpated on the lateral surface of the left scapula. Radiographically, a lytic bone lesion, without apparent soft tissue reaction, was seen in the neck of the scapula extending ventrally near the scapulohumeraljoint (fig. I). A needle aspirate obtained from the mass contained numerous multinucleated giant cells, accompanied by clusters of plump, homogeneous mononuclear cells with uniform ovoid nuclei (fig. 2). A provisional diagnosis of giant cell bone tumor was made. The dog was euthanized at the owner's request, and a complete necropsy was done. Grossfindings: An 8 X 4 X 3-cm mass was located on the central lateral face ofthe scapula extending to the neck, but not involving the joint space. This mass was graywhite, with a soft core and a firmer peripheral edge blending gradually with normal bone. A l-cm diameter whitish firm nodule was found in the left lateral hepatic lobe. The thyroid glands were pale and small (10 X 4 X 3 mm). The spleen contained one area of nodular hyperplasia. Histologic findings: The primary neoplasm was encapsulated only partially by a thin layer of connective tissue. On the medial side, individual spicules of mature bone were separated by neoplastic tissue, and no cortex remained. The neoplasm had a diffuse vascular network, large multifocal areas of necrosis with hemorrhage, and occasional discrete perivascular infiltrations oflymphocytes. Two main cell types were noted in the tumor. The first and most abundant type consisted of pleomorphic mesenchymal cells with round to ovoid nuclei containing coarse chromatin. Mitoses among these cells were common (3 to 4 per high power field). Multinucleated cells were the second cell type and were scattered uniformly throughout the tissue. These sectioned cells contained 2 to 80 nuclei (average of8), which were either aggregated centrally or aligned along the periphery of the cell. Cell diameter ranged from IS to

3 Giant Cell Bone Lesions J Fig. I: Lytic lesion of giant cell bone tumor in neck of scapula (arrow). Fig. 2: Needle aspirate of bone tumor with a few multinucleated giant cells and plump, ovoid mesenchymal cells. Wright's. Fig.3: Neoplastic multinucleated giant cells accompanied by numerous pleomorphic mesenchymal cells. HE. 90 urn (average of 35 urn) (fig. 3). No osteoid was seen, although numerous necrotic bone fragments were present. A delicate but irregularly distributed reticulum network was observed. With the PAS-Alcian blue stain, neutral glycosaminoglycans were detected in the ground substance. No glycogen was found in the cytoplasm of the giant or mesenchymal cells. A focal hepatic metastasis was present in the surface of the liver, with similar morphologic features as those described in the main osseous tumor. Ultrastructuralfindings: The multinucleated giant cells were round to slightly ovoid

4 218 Tr igo, Leathers, and Brobst Fig.4: Typical neoplastic mononuclear mesenchymal cell and neoplastic giant cell (inset) ; morphologic similarities, particularly in nucleus. Uranyl acetate lead citrate. Bar = 2/lm. with abundant multivacuolated cytoplasm, and nuclei oriented to the cell periphery in close proximity to the cell membrane. The cytoplasm contained numerous, uniformly distributed mitochondria, in different stages of degeneration. Numerous cytoplasmic vacuoles of various electron densities, size and shape, occupied most of the cytoplasmic volume. Rough endoplasmic reticulum and Golgi were scarce. Free ribosomes were observed commonly among cytoplasmic organelles. The nuclei had an ovoid or irregular shape with numerous small folds of the nuclear membrane. Nucleoli were prominent, and chromatin was condensed in close proximity to the nuclear membrane. The pleomorphic mesenchymal cells were ovoid to spindle shaped, with a single nucleus, and a less electron-dense cytoplasm. A close resemblance was noticed between these two cell types, particularly in the abundance and pleomorphism of mitochondria, the nuclear shape, presence of more than one nucleolus, and a similar organization of the nuclear and cytoplasmic membranes (fig. 4). In some areas of the tumor, cells in trans ition between the mononuclear mesenchymal type and the multinucleated giant cell were observed. These cells were of intermediate size and contained from two to several nuclei. The intercellular space was composed mostly of loosely dispersed fibrils, nonfilamentous electron -dense material and occasional collagenous fibers.

5 Giant Cell Bone Lesions 219 Case 2. Giant cell reparative granuloma of bone Clinical history: A l2-year-old spayed female golden retriever was presented to a local veterinary clinic with a history of a small focal swelling below the right eye. This mass had been expanding slowly for at least one month. It was diagnosed initially as an infectious process, and the site was drained. Three weeks later, the lesion continued to expand. At that time, the swelling had concentrated as a solid 3em mass in the mid portion of the right maxilla. No radiographs were made, but portions of this mass were removed surgically, and formalin-fixed tissues were sent for histologic evaluation. A diagnosis of reparative bone granuloma was made. The animal was euthanized several weeks later, but a necropsy was not done. Chronic arthritis affecting the rear limbs was the principal reason given by the owner for euthanasia. Histologic findings: The tissue was characterized by diffuse areas of osteoid production in conjunction with bone resorption. No bone cortex was discernible among the different tissues received for examination. Areas of necrosis were minimal and the vascular bed was developed poorly. Multifocal hemorrhages with hemosiderin deposits were scattered throughout the lesion. The predominant cell type was a homogeneous population of elongate to spindle-shaped cells. Individual cells contained pale, eosinophilic vacuolated cytoplasm, and a round or ovoid nucleus with a single prominent nucleolus. Mitoses were seen rarely. Multinucleated giant cells were infrequent and concentrated at the periphery of hemorrhagic areas. These cells measured from 20 to 90 Ilm (average 50 um), and often contained uniformly Fig.5: Multinucleated giant cells of reparative granuloma surrounded by spindle-shaped and ovoid mesenchymal cells. HE.

6 220 Trigo. Leathers, and Brobst distributed nuclei with a tendency towards central location (fig. 5). The number of sectioned nuclei per cell ranged from 4 to 40 (average of 12). An abundant connective tissue stroma was found throughout the tissue. The reticulum network was distributed uniformly. The ground substance was composed ofneutral glycosaminoglycans, with no glycogen present in the mesenchymal or giant cells. Discussion Giant cell tumor of bone is a rare neoplasm in human and veterinary patients [13, 26]. Only one such tumor was recorded among 403 primary canine bone neoplasms [13]. In another study of over a thousand primary tumors of canine bone, only 2% were classified as rare neoplasms, among which giant cell tumors were included [23]. Our accessions included 132 primary canine bone neoplasms in a five-year period, with 54% being osteosarcomas and only one giant cell tumor. All the recorded canine giant cell tumors of bone have occurred in large breeds [3, 6, 13, 15, 20], with ages ranging from two to 13 years, and males outnumbering females. The common origin of this neoplasm is in the epiphysis of long bones [13, 26], with associated lameness in the affected limb of dogs and cats [6, 12, 15, 16, 20, 22]. A rapidly developing, lytic bone lesion is seen radiographically at the epiphyseal end and adjacent metaphyseal region of a long and mature bone, without periosteal new bone formation [7, 12, 15-17, 20, 22]. However, other neoplasms can have a similar radiographic appearance, and a few giant cell tumors have originated in mid portions of cortical bone or in flat bones [4]. The giant cell reparative bone granuloma originally was described in man as a non-neoplastic process resulting from trauma and intraosseous hemorrhage, limited particularly to the maxilla [14]. This lesion also may arise in the mandible [14], temporal bones [10], or other bones in the skull. Radiographically, the lytic bone lesion is accompanied by new bone formation and sclerosis, without regrowth or metastases [11]. Needle aspirates of suspected giant cell tumors of bone are reportedly useful in 85% of the human cases [8, 25]. Aspirates of giant cell tumors contain large clusters ofplump spindle-shaped, or ovoid hyperchromatic tumor cells adjoining multinucleated giant cells [8]. The giant cell tumor ofthe eight-year-old dog had these features. It did not contain the osteoid observed in many osteogenic sarcomas or the cartilage or myxoid stroma seen in many chondrosarcomas [8]. Likewise, more oval and spindle-shaped cells would be expected in aspirates from reparative granulomas. The gross aspect of the neoplasm described here was quite similar to previous descriptions of such neoplasms in long bones of dogs [6, 15,20], cats [12, 16,22] and man [26]; however, it seems that giant cell bone tumors originating from the scapula are rare [4, 7,17,25,26]. We found a single metastasis to the liver with no involvement of local lymph nodes or lungs. Evidence of metastatic spread also has been recorded previously in canine and feline giant cell tumors of bone [6, 12]. In man, about 30% recur and approximately 6% metastasize [7, 17]. In contrast, giant cell reparative bone

7 Giant Cell Bone Lesions 221 granulomas heal through new bone formation and sclerosis, and recurrence is observed only in extensive lesions where surgical excision is not complete [11]; metastases never are present. Histologically, in the giant cell tumor of bone the neoplastic giant cells tend to be uniformly scattered throughout the tissue, whereas granuloma giant cells organize in the periphery of hemorrhages or around bone spicules. The mononuclear mesenchymal cells observed in the neoplasm are plump, round or oval with moderate uniform deposition of collagen, a regular delicate reticulum network and a rich vascular system with occasional hemorrhages. The inflammatory lesion contains abundant collagen with a thick prominent reticulum network, common multifocal hemorrhages, and hemosiderin deposits. Osteoid usually is seen in the reparative lesion, but less frequently in giant cell tumors of bone [26]. No consistent morphologic differences between the giant cells of both conditions were seen in our material, but some authors have stated that such differences occur [11]. Histochemically, neoplastic multinucleated giant cells, normal osteoclasts and chondroclasts are reported to be identical [25], therefore these methods are not reliable tools for differentiation. The giant cell tumor of bone also has been named osteoclastoma due to apparent morphologic similarities of the neoplastic giant cells and osteoclasts [24, 26], and because of their identical histochemical composition [25]. The term osteoclastoma implies that osteoclasts are the origin of the tumor. It has been suggested in different ultrastructural and histochemical studies, however, that the neoplastic giant cells originate from fusion of mononucleated stromal cells [10, 25, 27]. Furthermore, there is no evidence that neoplastic giant cells participate in active bone resorption, degradation of mineral matrix, or digestion of collagen [27]. No mitotic activity has been noticed in neoplastic giant cells either in vivo or in vitro [10, 27]. The ultrastructural features observed in the neoplasm reported here were quite similar to previous descriptions [10, 27], with two basic cell populations: multinucleated giant cells and mononuclear mesenchymal cells. The giant cell tumor of bone also must be differentiated from other bony and soft tissue lesions where giant cells are present, including nonossifying fibroma, chondroblastoma, aneurysmal bone cyst, the brown tumor of hyperparathyroidism [26], and the giant cell tumor of soft tissues [1, 2, 5, 19]. Acknowledgement Gratitude is expressed to Dr. N.W. Rantanen for the radiographic interpretation. References ALEXANDER, J.W.; RIIS, R.C.: DUELAND, R.: Extraskeletal giant cell tumor in a cat. Vet Med Small Anim Clin 70: , ASHLEY, D.J.B.: Histological Appearances of Tumours, pp , vol. 1, 3rd ed. Churchill Livingstone, Edinburgh, 1978

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