Palliative Radiation Therapy in the Treatment of Canine Appendicular Synovial Sarcoma

Introduction

A 5 yr old female spayed pointer dog presented for routine examination. The patient was acquired by the owner in the Phoenix, AZ area, was clinically normal, and was used for hunting. A small, undifferentiated soft tissue sarcoma was removed from the left ventral thoracic wall approximately 1 yr before initial examination. At examination, the patient had multiple, small, red raised nodules on her ventral abdomen, most consistent with low grade, solar induced, dermal hemangiomas and/or hemangiosarcomas. The owners reported that similar lesions were treated successfully with surgical excision or cryotherapy in the past.

Case Report

Physical examination revealed an approximately 2 cm diameter, well-defined, fluctuant, mass-like swelling on the lateral aspect of the left elbow, adjacent to the capitulum of the humeral condyle. The patient was not exhibiting signs of lameness. On radiographs of the left elbow, a soft tissue swelling was identified on the lateral aspect of the elbow with no underlying bony abnormalities. Gross examination of fluid aspirated from the fluctuant swelling was considered consistent with synovial fluid; however, it was not submitted for analysis. Differential diagnoses included synovial cyst, synovial hernia, and trauma-induced seroma. Neoplasia and infectious fungal disease were considered less likely given the patient's lack of lameness.

Three months after initial presentation, the patient exhibited a Grade 3 of 5 lameness of the left thoracic limb. The previously described, fluctuant, soft tissue swelling remained and was unchanged in size. Radiographic findings in the left elbow were unchanged from the previous examination. Fluid was aspirated from the lesion and was submitted for culture and sensitivity. No organisms were isolated. A complete blood count and chemistry panel were unremarkable, with abnormalities including mild hypoglobulinemia (2.5 g/dL, range, 2.6–4.5 g/dL), mild hypoglycemia (52 mg/dL, range, 60–125 mg/dL), mild alkalosis (28 mEq/L, range, 17–24 mEq/L), and mild leukopenia (4.6 thousands/μL, range, 5.7–16.3 thousands/μL) predominantly due to a lymphopenia (690, range, 1000–4800). Fungal titers for coccidioidomycosis were performed because the dog resided in Arizona. Immuonoglobulin-G and -M antibodies were negative for coccidioidomycosis on immunodiffusion. Differential diagnoses continued to include benign synovial effusion, synovial hernia, trauma, and, less likely, fungal synovitis or neoplasia. The owners were reluctant to pursue further diagnostics, and the patient was discharged to the owners with instructions to administer oral nonsteroidal anti-inflammatory medication^a as needed for pain associated with the left thoracic limb lameness. The patient's degree of lameness remained unchanged and was well controlled with anti-inflammatory medication for an additional 4 mo.

Seven months after initial presentation, the patient's lameness progressed to Grade 4 of 5. The patient was lame at a walk, with the lameness progressing to nearly nonweight bearing after any amount of exercise. Palpation of the left elbow revealed that the previously described fluctuant swelling on the lateral aspect of the left elbow progressed to an irregularly marginated, firm, nonpainful, mass-like thickening involving the soft tissues of the lateral, medial, and cranial aspects of the elbow. The soft tissue thickening extended distally along the cranial margin of the radius. No regional lymphadenopathy was identified. At this time, the owners sought a more aggressive diagnostic plan and authorized additional diagnostic testing, including repeat radiographs of the left elbow, pre- and post-contrast enhanced MRI of the elbow, and repeat analysis of the fluid within the mass.

Diagnostic Imaging and Findings

The patient was anesthetized using propofol induction and maintenance with an admixture of isoflurane and oxygen, and MRI of the left elbow was performed with a 1.0-T magnet^b. T1-weighted, T2-weighted, and proton density weighted images were performed in sagittal, transverse, and dorsal planes. Post-contrast T1-weighted images were acquired after intravenous administration of gadopentate dimeglumine^c at 0.1 mmol/kg. After the MRI examination, left elbow survey radiographs were obtained. Surgical preparation of the left elbow preceded synovial fluid aspiration. The MRI and radiographic images were interpreted by a board-certified radiologist (D.G.).

Survey radiographs demonstrated marked soft tissue swelling circumferentially around the left elbow, being most pronounced adjacent to the capitulum of the humeral condyle. The bony structures of the elbow were radiographically normal. No bone lysis or new bone production was present (Figures 1A, B).

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On MRI T1-weighted images compared with the adjacent normal musculature, there was a well-defined, isointense to mildly hyperintense lobular mass arising from the synovial structures of the left elbow (7.8 cm–height × 3.9 cm–width × 4.8 cm–length). The mass surrounded the medial, lateral, cranial, caudal, and proximal aspects of the left cubital joint and extended through the supratrochlear foramen of the left humerus. The cortical margins of the left humerus, radius, and ulna were within normal limits. On T2 and proton density weighted images, the mass was hyperintense to the adjacent normal musculature. There were multiple foci within the mass that were hypointense on T1-weighted images and markedly hyperintense on the T2-weighted images, confirming these areas as synovial fluid. After contrast administration, the mass surrounding the left elbow exhibited a moderate degree of heterogeneous contrast enhancement identified as mixed increased signal intensity on the post-contrast T1-weighted images (Figure 2). The presence of contrast enhancement indicated an abnormal blood supply to the tissues, and the pattern of contrast enhancement aided in the identification of the extent, borders, and shape of the mass, and provided further evidence of the mass being neoplastic in character.

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Based on the imaging findings of a heterogeneously contrast-enhancing mass involving the left cubital joint that contained areas of synovial fluid, a primary soft tissue neoplasm associated with the synovial structures of the left elbow was considered the primary differential diagnosis, even in the absence of bone lysis. Alternative differentials included fungal granulomatous inflammation and chronic synovitis.

Analysis of the red and opaque fluid aspirated from the mass revealed a 3.2 g/DL protein content, 4+mucin clot, poor viscosity, 135,000 red blood cells/μL, and 13,900 nucleated cells/μL. The synovial fluid consisted of moderate numbers of individual and clumped inflammatory cells composed of nondegenerate neutrophils and mononuclear cells, including histiocytes and small lymphocytes. No infectious agents, cartilage fragments, erythrophagic cells, or neoplastic cells were identified. The interpretation was consistent with mixed neutrophilic and mononuclear cell synovitis with blood. Aerobic culture of the fluid revealed no growth. The patient was referred for a surgical, incisional wedge biopsy of the lesion.

Outcome

Histopathologic evaluation of the mass revealed a Grade III synovial sarcoma. Immunohistochemistry was negative for cytokeratin (an epitheliocyte marker) and revealed only a few positive cells for CD18 (a histiocyte marker), which were likely infiltrating macrophages.^1,2 Given the histopathology findings and immunohistochemical tests demonstrating a lack of significant staining for CD18, a fibrocytic-type synovial cell sarcoma, rather than synovial histiocytic sarcoma, was considered most likely. Differentiating these two tumor types was necessary, as dogs with synovial histiocytic sarcoma have a poorer prognosis, surviving on average only 5.3 mo.² Thoracic radiographs were obtained to evaluate for pulmonary metastasis and an approximately 2 cm, well-defined, soft tissue mass was identified dorsal to the carina. Differentials for the mass included primary pulmonary neoplasia, metastatic neoplasia, and granuloma. Amputation of the left thoracic limb followed by chemotherapy was recommended. However, given the presence of possible pulmonary metastatic disease and the owner's reluctance to amputate the dog's limb, these treatment options were declined. The owners hoped that other treatment modalities might be available to alleviate some of the patient's clinical signs.

Toward that goal, the patient was referred to a board-certified radiation oncologist (P.T.). After discussion pertaining to the use of palliative radiation therapy in the treatment of pain associated with canine appendicular osteosarcoma, the owners elected to pursue palliative radiation therapy.³ The owners were informed that there was little supportive evidence for the efficacy of palliative radiation therapy for synovial cell sarcoma.^4,5 Using a linear accelerator^d, 6 Gy was administered once per week for 4 weeks. Before each dose, anesthesia was induced with propofol and maintained with an admixture of isoflurane and oxygen. Radiotherapy planning was by manual methods, with the size of the treatment field determined through a combination of palpation, manual measurement of tumor size, and correlation of mass size and position with the MRI study. The treatment field extended 3 cm beyond the palpable margins of the tumor. The dose was administered in equally weighted, parallel opposed fields. A 1 cm tissue equivalency bolus was placed along the medial and lateral aspects of the limb during each treatment to allow electronic equilibrium. Short-term effects of radiation included hair loss and mild reddening of the skin within the treatment field. The owners reported almost an immediate response to palliative radiation therapy, with the mass decreasing in size and becoming less firm after the initial dose. The patient's lameness completely resolved after the second treatment. At the completion of therapy, the mass was no longer palpable, and the dog no longer exhibited any signs of lameness, even with strenuous exercise.

A repeat MRI of the left elbow was obtained 60 days after the completion of radiation therapy. The scan sequences obtained were similar to those acquired in the pre-therapy MRI. The MRI demonstrated that the mass surrounding the left elbow was much smaller in size and extent (5.2 cm–height × 2.2 cm–width × 3.3 cm–length), and only a small area of contrast-enhancing tissue remained cranial to the proximal left radius (Figure 3). Noncontrast-enhancing tissue remained present within the supratrochlear foramen of the humerus. The dog demonstrated no left forelimb lameness and no recurrence of the mass on the left elbow.

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Seven months after completion of palliative radiation therapy, the patient developed an acute abdomen. Hemoabdomen and a splenic mass were detected on abdominal ultrasound and an exploratory laparotomy was performed. Histopathology of the splenic mass confirmed hemangiosarcoma. The owners declined thoracic radiographs before surgery and initiation of chemotherapy. The patient underwent full course chemotherapy consisting of 30 mg/m² intravenous doxorubicin administered every 21 days for a total of five doses. The patient was ultimately euthanized 6 mo after splenectomy for recurrence of hemoabdomen and suspected hepatic metastasis identified on abdominal ultrasound. At the time of euthanasia, the patient was 13 mo post-palliative radiation therapy of the left elbow synovial sarcoma. In addition, the left elbow was grossly normal and palpated within normal limits, and the patient exhibited no clinical signs of left thoracic limb lameness.

Discussion

Synovial sarcoma is a rare tumor of dogs, occurring in approximately 14.3–27% of neoplasms involving joints, and has been reported in other species, including humans, cattle, cats, and horses.^1,2,6–8 The mean age of dogs at the time of diagnosis is approximately 8 yr, with males more likely to be affected than females.^1,5,7–10 Large, but not giant, breeds of dogs are primarily affected.^1,5,7,9 Persistent lameness and an initially nonpainful, soft tissue mass near a joint are the two primary presenting clinical signs.^5,7–11 The tumor mass is firm, but may have soft, fluctuant areas.^7,10 There is great variability in the duration of clinical signs.^1,5–7,10 The course of disease may be chronic with acute onset of lameness attributable to growth of the tumor, involvement of the joint structures, or pathologic fracture.⁵ The involvement of synovium in an invasive neoplastic process is debilitating because of the high number of pain fibers present within synovial tissue.¹¹ In addition, the degree of lameness can usually be correlated with the degree of bone involvement seen radiographically.^7,10

The most common sites for canine synovial sarcoma are the stifle and elbow, although involvement of the shoulder, carpus, tarsus, coxofemoral joints, lumbar and cervical vertebrae, tendon sheaths, and phalangeal joints have been reported.^1,5–11 Radiographic findings include a soft tissue opaque mass with relatively discrete margins, closely associated with a major joint of a limb.^6,7,9 In some cases, the soft tissue swelling is associated with an ill-defined, spiculated periosteal reaction that may be the first sign of bony involvement and may precede bone lysis.⁶ Subsequent invasion and destruction of adjacent bone may occur, with the underlying bone remaining normal during early development of the neoplasm.^6,7,9 Invasion of subchondral bone occurs as tumor cells infiltrate the joint capsule insertion line, erode the articular margins, and invade the subchondral bone.^6,7 Neoplastic tissue also gains access to the epiphyseal cancellous bone by entering the bony vascular channels of the epiphyseal vessels.⁷ Therefore, radiographs demonstrating periarticular soft tissue swelling with osteodestruction on both sides of a joint in an older, large breed dog are suggestive of synovial sarcoma, although a soft tissue mass may be the only radiographic abnormality.^6–8,10 Radiographic differential diagnoses may include histiocytic sarcoma, fibrosarcoma, other sarcomas, and villonodular synovitis.^1,2,12

The regional and distant metastatic rate of synovial sarcoma is moderate, reported at approximately 22–31%.^1,9,10 Primary sites for metastasis are regional nodes and lung, and metastasis to the brain has been reported once.^1,5,9,10,11 The patient of this report had a possible pulmonary metastatic lesion; however, this was not histopathologically confirmed.

The recommended treatment of canine synovial sarcoma is amputation. Local excision is not recommended because of the high probability of tumor recurrence.^1,5,8 Some dogs may remain free of tumor after amputation dependent on the grade of the tumor.^7,8 Adjunctive chemotherapy utilizing a combination of doxorubicin and cyclophosphamide is recommended post-amputation for dogs diagnosed with Grade III tumors.¹ The survival time for dogs with synovial sarcoma is quite variable and may be related to the patient's degree of lameness, local tumor burden, presence of bone lysis, presence of metastatic disease at the time of diagnosis, and choice of treatment.¹¹ Early diagnosis is encouraged and may improve survival time in dogs with synovial sarcoma.⁵ However, early diagnosis can be challenging because of the often protracted clinical course of the disease, variable time to metastasis, and the possibility of metastatic lesions being present at the time of initial examination.^1,5,7,10,11 Histologic grade has been reported to have a significant influence on disease-free interval and survival time, and three histologic criteria, including mitotic rate, percentage of necrotic tumor, and degree of nuclear pleomorphism, have been incorporated to develop a histologic grading scale of I, II, or III.¹ A negative prognosis is given if the tumor is high grade, has invasion into bone, is cytokeratin positive on immunohistochemical staining, or is positive for metastasis to the regional nodes.¹ In one study of 36 dogs with synovial sarcoma,¹ dogs with Grade I or Grade II tumors, or tumors that stained negative for cytokeratin, had a cumulative median survival of >48 mo, whereas dogs with Grade III tumors, or tumors that stained positive for cytokeratin, had median survival times of 7 and 4 mo, respectively. In that same study, dogs without evidence of metastasis to regional or distant sites had a significantly longer survival time than those with evidence of metastasis.¹ In another report of 16 cases, dogs with Grade I and Grade II tumors had median survival times of 365 and 156 days, respectively, although this difference was not statistically significant.¹¹ Additionally, the pattern of cytokeratin staining was not found to be associated with survival times.¹¹ There was a significant difference in median survival length between dogs that received amputations (840 days) and those receiving no treatment (93 days).¹¹

Although this dog's tumor grade was high, there was a lack of radiographic evidence of bone lysis; the mass was characterized histopathologically as a fibrocytic-type synovial sarcoma, and it had negative staining for cytokeratin. These are some of the factors that were associated with longer survival times.^1,2 Although the dog had a solitary lung mass, it was not definitively confirmed as metastatic neoplasia. Importantly, the patient's severe clinical lameness needed to be addressed. The traditional recommended treatment of amputation and adjunctive chemotherapy were declined by the owner due to concerns about amputation and the possibility of pulmonary metastasis at the time of diagnosis. Palliative radiation therapy was shown to be useful in controlling pain in canine patients with appendicular osteosarcoma and was reported for two cases of canine synovial sarcoma.^3–5 Regarding those two cases, one dog was treated with three, 8 Gy fractions on days 0, 7, and 21. That dog developed metastatic disease 74 days after the beginning of therapy and was still alive 121 days after the first radiation dose without obvious symptoms.⁴ The second dog was a 7 yr old, male, standard poodle with a 12 wk history of lameness due to a synovial sarcoma of the left elbow. That dog was treated with four, 10 Gy doses, and had an 8 mo period of remission before the tumor recurred.⁵ For the patient reported here, palliative radiation therapy, administered in four weekly fractions of 6 Gy for a total of 24 Gy, proved to be a viable treatment plan and provided excellent results, including a decrease in tumor size, complete resolution of the patient's clinical lameness, 13 mo disease-free interval after therapy, and lack of tumor recurrence. The chosen radiation therapy protocol resulted in minimal acute effects of alopecia and erythema, which resolved without treatment. Late effects of radiation therapy are not expected with palliative radiotherapy, but reported late effects to bone include osteopenia, osteonecrosis, and fracture.^13,14 Possible mechanisms for the excellent tumor control after palliative radiation therapy in this patient included tumor cell death, a decrease in local inflammatory factors, resolution of small microfractures, and a decrease in intratumoral pressure that perhaps decreased pressure on the periosteum and periosteal nerves.

Although the dog in this report eventually did undergo chemotherapy for splenic hemangiosarcoma, the chemotherapy was thought to have little influence on the synovial sarcoma of the left elbow due to the lengthy period between the completion of palliative radiation therapy and hemangiosarcoma occurrence. In addition, the MRI obtained post-radiation therapy demonstrated excellent local tumor control and reduction in tumor size. The tumor size remained grossly unchanged between the completion of palliative radiation therapy and the initiation of chemotherapy treatment of splenic hemangiosarcoma. A clear relationship between this patient's history of dermal hemangiomas and/or hemangiosarcomas and subsequent development of splenic hemangiosarcoma could not be accurately determined. A report in the literature suggested that dermal hemangiosarcomas could metastasize, but it was typically to distant dermal sites.¹⁵

Conclusion

The goal of palliative radiation therapy is not to provide long-term or definitive tumor control but to relieve pain, improve dysfunction, and alleviate disease by stabilizing the tumor burden.^4,16 In addition, palliative radiation therapy requires only a few treatments compared with curative intent radiation protocols, thereby decreasing the financial and time commitments of the owner.^4,16 The case reported here demonstrated that palliative radiation therapy could be offered as reasonable treatment in selected cases of canine synovial sarcoma, particularly cases that exhibit little to no bone involvement, where local tumor burden negatively impacts the patient's quality of life, and when the owners are reluctant to amputate. In this particular case, palliative radiation therapy provided excellent clinical outcome and markedly improved this patient's quality of life, allowing this patient to survive 15 mo after definitive diagnosis of left elbow associated synovial sarcoma.