Canine Osteosarcoma:A clinico-pathologic study of 194 case

Philip Johnson, Dr. C. Runyont, Dr. R. L. Grier

Iowa State University Veterinarian: Vol. 43: Iss. 1, Article 4.

Osteosarcoma, the major form of bone cancer in dogs, is reviewed. Incidence rates relative to breed, age, and sex characteristics are outlined. Prediliction sites are also stated. The clinical, radiographic, and metastatic characteristics of osteosarcoma are explained.

Theories on etiology including work by Brodey, Wolke and Nielson are discussed.
Alternate treatment regiments are examined, including an indepth look at a case at the Iowa State University Clinic which was treated using a combination ofostectomy and allograft, local hyperthermia, bleomycin, and

A Review of Osteosarcoma
Osteosarcoma is the major form of bone cancer seen in the dog. 6,10,16,22,30 One study showed that 85% of the primary bone tumors seen in dogs. were osteosarcoma, while chondrosarcomas, the second most common
primary bone tumor, occurred only 10% of the time. 6 Canine osteosarcoma is nearly always malignant, as compared to a 50% malignancy rate in cats and a generally benign situation in cattle and in horses.

22 Several surveys have shown that large and giant breeds have a much higher incidence of osteosarcoma and are at a significantly greater risk of devleoping osteosarcoma than smaller breeds. 5 ,6,10,19,29,30 Among giant dogs
the risk of bone sarcoma is estimated to be 5 to 30 times the risk of any other cancer. The excess risk of bone sarcoma appears to be characteristic of large breeds as a group and not ofone or several particular breeds. 29

                           The incidence of osteosarcoma increases in middle aged and older dogs. 6,7,10,19 Giant dogs with osteosarcoma seem to be slightly younger at the time of disease development than those in other weight groups.19 The average age in a survey of 194 osteosarcoma cases was 7.7 years6, while in another survey of65 cases the median age was 6.0 years. 5

Most surveys ofosteosarcoma indicate that the incidence is higher in males than females 5 ,6,19 but at least one survey failed to note a difference in incidence rate between the sexes. 10 The surveys stating a higher male
to female ratio varied slightly in their numbers with ratios of 1.2:1.06,3.0:2.0 5 , and 1.7: 1.019 being reported.

                         Most cases of osteosarcoma occur in the appendicular skeleton, primarily in the long bones. 6,7,16,17,30 There was a higher incidence in the pectoral limbs than in the pelvic limbs. 6,30 A study of Wolke and Nielson showed 47% of the total cases of osteosarcoma occurring in the pectoral limbs, while 29% of the cases occurred in the pelvic limb. This figures out to a 1.6: 1.0 ratio, corresponding to the ratio of weight distribution between front and rear legs. 3o

Six sites in the long bones have the highest incidence of osteosarcoma development.

These sites are the proximal humerus, distal radius, proximal and distal femur, and proximal and distal tib~a.6,7,I6,I7,30 In the Wolke and Nielson survey, the distal metaphysis of the radius was the most common site, with
23% of the total cases. The proximal metaphysis of the humerus was second in incidence, with 19% ofthe cases. 30

                           In some circumstances osteosarcoma may originate in tissues other than bone. It has been reported in the esophagus of a dog, adjacent to a chronic lesion produced by the spirurid worm, Spirocerca lupi. A second
extra-osseous site is in a mixed tumor of the mammary gland. 26

One of the first clinical signs of osteosarcoma in the metaphyseal region of a long bqne is lameness. One to two weeks later there is generally a cool, palpable swelling in the~ area of the lesion. Eventually there is a visible
enlargement at the site of the lesion that iswarm and painful due to stretching of the periosteum. 22

                         Radiographically, this tumor is usually found at the extremity of a long bone and produces a radiolucent enlargement arising in the metaphysis which erodes the pre-existing calcified bone ofthe cortex. 26 The destructive
process may be restricted to the medulla, but usually involves the cortex as well, by the time the tumor is manifested clinically. 27

In addition to cortical destruction, another type of radiographic change that occurs with osteosarcoma is periosteal response. The degree ofperiosteal reaction does not depend on the degree of cortical destruction. I7 This periosteal response can lead to a large soft tissue mass contiguous to the bone. This soft tissue swelling around the osteo-sarcoma lesion is also related to reactive fibroplasia in the subcutaneous and intramuscular tissues, which leads to impaired circulation and edema. 27

All osteosarcomas are collagenoblastic tumors in which the collagen fibers are organized into varying amounts of osteoid, bone, and cartilage. 22 Depending on which of these components is dominant, three major subtypes are recognized: osteoblastic, fibroblastic, and chondroblastic. 12

The critical, identifying characteristic of cells of osteosarcQma is their ability to produce ostedid. 26 Osteoid is the collagenous matrix of bone, the primary product of the metabolic activity of osteoblasts, which Issue No.1, 1981
possesses the specific bOinding sites of bone mineral. 11

In primary bone neoplasms, when the neoplastic bone cells have retained the ability to produce osteoid, it is laid down in grossly anomalous patterns. Mineralization takes place as long as there is blood supply and the retention ·of the basic molecular characteristics ofnew collagen. A characteristic feature of neoplastic bone is the inconsistency or
nonuniformiiy of the osteoid, reflecting the degree of undifferentiation of the cells that form it II

As the tumor grows by this process of laying down osteoid, bone, and/or cartilage, the periosteum in tne area of tumor growth can be elevated. This elevation causes a triangle to be formed where it joins normal cortex, known as Codman's triangle. 17 This is another distinctive radiographic feature of osteosarcoma and is a valuable aid to

Osteosarcoma does not often invade adjacent bone (i.e. in distal end ofradius or tibia), but this has been reported. 23 More often, the adjacent bones may show radiographic evidence ofperiosteal reaction to the tumor. 17 This reaction causes new bone to be laid down and gives the bone a rough appearance, suggesting involvement with the tumor.
                                            The metastatic route of osteosarcoma is typically hematogenous. 21 ,23 The lungs are
the'most common site of metastasis. 6,17,23,27 Other sites of metastases are the liver, kidneys, amputation stump6 and, on rare occasion, to adjacent bones.

Neoplastic cells may embolize from the site of origin without unusual trauma. Manipulative trauma definitely increases the number of cancer cells in circulating blood. Both surgical and non-surgical trauma probably play a role in disseminating these cells into the circulating blood. It has been suggested that biopsy of malignant tumors of the
extemities should be performed under tourniquet whenever possible, and when indicated, definitive, ablative opertions should be carried out without releasing the tourniquet. 21

The etiology of osteosarcoma is unknown, but there have been several theories put forward, all supported by at least some clinical evidence. Brodey advances the theory that the occurance of osteosarcoma can be correlated with the high growth potentials of various metaphyses of bones. 6 For example, the distal radius has a much higher growth potential than the proximal radius and also has the higher incidence of osteosarcoma of the two. A similar situation exists with the proximal humerus, which exceeds both the growth potential and osteosarcoma incidence of the
distal humerus. Brodey continues with the correlation by showing that the proximal and distal femur and the proximal and distal tibia have nearly equal growth potentials and a nearly equal incidence ofosteosarcoma.

                                   Brodey hypothesizes this rapid, maximal growth at the metaphysis in giant breed dogs
leaves behind small foci of retained hyaline cartilage. These foci have not been seen in smaller dogs. These foci may serve as sites of origin for later tumor growth. 6

Wolke and Nielson consider other factors to be involved in the etiology. They suggest that weight bearing stresses on the metaphysis of the long bones lead to the development of osteosarcoma. They suggest that the relativly higher incidence in the pectoral limbs versus the pelvic limbs is directly proportional to the relative weight distribution between the front and back legs. They also site the increased incidence in heavier dogs as further proof of their weight-bearing stress theory.30 Another study basically agrees with this theory, stating that repeated trauma to the growth plates in young giant breed dogs (caused by weight bearing stresses), may partly be responsible for the development ofosteosarcomas at these sites in later life. 14

Another theory concerns the relationship of healed fractures to the development of osteosarcoma. Bennett, Campbell and Brown suggest that cartilage cells produced during the healing of a fracture may persist long
after the fracture is healed, potentially forming a focus for neoplastic development. 4 This is similar to the Brodey theory of retained hyaline cartilage cells providing the foci for tumor growth, differing only in the origin of
the cartilaginous cells.

There have been reports of dogs and cats that have developed tumors after metallic surgical implants were used to treat bone fractures. 2 ,25 Implanted metals may form corrosive products such as metallic salts or fine particles. The animal's response to metallic implants can vary from inflammation to allergic reaction to tumorogenesis. 14 A study
of S clinical cases strongly supported this theory. AIlS cases ofosteosarcoma arose midshaft of a long bone, a very atypical location, and were in close proximity to a corroded metallic implant. 25 Obviously, not every dog that develops osteosarcoma has had a fractured bone and/or a metallic implant, so these last two theories are not the definitive answer to the etiology of osteosarcoma, but they may eventually help to find that answer.

Successful treatment of osteosarcoma has advanced about as much as the search for its cause. Amputation, irradiation therapy, chemotherapy, immunotherapy and a combination of these and other modalities have been attempted with little success thus far. 5, 15 It is felt that early diagnosis is the key to the success of any attempted therapeutic regime. 17 Unfortunately this presents a very early stumbling block in the battle against the disease. By the nature of the disease, the tumor may already be metastasized before it is clinically recognized. In addition, clinical
recognition is often slow due to such things as blaming early lameness on other minor traumatic episodes, radiographs not being taken or poorly interpreted, or possibly even an inadequate biopsy being taken, missing the
diagnostic area ofthe lesion. 17

To overcome these problems of diagnosis, all dogs with lamenesses- involving high incidence sites, particularly in large or giant breeds greater than two years old, should be thoroughly examined. Radiographs should be taken of the leg and carefully evaluated. If a biopsy is to be performed, it should be done with the aid of two radiographic views of the suspected area. Broad areas of dense bone should be avoided and a punch biopsy or a 2- 3mm slice oftissue should be taken. The cortex should be completely penetrated and the medullary cavity entered.Post-operative radiographs should be taken to evaluate the success ofthe procedure. 17

The thorax should also be radiographed when a malignant bone tumor is suspected. If metastasis to the lungs has already occurred, amputation is merely palliative and probably should not not be done. Radiotherapy can be
used in these cases to ease pain and to slow tumor growth. 5 Radiotherapy has been shown to be of little benefit in other phases of osteosarcoma treatment. It has failed to resolve the primary tumor, to prevent pulmonary metastasis and has undesirable side effects on normal tisuses. Radiotherapy may have also caused an increase incidence of

side effects from cytotoxic drugs in combination therapy. 15

Amputation of the diseased limb has been the treatment of choice for several years, but even with amputation the survival rate is poor. Brodey points out that there is no baseline data for long-term survival of dogs with osteosarcoma that were not treated. There are known cases where dogs with osteosarcoma did survive without treatment, and it is therefore concluded that not all longtime survival can be credited to the treatment under consideration, as some of those dogs may have lived anyway. 5

Chemotherapy and immunostimulants have been recent developments in the fight against osteosarcoma. Methotrexate, vincristine sulfate, doxorubicin, cyclophosphamide, and bleomycin are some ofthe many different
chemotherapeutic agents that have been or are being tested. Thus far there is insufficient data to determine if these drugs will be useful or not.

The same observation is true for immunomodulators such as BCG (bacillus Calmette-Guerin) vaccine and levamisole.
There is some evidence that BCG vaccine will help delay metastasis following amputation by activating macrophages non-specifically and causing them to recognize and destroy malignant cells. 15 . 2o However, it has also been
demonstrated that BCG vaccine treatment, at best, only delays and does not cure osteosarcoma. More specific immunotherapy needs to be developed.

Thus, even with therapy, the prognosis for a dog with osteosarcoma is very poor. In one study of 194 cases of osteosarcoma 85 % were dead by 8 months, and ofthe other 15 %, only one dog was considered cured. 6 In another
survey of 65 cases the results were similar, with only 10.7% of the cases surviving one year past the time ofdiagnosis. 5 There is some hope that combination therapy and earlier diagnosis will help to improve these figures.

Case Report-No. 582704- An Experimental Treatment Regime
On June 24, 1980 a 7 year old, 80 pound, mixed (Collie-Shepherd) spayed female dog was presented to the Iowa State University Small Animal Hospital with a history of lameness in the left front leg oftwo days duration. The dog had been in a kennel for 10 days and had not been lame prior to boarding. At the time of admission there was
palpable swelling of the distal left radius. Radiographs strongly suggested a primary bone tumor such as osteosarcoma. At this time the lungs showed no evidence of metastasis.

A bone biopsy was taken and frozen sections indicated osteogenic sarcoma. Paraffin sections confirmed this diagnosis. The owner emphasized that he did not want the left forelimb amputated and it was decided that
the dog would be released to return to the clinic once a treatment protocol was developed.

The dog returned to the clinic on July 14, 1980 and the left radius was again radiographed. It was originally hoped to
debulk the tumor since at the time of first presentation it had not invaded the opposite cortex. However, the second set of radiographs revealed rapid progression of the osteosarcoma in the radius and marked involvement of the opposite cortex. There was still no evidence of pulmonary metastasis. The soft tissue swelling was not very extensive.
Clinical pathology showed an elevated alkaline phosphatase of 105.9 lUll (normal 10-80 lUll) which suggested bone cell activity probably related to the osteogenic sarcoma.

Figure 1: Lateral and dorso-ventral radiographs of the left frontleg on July 14, 1980

The protocol for treatment was agreed upon (Table 1). The regimen called for local excision of the tumor, bleomycin chemotherapy, levamisole immunomodulation and local hyperthermia.

The distal one third to one half of the radius, including the distal epiphysis and articular surface, were removed. Frozen section histopathology revealed that the proximal end of the excised bone segment was free of the tumor. Two screws were placed through the proximal radius into the ulna to temporarily stabilize the elbow joint. Two
Hemovac tubes were inserted in the incision site for local hyperthermia treatment. The perforated portion ofeach tube was placed in the defect where the distal radius had previously been. The rationale for adjunctive local hyperthermia was the possibility of tumor extension into soft tissues and proximal to the excised portion of the bone as well as the fragmentation of the neoplasm that occurred at the time ofexcision.

The dog was given one half bolus, 92mg or approximately 2.71 mg/kg, oflevamisole 3 hours prior to surgery. Hyperthermia by hydrothermic perfusion followed closure of the wound, synchronized with 10 units of intravenous bleomycin. The log for the hyperthermia treatment can be found in Table 2. In the course of the procedure the thermometer was postitioned too close to the skin on the far side of the leg. The tissue temperature was thought to be too low during the first part of the procedure, when actually it was probably too high. Consequently the
tissue readings were in error and the possibility ofthermal burn to the leg was high.

A lymphocyte transformation test was run upon admission to the hospital on July 14, 1980. This test was used to measure the immune status of the dog, and it indicated she was immunosuppressed. (Table 4) This result
was not surprising due to the presence of a well established neoplastic condition. The dog was sent home 3 days postoperatively with a surprisingly small area of thermal burn.

The dog was re-admitted one week postoperatively for the second phase oftreatment. The proximal incision was draining at this time, and Pseudomonas was cultured from the wound. The dog was put on Tribrissena therapy for 5 days. The lymphocyte transformation test showed improvement of the immune status. (Table 4) The dog was then
given her second hyperthermia treatment in synchrony with 10 units of intravenous bleomycin. At the end of the procedure the tubes were removed. The log for the second hyperthermia treatment can be found on Table 3. The area of the thermal burn on the proximal part of the leg was extensive after the second hyperthermia treatment. The
burn was treated topically with sulfamylon and bandages. The dog was sent home for the weekend two days post-operatively.

The dog was re-admitted the following Monday, July 28, 1980. The left leg was radiographed and the ulna had fractured at the distal screw due to excessive activity while home. Bleomycin and levamisole treatments were continued as called for by the protocol. The wound cultured negative for Pseudomonas on two cultures, two days apart, so systemic antibiotics were discontinued and the burn was treated topically. The lymphocyte transformation test showed some deterioration in the immune status ofthe dog. A urinalysis and CBC were normal and the alkaline phosphatase level was still elevated with a 207 lUll. The dog was again sent home with the leg encased in a Robert-Jones dressing for protection and support.

Figure 2: Lateral and dorso-ventral radiographs of left front leg on July 28, 1980. Note fractured ulna

On August 1, 1980 a whole cortical bone allograft from a St. Bernard cross donor dog was used to replace the distal one third to one half of the radius. The radiocarpal joint was arthrodesed and- both ends of the graft were
stabilized with Dynamic Compression Plates. A cancellous bone graft from the greater tubercle of the humerus was packed at the ends and around the allograph. The alignment was considered excellent on postoperative radiographs. The thermal burns on the lateral side of the leg were debrided and sutured as much as possible.

Figure 3: Two lateral radiographs of left front leg on August 1,1980 after allograph.

The dog was placed on Ecotrinb for a few days post-operatively to decrease discomfort.

On August 4, 1980 the wound again cultured positive for Pseudomonas with only a slight sensitivity to gentocin. Beginning August 5, 1980 the dog was treated daily on an out· patient basis. By August 12, 1980 the wound over the proximal entry site of the infusion tube was starting to granulate in and the dog was showing steady improvement.
Lymphocyte transformation tests continued to demonstrate immunosuppression. (Table 4) The bleomycin and levamisole therapy was continued as ordered in the protocol.

The lymphocyte transformation test of August 26, 1980 revealed the continued immunosuppression. (Table 4) The dog is bearing nearly full weight on the leg and the wounds have nearly closed, but due to licking by the dog, constant bandaging and continued Pseudomonas infection, the healing process is slower than normal.

The lymphocyte transformation test was repeated on September29, 1980 and again on November 18, 1980. These tests continued to show immunosuppression. (Table 4)

The most recent radiographs show the ulna fracture to be healed and the allograft in proper position and apparently becoming incorporated into the bone as of December 5, 1980. There is no evidence of recurrence of osteosarcoma at the primary, distal radial site and the lungs continue to be free ofmetastasis and fibrosis.

The approach to treatment of this case of osteosarcoma in a dog was an experimental one. Part of the reason for this approach was the need to select a route of therapy designed to preserve the limb, as the owner did not wish the leg to be amputated. Another reason was Drs. Grier's and Runyon's desire to evaluate combination therapy with limb
preservation in mind, as described in recent literature. 28

The particular combination ofbleomycin, local hyperthermia and levamisole was derived with certain advantages in mind and hopefully, a minimal number of disadvantages.

The principle reason bleomycin was selected as the chemotherapeutic agent was its synergistic effect with local hyperthermia. 18 Also, in mice this drug has been found to concentrate in the lungs, along with skin, kidneys, peritoneum and lymphatics. I Since metastasis to the lungs is a major concern with osteosarcoma, it was hoped to use this to an advantage. The major disadvantages of bleomycin were cost, at $157.00 per 15 units, and the possible side effect of pulmonary fibrosis. Thus far pulmonary fibrosis has not been detected on radiographs ofthis dog.

                                Local hyperthermia was advantageous in several ways. As noted previously, bleomycin is markedly potentiated when administered simultaneously with hyperthermia, suggesting a true interaction. Results of simultaneous combination therapy in mice were better than either bleomycin or hyperthermia alone or when given 24 hours apart. The main disadvantage is that bleomycin is enhanced significantly only near 43° C, which is near
the top ofthe therapeutic range and leads to a greater hazard ofpossible toxicity. 18

Another advantage of hyperthermia is that it has been shown to increase the immunogenicity ofsome tumor cells, perhaps by" unburying some of the cell surface antigens from surrounding lipids. 24

It also seems relevant that, as compared to surgical removal (which eliminates potential antigens); and radiotherapy, chemotherapy, and whole body hyperthermia (which suppresses antibody formation), local hyperthermia may cause a slow release of antigens with no inhibition, and possibly even an increase, in antibody formation. 24

                                   Problems possible with local hyperthermia are cardiac arrhythmias, hepatic and renal dysfunction, low grade fever due to necrosis, and cutaneous burns. 24

Levamisole was used in this case in an attempt to help restore the immune responses of a predictably immuno-suppressed dog. Though the mechanism ofaction is unknown, it is well understood that the best results are
obtained in immunodeficient patients. The drug modulates immune function at 2 to 3 mg/kg of body weight. At higher doses, it may actually suppress immune function. 8

Though the mechanism of action is unknown, levamisole in vitro and levamisole therapy in vivo correct defective motility in phagocytic cells. The drug also stimulates phagocytosis in cultured monocytes. 8

Some immunodeficient patients do not improve with levamisole treatment. It may be due to the inability of the individual tp produce levamisole-induced serum factor needed to increase lymphocyte funciton. 8 If the lymphocyte transformation test is accurate in its assessment of the animal's immune status, then the results of the levamisole therapy to date is discouraging, as the dog continues to be immunosuppressed.

The reliability ofthe lymphocyte transformation test is a controversial matter. Some feel it is a good prognostic test, while others do not. 9 The work on this project has assumed the test to be reliable and will continue to do so. There are very few good ways to assess immunostatus in such a quantified manner as with this test.

To close this report no definite conclusions can be drawn from this one clinical, experimental case that has yet to run its complete course. Additional cases treated using this therapeutic protocol, each individual drug and other drugs as well as controls, are Issue No.1, 1981 needed to factually evaluate the results. This will take a great deal of time, energy and money and will require cooperation among many researchers involved in cancer work.

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