Ultrasonography of Osteosarcoma in Dogs
Sonography Atlas of Dogs

Breed
Using artificial selection, man has created hundreds of different canine breed types, all of which have different predilections for OS. That OS is a disease of large breeds has long been recognized by practicing veterinarians. Indeed, the risk of OS in dogs greater than 80 lb has been estimated to be 61-185 times the risk for dogs weighing less than 20 lb [31]. In a review of 194 dogs with OS, only 4 percent weighed less than 25 lb [27]. Thus, OS is a sizerather than a breed-related disease. The major large breeds affected are St. Bernard, Great Dane, Boxer, German Shepherd, and Irish setter. The proportions of these breeds affected vary with the population characteristics of dogs in the study area. The demonstration that OS was far more common in large dogs was the basis of a study in children which indicated that children with osseous malignancies were of larger skeletal size than those with non-osseous neoplasms [32]. Achondroplastic dogs such as Dachshunds, and Bassett Hounds have an exceedingly low incidence of OS [27]. The Beagle, an exceedingly common breed for laboratory research in cancer, has an exceedingly low natural incidence of OS [33]. Mixed breed dogs also have a much lower than expected incidence of OS, probably because most of them tend to be small in size [27]. A study conducted at the University of Pennsylvania Veterinary Hospital (UPVH) from 1952-1963 inclusive indicated a breed-specific crude rate per thousand for OS of 2.1 for all breeds compared to 6.9 for Boxers [19].

Genetic Factors
OS was found in six of 148 first-degree relatives of 21 index St. Bernard dogs with histologically proved OS at the University of Pennsylvania Veterinary Hospital, but was not found in any of the 110 first-degree relatives of 18 breed, age, and sexmatched controls [34]. Analysis of a composite pedigree constructed from individual four-generation pedigrees showed that all 21 index dogs were related. The average coefficient of relationship for members of the OS-bearing group was significantly higher than that for members of the control group. The average coefficient of inbreeding of the OS-bearing group was lower than, but not significantly lower than, that of the controls. This suggests that the presence of specific genes within certain family lines, and not inbreeding per se, influences susceptibility to OS. The lack of information on entire litters precluded the formal testing of specific genetic hypotheses, but examination of the pedigree excluded fully penetrant autosomal dominant and X-linked recessive inheritance. Other monogenic models or more complex modes, perhaps involving an interaction between genetic and environmental factors, cannot be excluded, nor can vertical transmission of an infectious agent. Based on the familial pattern of occurrence of affected dogs, developing a strain with a high incidence of OS should be possible by selective breeding. A method for identifying ancestors having a major contribution to the genome of the group of index dogs was also described.

Sex
In 272 dogs with OS at the University of Pennsylvania Veterinary Hospital, 160 were males, and 112 were females, a M:F ratio of 1.5:1.0 [35]. In Alameda County, California, canine bone tumors comprised 2.85 percent of all cancers in males and 1.7 percent in females [17]. However, the sex ratios vary from breed to breed and these differences are presently being evaluated.

Site
In general, 77 percent of canine OS arises in the long bones, and 23 percent in the flat bones. The four major weight-bearing bones (radius, humerus, tibia, and femur) account for 70 percent of the OS [27]. Generally the forelimb to hind limb ratio is nearly 2 to 1, but this ratio varies greatly from breed to breed, e.g., in 45 Boxers it was 1.2:1; whereas in 27 Great Danes it was 5.7:1. Furthermore, the long bone to flat bone ratio varies widely from breed to breed, e.g., Boxer 2.1:1 and Great Dane 26: 1. The five most common breeds appeared to fall into three major groupings relative to site distribution: I. Irish Setters and German Shepherds; II. Boxers; III. Great Danes and St. Bernards [27]. Metaphyseal origin is far more common than diaphyseal. The major sites in the forelimbs are quite specific, proximal humerus and distal radius; the elbow region is only infrequently affected. The predilection sites in the forelimb appear to correlate with the approximate times of epiphyseal closure, e.g., the later the time of closure, the greater the frequency of OS. The closure times of the proximal and distal epiphyses of the humerus are 10-12 months and 8 months, whereas those of the proximal and distal radial epiphyses are 9 months and 10-12 months, respectively. In the hind limb, OS is commonly found on both the proximal and distal femur and tibia.
The major sites of axial skeleton OS are the skull (24 of 42 in one study) and the ribs, particularly at the costochondral junction (8 of 42 cases). Other flat bones are also involved but with far less frequency [27].
The tremendous variations in site frequencies is being studied further. Age, sex, breed, and site information has been collected from 1,400 dogs with OS [35]. Analysis of this data should give us a great deal of epidemiological information on the interrelationships of these four parameters. The site predilections for naturally occurring OS in man and dog differs from those observed with irradiation induction, suggesting a cause other than bone-seeking radionuclides [36].

Clinical Findings
The two major findings are lameness and swelling. The median duration of lameness is six weeks and 75 percent of the dogs have signs ranging from 1-9 weeks. Clinical signs have been observed for six months, but this is rare. The lameness may or may not precede the swelling. The affected area contains a hard fusiform and often painless swelling. In severe cases lymphedema may be present distal to the tumor. The growth of the mass is usually very rapid. Pathological fracture may be the presenting sign in a few very lytic tumors, or it may occur later in the clinical course. Clinical signs of pulmonary involvement are very uncommon initially, although pulmonary signs are very common in the later stages [27]. Pulmonary metastases commonly lead to the development of hypertrophic pulmonary osteoarthropathy (Fig. 2), a syndrome that has already been studied in man and dogs [27,37]. New concepts concerning its pathogenesis in man developed from studies of limb blood flow initially performed in affected dogs [37].

Radiological Features
Canine OS shows all the features of a highly aggressive bone lesion with varying admixtures of osteolytic and osteoblastic changes. Purely lytic tumors account for approximately 5 percent of all OS [38]; pathological fractures are most common in this group. Characteristic findings include sunbursting, Codman's triangle, irregular osteolysis, varying degrees of reactive periosteal new bone formation, and origin at a metaphyseal site. All of these findings are not always present in any given case [27,28] (Figs. 3 and 4).
Pulmonary metastases (Fig. 5) are seen in less than 10 percent of dogs at the time of initial radiographic examination [25], but are extremely common at a median time of 18 weeks after limb amputation [39].

Histopathologic Features
Canine OS is identical to its human counterpart. The characteristic finding is the direct formation of osteoid by the sarcoma cells (Fig. 6). Many canine OS also produce varying amounts of chondroid and collagen, so that a mixed type of sarcoma is present [27,28].

CONTRIBUTING FACTORS

Medullary Infarcts These infarcts were first described in 1972 in four dogs, all of whom had superimposed sarcomas [40]. Since then, six more cases have been detected by the same authors. Nine of the 10 neoplasms were OS, and one was a fibrosarcoma. Most of the tumors arose in the tibia and femur. Most dogs were of the smaller breeds, and 4 of the 10 were Miniature Schnauzers, a breed rarely affected with OS. The cause of the infarcts is not yet known, but intramedullary occlusive vascular disease appears to play a role. Most dogs had multiple bony infarcts but only one site of sarcoma formation. One dog presented with two primary OS. Similar cases have also been reported in man [41]. We suspect that the stress of repair in the infarcted areas leads to a greatly increased risk of OS.

Metallic Bone Implants
Since the first canine OS associated with metallic bone implants was observed in 1959 [24], an additional 11 case reports have been published [42-44]. Corrosion products from these implants are suspected to have a carcinogenic potential. A review of the case histories of the 12 reported canine cases revealed the following significant features. The latency periods between the introduction of the metallic implant and the development of the OS ranged from 1-11 years with a median time of four years. Eight of the 12 tumors arose in the midshaft of a long bone, most often the femur (in OS unassociated with metallic implants, the metaphysis is a far more common site than the diaphysis). The types of implants used were as follows: Jonas splint-5; Jonas splint plus Steinman pin-1; bone plate-3; Steinman pin-2; and Steinman pin plus cerclage wire-1. The Jonas splint, a self-retaining intramedullary splint consists of three components. Metallurgical studies have indicated that each component has a different composition and characteristics. These dissimilar metals in contact with each other caused an electrolytic reaction that accelerated the corrosion of the more ionic metals and increased the dispersion of metallic products into the tissues. Chronic inflammation and drainage often developed after the insertion of this device.

In the past few years, six additional sarcomas (five osteosarcomas and one fibrosarcoma) have been observed in association with metallic implants at the UPVH [45]. Undoubtedly the number of implant-associated OS actually observed in dogs greatly exceeds that which is recorded in the literature. The canine findings strongly suggest that sarcomas in man are also associated with such devices far more often than the three case reports in the present literature [46-48] would indicate.

Trauma
Four or five OS arising at the site of a pre-existing healed fracture have been observed but such occurrences are exceedingly rare [26,35]. Immediate trauma seems to have no relationship whatsoever to OS induction in dogs. Indeed, fractures are exceedingly common in dogs, primarily because of automobile injuries, whereas OS following such injuries (excluding metallic implant fixation) is very rare. While a single traumatic incident plays no known role in the development of canine OS, small oft-repeated traumas associated with weight bearing may be of some importance. The large and particularly giant breed dogs bear more weight on their forelimbs than on their hindlimbs, and correspondingly develop considerably more OS on their forelimbs. Weight bearing and biomechanical balance are presently being studied by the author in 1,400 dogs with OS.

THERAPY

Surgical Therapy Surgical excision of OS in 65 dogs (limb amputation in 62 and rib removal in 3) resulted in a median survival of 18 weeks. When this was combined with a preoperative median duration of clinical signs of six weeks, the total median duration of disease was 24 weeks. The survival times ranged from three to greater than 578 weeks. Only 13.8 percent lived more than 9 months after surgery, and 11 percent survived for one year. Two dogs were alive and free of disease more than two years postoperatively, and four other dogs died of causes unrelated to osteosarcoma. No correlation could be found between postsurgical survival time and the duration of presurgical signs, the age, sex, or breed of the dog, the site of the tumor [39]; or the radiographic features [38]. Histologic features of OS do not correlate with biological behavior except in a few OS where the tumor is predominantly fibroblastic [49].
 Recently a few dogs have been treated by segmental resection of an affected ulna or fibula followed by chemotherapy [50].
Because many dogs with OS are euthanatized rather than dying a natural death, there is some variability in the survival results obtained, e.g., some owners may have their pets destroyed as soon as radiographic evidence of lung metastasis is detected, whereas others may wait until terminal signs of disease become evident. For this reason, the first detection of metastatic disease radiographically is a more objective and sensitive indicator of treatment failures. The median interval between amputation and the onset of radiographically visible metastatic lung disease was 73 days (range, 50-160 days) in nine dogs treated by amputation and doxorubicin [51].

Immunological Monitoring
Cell-mediated reactivity (CMR) and serum blocking activity (SBA) were assessed sequentially in 11 dogs treated surgically for OS. Six dogs received postoperative BCG and five served as controls. SBA decreased significantly soon after surgery in both groups. No consistent relationship between CMR and SBA and clinical356 ROBERT S. BRODEY metastasis was detected in the postsurgical period in either group [52,53]. Presently our sequential immunologic monitoring studies include lymphocyte transformation with various mitogens, leukocyte migration inhibition, and determinations of effector T lymphocytes by the rosette technique both preoperatively and during adjuvant therapy. Immunological studies of canine OS are still in their infancy.

Immunotherapy
Very little work has been done in dogs with OS. Six dogs given freeze-dried BCG (Glaxo strain, 50-250 x 106 viable organisms) intravenously 1, 2, 4, and 8 weeks after amputation had a median survival of 52 weeks (range 16-65 weeks) as compared to a mean survival of 11 weeks (range 6-17 weeks) for five control dogs [54].
Another group of six dogs was treated postsurgically with intradermal BCG (Trudeau strain, 1.5 x 107 viable organisms) at two-week intervals for one year. Their median survival was 40 weeks as contrasted to five controls having a median survival of 13 weeks [53]. However, when the results of the two studies were combined, there was a statistically significant difference in survival times (p<0.01) even though the strain of BCG and route of administration were different. More recently I.V. administration of Glaxo BCG given to 20 dogs following amputation for OS was associated with a mean survival time of 25 weeks. Seven of these dogs were alive one year later [55]. Although these early results appeared encouraging, a recent controlled study of dogs with OS indicated that survival times in 11 amputated dogs were similar to that of 12 dogs that were amputated and given postoperative BCG and autologous tumor homogenate [56].

Chemotherapy
The small numbers of dogs treated by chemotherapy that have been reported and the variation in treatment plans makes detailed assessment of the results rather difficult at present. In 1964, 17 dogs with malignancies of bone, most of which were OS, were treated with triethylene glycol diglycidyl ether. The drug was given intraarterially to five dogs, by regional perfusion to five dogs, and using a technique to occlude the aorta and limit the drug to the cranial half of the body, it was administered to three others. Regression of the neoplasms occurred in 12 dogs but was maintained for two months or more in only five of these. The longest period of regression was five months. Following perfusion there was local relief of pain, but edema often developed and in four dogs gangrene was observed [57].
In 1978, 14 dogs treated by amputation and doxorubicin (30 mg/iM2 of body surface area) were reported. Doxorubicin therapy was initiated three weeks after surgery, and was given intravenously every three weeks for 24 weeks. Drug therapy was discontinued if pulmonary metastases were detected radiographically. The median survival was 15 weeks (range 52-368 days) and 14 percent survived more than one year [51]. These findings were almost identical to that following amputation alone in 65 dogs [39].
At present, several chemotherapy or chemotherapy-immunotherapy protocols are being evaluated, but the studies have yet to be completed.
A major problem in canine therapy trials involves the cost to the owner. Hopefully,
a greater appreciation of the value of these naturally occurring animal models will make money available to help owners defray some of the costs for multimodality therapy.

Radiation Therapy
Prophylactic lung irradiation using 600 R on two occasions at a one-week interval was found to be of no value in dogs with OS [58]. Seventeen dogs had their affected limbs treated with fractionated doses of 4,000-4,500 R of X-irradiation from a 15 MeV linear accelerator giving 120-130 rads/minute with 100 percent penetration at 3 cm in tissue. Doses of 1,000 R were given at weekly intervals. Reduction in pain was remarkable but mean pain-free survival was only four months with a range of 1-12 months [59].

Combined Modality Approach
Many exciting possibilities exist for future studies. If it can be shown that microand macrometastatic disease can be successfully treated medically, then trials concentrating on limb-saving technics can begin. Combinations of irradiation with hyperthermia and radiation sensitizers may be of considerable value in treating the primary tumor with or without segmental resections. Carefully designed multimodality clinical trials in dogs with OS should generate valuable biological data in a much shorter time than is possible in man.

PROGNOSTIC VARIABLES
A recent necropsy study of 144 untreated dogs with OS indicated that 49 had metastases, 44 of which involved the lungs [60]. Histologic subtype (excluding the fibrosarcomatous type) and grade, mitotic index, amount of intercellular substance, numbers of peritumorous lymphoid and plasma cells, duration of clinical signs., breed, sex, and age of the dogs were not of prognostic significance. The occurrence of pulmonary metastases was closely correlated with tumor diameter and volume as well as with extension of the OS into adjacent soft tissues and the origin of the OS in bones of the hindlimbs. Future design of prospective randomized clinical trials in dogs should take these prognostic variables into account so that patient groups are biologically balanced to ensure more accurate evaluation of the results.

ADVANTAGES OF STUDYING NATURALLY OCCURRING CANINE OS

1. OS is much more common in dogs than in man. It is a striking disease clinically and usually is easily recognized in the field. Centers carrying out therapeutic trials or other studies have not had difficulty attracting cases from local veterinarians. At the UPVH we have seen approximately 50 dogs with OS during the past year alone. This great increase in case load has primarily been due to the combined surgical, chemoand immunotherapy trial now under way.

2. There is a tremendous similarity in the clinical, radiological, and histological features of OS in dogs and man (Table 1), making an affected dog of tremendous value for a variety of etiological, epidemiological, immunobiological, and therapeutic studies.

3. As both dog and man often share a common environment, similar causative factors may be operative in both species. Dogs with OS and other neoplasms may be important environmental monitors for such diseases in man. Future epidemiological research should correlate human OS incidence data with that in other species in given geographic areas.

4. The large size of the canine patients makes them ideal for obtaining adequate samples of blood, tumor tissue, etc.-a problem that is often of major importance in laboratory rodents.

5. Veterinary oncology expertise has risen sharply in the last decade. An increasing number of veterinary schools and other institutions have oncology sections and many of these are carrying out various therapy protocols. Since most of these protocols are on an outpatient basis, the research costs are greatly reduced.

6. Recent pedigree studies indicate we now have the necessary genetic knowledge to develop strains of dogs with heightened susceptibility to OS. Such strains would be invaluable, particularly in studying etiological factors and host-tumor interactions in the early stages of the disease.

7. Many owners of dogs with OS would be very grateful to know that treatment or other related investigations in their pets might also help humans with OS. Because cancer will afflict one of every four persons in the U.S., it is reassuring to such owners to know that therapeutic research in their pet may someday help them or their families.

8. Rat and mouse bone is non-osteonal, i.e. lacks Haversian canals, unlike bone in rabbits, all domestic mammals, and man [61]. Thus the development of OS in species having osteonal bone most closely approximates OS in man.

DISADVANTAGES
1. The large size of affected dogs (95 percent weigh more than 30 lb) means that housing them will often demand larger kennel areas and increased feeding costs. Similarly, drug costs will be greater because of the large size of many of the patients when compared to laboratory rodents. However, most of these objections can be circumvented by relying primarily on outpatient studies.

2. Beautifully controlled studies such as those in experimental murine hosts are not as likely in canine OS because of the variability of owner responses to the stress of treatment. Similar problems are encountered with human patients and their families.

OTHER NATURALLY OCCURRING OS
Dogs and humans are the two mammalian species most commonly affected. Domestic cats are the third most common species to develop OS. The most common sites in cats appear to be the humerus, femur, tibia, and skull [62]. Flat bones are involved as commonly as long bones, and the hindlimbs are involved more often than the forelimbs [35]. It has been suggested that feline OS has a lower metastatic potential than in man or dog [51], but more cases must be studied before this can be documented. Many of the clinical, radiological, and pathological features of feline OS closely approximate those of OS in man and dog. The major difference is that OS in cats occurs primarily in older animals [62]. Almost no information relevant to therapy has been published. Three cats with limb OS were treated by amputation and postoperative doxorubicin. One was euthanatized 180 days after surgery because of unrelated disease, another at 143 days because of lung metastases. A third cat was alive 436 days postoperatively despite the presence of lung metastasis [51].
Osteosarcoma developed in the thoracic vertebrae of three piglets and in the lumbar vertebrae of another piglet in England. Ages of affected animals were 4, 5, 9, and 11 weeks. Two of the piglets originated from the same farm. In India OS of the ribs was diagnosed in two pigs that were nine months old [63]. More careful studies of young pigs may reveal that OS is more common than is presently realized. Interestingly the age incidence of pigs with OS closely approximates that of humans with OS.
In sheep OS is rare, although chondrosarcoma arising from the rib cage has been reported in a number of instances [64]. The ultrastructure of an OS obtained from the pelvic region of an adult ewe was studied. The pattern of distribution of the organized interchromatin-like granules in almost every tumor cell nucleus was similar to that observed in human rhabdomyosarcoma where a viral origin is suspected [65].
In all other domestic mammals OS is exceedingly rare; however, OS has been reported in a few other subhuman primates, e.g., an adult male squirrel monkey had an OS of the proximal humerus. It was reported to be clinically well 20 months after amputation. A 10-month-old lemur developed an OS in the carpal region. No metastases were detected at post mortem [66].

CONCLUSION
This review of naturally occurring canine OS (it also occurs in cats, swine, etc.) and artificially induced OS in rabbits, rodents, swine, and dogs indicates that a wealth of biological data already exists on this deadly disease. It is the responsibility of all of us interested in the biology and treatment of cancer to glean as much knowledge as possible from these mammalian systems, each of which offers many clues. Such a broad-based knowledge will undoubtedly influence our conceptual approach to research, and clinical options. To concentrate solely on OS in humans and rodents greatly limits these options, for as Robert Burns so clearly stated, "the best laid schemes of mice and men gang aft a-gley."

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