Vaccine-Associated Sarcomas: Diagnosis and Treatment Strategies

Margaret C. McEntee, DVM, DACVIM (oncology), DACVR (radiation oncology)
Cornell University

Introduction

Vaccine-associated sarcomas have been reported to occur within a few months up to 10 years after vaccination. Even once the cause of vaccine-associated sarcomas has been eliminated, the problem will persist for another decade. The current discussion will focus on the diagnostic and treatment strategies used in the management of vaccine-associated sarcomas.

Patient Evaluation

The Vaccine Associated Feline Sarcoma Task Force has published a set of guidelines for both the diagnosis and management of vaccine associated sarcomas. Client education can play a critical role in the early detection of masses at vaccine sites. Lesions that develop soon after a vaccination may just be a vaccine reaction as opposed to a tumor. It is important to perform a biopsy prior to the definitive surgery to determine the nature of the lesion. Surgical excision of a vaccine-associated sarcoma will require wide margins as opposed to a vaccine reaction. Although it is recommended that any mass located at a vaccine site that persists for more than three months after vaccination be excised, the impact of resection on subsequent tumor development is not known.

The evaluation of a patient with a possible vaccine associated sarcoma should include: thoracic radiographs, an incisional biopsy, tumor imaging, and in some instances abdominal ultrasound. Routine blood work should be done including a complete blood cell count, chemistry panel and urinalysis. FeLV and FIV testing may be advisable. There is no apparent association between viral status and tumor development, but it is possible that the course of the disease may be altered due to compromise of the immune system.

Biopsy

The gross appearance of the tumor is typically a grey-white firm mass with a necrotic and oftentimes fluid filled center. The biopsy site should be placed such that the skin incision and biopsy tract can be excised at the time of definitive surgery. Options include punch biopsy, Tru-cut^� biopsy or an incisional biopsy using a scalpel blade. There is often a fluid component to vaccine-associated sarcomas and careful attention to hemostasis and prevention of leakage of material at the biopsy site is important. Tumor cells can potentially track along fascial planes and seed tumor at a distance from the primary mass.

Histopathologic features of VAFS have been well described, and most pathologists will now report that a tumor appears to be a vaccine-associated sarcoma based on these features. The most common diagnosis is fibrosarcoma or undifferentiated sarcoma. Other tumor histology's that have been reported include osteosarcoma, rhabdomyosarcoma, liposarcoma, and malignant fibrous histiocytoma (or myofibrosarcoma). The majority of the cells have a fibroblast or myofibroblast phenotype and multinucleated giant cells are common. Vaccine-associated sarcomas have a highly variable mitotic rate, and there is no apparent association between histologic grade and outcome.

Patient Imaging

Three view thoracic radiographs should be obtained in any patient with a suspected vaccine-associated sarcoma. The metastatic rate on initial presentation is relatively low at approximately 5%, but the presence of metastasis would significantly alter the treatment recommendations. Radiographic examination of the tumor site will reveal a soft-tissue opacity. Rarely there will be evidence of underlying bone involvement with bony lysis observed on radiographs.

The gross appearance of vaccine associated sarcomas and apparent size can be misleading. Even relatively small tumors upon imaging have been shown to be extensive and locally invasive. Palpation may suggest that the mass is moveable and not fixed to the underlying tissues but this may or may not be the case.

A study was conducted to determine the utility of contrast enhanced computed tomography in treatment planning for cats with vaccine-associated sarcomas. The volume of tumor based on the contrast enhanced CT images was on average twice the size of the tumor based on physical examination (caliper measurements). Additionally there was a wide range noted in the number of muscles involved based on the CT images. The study emphasized the importance of accurate delineation of the extent of disease for surgical and/or radiation treatment planning. It is strongly recommended that a contrast-enhanced CT scan or MRI be done to determine the extent of disease prior to therapeutic intervention despite the additional initial cost involved.

Patients are often referred after one or more failed attempts at surgical excision. CT imaging in the post-operative setting can still provide useful information on the extent of the surgical field and therefore the area to be included in the radiation treatment field.

Treatment Options

Surgery

Surgery is the best chance for cure. Attempts at limited excision of vaccine-associated sarcomas are seldom curative and ultimately lead to local recurrence and a more difficult second surgical procedure. However, even attempts at aggressive wide surgical excision are often incomplete and result in a 30 to 70% local recurrence rate. Tumor recurrence after incomplete resection has been observed as early as two weeks, but typically occurs by 6 months after surgery. Tumor recurrence in cats has occurred up to four times after surgical resection. Hind limb amputation may result in a higher rate of cure than does surgery in the interscapular space, but in some instances even amputation and/or hemi-pelvectomy may not be curative. Even when a histopathology report indicates that there is no evidence of tumor at the surgical margins, there may be a 50% local recurrence rate. Many cats are now referred with vaccine-associated sarcomas prior to the first surgery. In many instances it is appropriate that a surgeon experienced with aggressive tissue resection in the interscapular and pelvic region be involved from the beginning to increase the likelihood of a successful outcome.

The entire resected specimen should be submitted for histologic examination. Prior to submission the specimen should be properly marked and oriented. There are a variety of systems that can be used to mark the surgical margins including placement of suture tags and the use of marking dyes. The Davidson Marking System^� provides 6 different colors (black, blue, green, yellow, red and orange) that can be used to mark the surgical margins and allows orientation of the tissue. The dye is taken up only in the superficial layer of the tissue and can be seen on surgical margins when examining the sections under the microscope.

Adjunct therapy, typically radiation therapy, is often required to effect local tumor control. The placement of hemoclips in the surgical bed at the time of the definitive surgery allows the appropriate radiation treatment in terms of placement and size of the radiation field. It is also important that normal tissues be excluded from the radiation treatment field given that vaccine-associated sarcomas are commonly located over critical normal tissues such as the heart, lung, kidney and gastrointestinal tract. Confidence in identifying the surgical bed allows application of a smaller radiation treatment field.

There are several reports on the results of surgery in the management of vaccine-associated sarcomas. In a report by Davidson, et. al. cats (n = 11) treated with one surgical procedure had a median tumor-free interval of > 16 months, and a median survival time of > 16 months. Cats (n = 7) that had two or more surgeries had a median tumor-free interval of > 5 months and median survival time of > 13 months. Cats (n = 17) treated with surgery and post-operative radiation therapy had a median tumor-free interval of 4.5 months and a median survival of 9 months. The authors concluded that radiation therapy did not extend tumor-free interval or survival. However, cats in this group were irradiated because surgery was not expected to achieve local control and therefore this represented a group of cats at high risk of failure. Overall, cats with complete excisions had significantly longer median tumor-free interval (> 16 versus 4 months) and survival time (> 16 versus 9 months) than those with incomplete excisions.

A recent report by Hershey, et. al. evaluated the time to first recurrence and overall survival in 61 cats treated by excision of the tumor. The median time to first recurrence was 94 days and the median overall survival was 576 days. A more aggressive first excision resulted in a significantly longer median time to first recurrence (325 days) than did marginal first excision (79 days). Additionally, cats with tumors located on an extremity had longer median time to first recurrence (325 days) than cats with tumors located at other sites (66 days). The authors concluded that a radical first surgery is essential for extended time to first recurrence.

Radiation Therapy

Radiation therapy can be used successfully in both the pre-operative and post-operative settings. Because local tumor control requires a combination of complete surgical resection and radiation therapy the combination of surgery and radiation therapy has increased the tumor control rate. Radiation therapy alone is not recommended to treat vaccine-associated sarcomas if the intent is cure. Irradiation of bulky disease is palliative. The goal of palliation in this setting is to reduce the tumor in size and increase patient comfort but is not expected to improve longevity.

A report by Cronin, et al discussed the results of Cobalt 60 radiation therapy followed by surgery in 33 cats. The authors indicated that this was a study of pre-operative radiation therapy, however, 24/33 (73%) cats had at least one surgery prior to radiation therapy. All cats underwent another surgery after radiation therapy, and hence it was considered to be a study to assess the efficacy of pre-operative radiation. All cats received 48 Gy in 16 daily 3.0 Gy fractions. Acute radiation reactions were limited to dry desquamation. Radiation pneumonitis was seen in some cats but it resolved and was not considered to be clinically significant. The median disease-free-interval was 398 days and the median survival was 600 days. There were a total of 19 treatment failures. The local failure rate was 45% (15/33). Eleven cats had local recurrence; 4 cats developed metastatic disease; 3 cats had local recurrence followed by metastasis; and 1 cat had simultaneous local and distant disease. The presence of tumor cells at the surgical margin post-irradiation was the only variable found to influence treatment success. The median disease free interval in 5 cats with tumor cells present at the surgical margin was 112 days versus 700 days for 26 cats with negative surgical margins. All cats included in this study would be considered advanced stage and most had failed surgery prior to this treatment regime. Based on the high rate of local recurrence with conventional margins for both radiation therapy and surgery, future treatment recommendations were modified. Larger treatment volumes were planned for irradiation and more aggressive surgery was conducted after irradiation. A retrospective study of 189 cats reported an overall median survival of approximately 19 months (n = 43 cats; surgery and radiation therapy) and 26 months (n = 26 cats; surgery, radiation and chemotherapy). The longer median survival with the chemotherapy was not statistically significant. Initial metastatic rate was approximately 5% and after treatment increased to approximately 17%.

In a recent report by Bregazzi, et. al., on 25 cats treated with either a combination of doxorubicin, surgery, and radiation versus surgery and radiation, the authors did not detect a significant difference in survival between the two groups. The median time to first recurrence was 661 days, with a median survival time of 674 days for cats that were treated with doxorubicin, surgery and radiation. The median time to first recurrence has not been reached for the group treated with surgery and radiation alone, and the median survival time was 842 days. Radiation was delivered post-operatively with a 6 MV linear accelerator (6 MV photons or 5-12 MeV electrons) daily Monday-Friday, 3 Gy/fraction for a total dose of 57 Gy. In those cats that received doxorubicin, treatment was initiated 2-4 weeks after the completion of radiation therapy and a total of 5 doses were administered.

The importance of complete surgical excision in the management of vaccine-associated sarcomas cannot be overemphasized. This is in contrast to the relative success of radiation therapy in the post-operative setting for incompletely resected soft tissue sarcomas in dogs. In dogs with soft tissue sarcomas it is possible to effect long-term control of microscopic disease with post-operative radiation therapy.

Chemotherapy

Several chemotherapy agents, including carboplatin, doxorubicin, liposome-encapsulated doxorubicin, mitoxantrone, cyclophosphamide, and vincristine have been used in cats with vaccine-associated sarcomas. The use of various chemotherapy protocols has resulted in some partial and complete responses, however chemotherapy alone should not be considered for definitive therapy. Chemotherapy may have a significant role in a multi-modality approach to sarcomas in cats. Chemotherapy in the pre-operative setting may reduce the tumor in size thereby facilitating surgical resection. Chemotherapy has been used in conjunction with radiation therapy as a radiation sensitizer using a low dose. For large unresectable tumors chemotherapy may provide palliation and allow the patient to live more comfortably. The use of combination doxorubicin and cyclophosphamide in 12 cats with nonresectable fibrosarcomas resulted in a partial response in 50% (n = 6 cats), with a significant improvement in survival in those cats that were responders. The median survival in cats that responded to chemotherapy compared with nonresponders was 242 and 83 days, respectively. Incorporation of chemotherapy into a more aggressive treatment plan is being evaluated at several institutions. Some institutions are now taking a more aggressive stance and combining aggressive surgery with pre- or post-operative radiation therapy, followed by or in conjunction with a course of full dose chemotherapy.

Initial reports indicated that metastasis had not been identified or confirmed in cats with vaccine-associated sarcomas. Numerous reports have now documented that there is a risk of distant metastasis in vaccine-associated sarcomas. Most vaccine-associated sarcomas are locally invasive, but approximately 10 and up to 24% metastasize to the lung and other sites. Other sites of metastasis include skin or subcutaneous tissues, regional lymph nodes, mediastinum, liver, and pelvis. In one report of 45 cats with vaccine-associated sarcomas, 2 of the total of 9 cats that developed metastatic disease had extensive metastasis to multiple organs. Systemic chemotherapy may play a role in the delay or prevention of the development of systemic disease in cats with vaccine-associated sarcomas and should be investigated further.

Summary

A comprehensive protocol for evaluation and management of vaccine-associated sarcomas in cats has evolved over the past decade. However, significant questions persist regarding optimal treatment recommendations. Current data, accumulated after the emergence of vaccine-induced sarcomas, have shaped the management recommendations for cats presented with advanced and recurrent disease. A combination of radiation and aggressive surgery is recommended for local control in this subset of patients. The role of chemotherapy for local and distant disease management is yet to be determined, however, early reports are encouraging. It is yet unknown whether aggressive surgery alone will be sufficient for long term control in cats with relatively small (<3 cm), discreet and non-infiltrative tumors that have not previously been resected. Cats with early stage tumors are receiving definitive management and data are currently being collected to evaluate the extent of therapy required for permanent control in this group. Continued efforts to identify biological or clinical parameters that are predictive of behavior is imperative. Until such factors have been identified it is necessary to continue to recommend aggressive therapy for all cats with vaccine-associated sarcomas.

Vaccination recommendations have resulted in movement of tumors away from anatomic locations where management is particularly difficult. However, the potentially long latency period of tumor development and the only recent development of new potentially non-tumorigenic vaccines requires continued efforts to minimize the impact of this problem. We will continue to deal with cats affected with this condition until the cause of tumorigenesis can be identified and overcome.

Table 1: Guidelines for the Diagnosis and Management of Suspected Sarcomas^a

^a This material is being reproduced with the permission of the Vaccine-Associated Feline Sarcoma Task Force. Originally published in JAVMA 1999;214:1745.