VACCINE ASSOCIATED SARCOMAS IN CATS: AN UPDATE
William S. Dernell, DVM, MS, Diplomate ACVS
Colorado State University, Fort Collins, Colorado
2001 ACVS Veterinary Symposium Small Animal Proceedings
Keywords:
Feline, Vaccine Associate Sarcomas, VAS
An association between soft tissue sarcoma formation and sites of vaccination was first recognized in the early 1990’s.(1) Since that time, recognition of this phenomenon has increased exponentially, exploding into a public and political disease issue. The true etiology or at least the relationship between vaccination (or other injection) and the formation of what are now called Vaccine Associated Sarcomas (VAS) remains unknown. Initial suspicions revolved around vaccine adjuvant materials, especially adjuvants containing metals (aluminum). Further investigation revealed VAS formation without adjuvant products and has raised the suspicion of metaplastic and neoplastic change secondary to an inflammatory reaction that appears to be unique to cats. Although vaccine reactions occur in dogs, they are less frequent and VAS formation has not been documented. Until the etiology and/or association can be elucidated, our attention needs to be focused on appropriate treatment, control or prevention.
The incidence of VAS is estimated to be somewhere between 1/1,000 to 1/10,000 cats vaccinated. Although feline leukemia vaccine and rabies have been most widely implicated, all feline vaccines and a number of non-vaccine injectable agents, generally repository type medications, have been associated with sarcoma formation. A suspicion of VAS is raised by the finding of any one or more of several pathologic criteria. These tumors are generally high grade (grade III if evaluated by the canine soft tissue sarcoma scheme) with substantial evidence of an inflammatory component. The inflammation most often consists of mononuclear cells, particularly macrophages. The finding of refractile material within the cytoplasm of inflammatory cells may represent metallic vaccine adjuvant and has been associated with VAS.
These tumors behave in a very aggressive manner, yet are generally confined to local tissue growth and invasion, rather than distant metastasis. The distant metastatic rate is estimated at 10-25%, and is often seen as a late event. This rate may actually increase as control of local tumor disease improves, allowing metastasis to occur. Local recurrence rates are high and are only partially related to the status of surgical margins. Although it is suspected that macroscopically or microscopically incomplete margins are associated with an increased rate of recurrence, recurrence rates seem to be higher than expected for cases in which a microscopically complete resection is obtained. Local recurrences in the face of clean margins (complete resection) are often referred to as ‘field recurrence’, ‘skip lesions’ or regional ‘metastases’. These terms refer to local re-growth that is not necessarily within the original surgical wound bed. Mechanistic theories for this include: induction of distant tissues through macrophages containing inductive material traveling through lymphatics; metaplastic induction secondary to the ‘regional’ inflammatory response; and true metastases of tumor cells through lymphatic or vascular channels. The latter theory is not as well supported owing to the fact that the distant metastatic rate is relatively low. Regardless of the mechanism, this biology requires that local therapy be aggressive or more appropriately, be regional in nature.
Cats are generally presented for a palpable mass in or near the injection site. The timing of VAS occurrence following vaccination is highly variable. The minimum time appears to be somewhere between 3 and 6 months following vaccination. The maximum time is not known, however, there have been reports of VAS occurring several years following vaccination in a particular site. Most masses evaluated prior to 3 months after vaccination are histologically consistent with granuloma. Because it appears that long-standing granulomas may be associated with VAS formation, it is recommended that any mass present for longer than 3 months undergo incisional or excisional biopsy. Care must be taken in planning the biopsy track for ease of subsequent removal at the time of definitive surgery. This is especially true for excisional biopsies since it is unlikely that this procedure will result in complete margins if the mass is diagnosed as a VAS. Although the metastatic potential of VAS is low (10-25%), staging with 3-view thoracic radiographs is still recommended. The finding of metastases is a negative prognostic indicator, yet it is possible that these lesions may progress slowly and local site treatment may still be warranted. Repeating the thoracic radiographs in 3-4 weeks will help to identify metastases with a slow doubling time which would be indicative of slow growth. Further staging involves evaluation of regional lymph nodes through palpation or imaging (ultrasound) followed by fine needle aspiration cytology of enlarged lymph nodes. Lymph node spread, however, is rare.1
The assessment of local disease extent and thus the surgical dose required for resection of larger, longer-standing lesions can be greatly aided by advanced imaging. The use of contrast-enhanced computed tomography (CT) has been shown to improve assessment of tissue plane invasion beyond what can be discerned by palpation, ultrasound or non-contrast CT. Due to the large inflammatory component to these tumors, CT may overestimate tissue involvement due to inflammatory changes within surrounding tissues. The use of CT images for radiation therapy computerized planning is very helpful in cases of VAS, especially larger, deeper masses, as involvement with multiple tissue planes within the radiation field is likely.2 Fields will often include dose-limiting tissues such as spinal cord. If radiation therapy is planned to follow surgery, computerized planning of radiation from CT images obtained after surgery is recommended, rather than from preoperative images, in order to better assess the position of tissue planes involved. Magnetic resonance (MR) imaging may be a very useful tool, in assessment of the degree of local disease, but it has yet to be evaluated for VAS.
Early local failure following treatment of VAS resulted in the institution of more aggressive surgical resections. The accepted standard for soft tissue sarcomas of 2-3 cm lateral margins and one additional tissue plane deep to what the tumor touches (Figure 1) will generally result in microscopically clean margins, yet an unacceptably high recurrence rate. The present recommendations are 3-5 cm laterally and 2 additional tissue planes deep to the discernible mass. Obtaining these resection margins may require partial scapulectomy, thoracic or abdominal wall resection or extremity amputation. In these cases, the decision to attempt surgical cure needs to be balanced against the potential for patient compromise. The overall (national) recurrence rate is estimated to be 50% at 1 year following surgery alone. This includes a wide array of margin distances. In one study, the institution of 5 cm lateral and 2 tissue plane deep margins has resulted in an improved local recurrence rate of less than 5% after a median of 6 months follow-up.3 Although this study is somewhat immature, it does hold promise of surgical cures with aggressive resection.
Figure 1. Schematic diagram of three-dimensional planning surrounding a malignant neoplasm. [From: Dernell WS, Withrow SJ. Preoperative patient planning and margin evaluation. Clin Techniques in Small Anim Pract. 1998;13(1):20.]
Due to lack of local tumor control early in the treatment of VAS, radiation has been implemented either as a primary treatment or in the adjuvant setting. Until the true efficacy of surgery alone (including radical resection) can be elucidated, the use of adjuvant radiation for the treatment of VAS is recommended. The advantage of radiation is that it allows regional therapy without compromise. Early reports of local disease control following radiation ranged from 50% with radiation alone to 75% with a combination of radiation and surgery. Earlier radiation protocols ranged from as low as 45 Gy to as high as 64 Gy in daily or every-other-day schemes. With experience, it has been shown that cats appear very tolerant to higher doses of radiation, especially in truncal areas where skin is the acutely responding tissue. Dogs show severe moist desquamation and often go through a period of intense pruritus. Cats, on the other hand, tend to show a dry desquamation that is associated with few clinical signs. This has allowed for protocols with increased total radiation dose, improving tumor control. Presently recommended protocols administer total doses in the low 60 Gy range. The use of electron therapy (as opposed to photon therapy) can be beneficial in that electrons are more superficially penetrating and will often spare deeper tissues from appreciable radiation doses. This is especially true for masses over the thorax, so that lung and heart can be spared, and over the spine to allow increased dose yet spare the spinal cord. Electron therapy requires a linear accelerator for administration. Increasing fractionation schemes (hyperfractionation) may also allow increased dose delivery with better sparing of normal tissues than coarse fractionation schemes.
Many institutions and practices advocate radiation therapy prior to surgery for VAS. The advantages of preoperative radiation are based on two main premises. The first is that surgery disturbs tissue planes through dissection as well as postoperative edema and hemorrhage, potentially increasing the field size, depth, and margins needed for effective treatment. Part of this concern stems from the radiation therapist being unaware of the boundaries of the surgical resection. Close association and communication between the surgeon and radiation therapist can decrease this concern. In addition, the placement of metallic clips (Hemoclips) at the boundaries (lateral as well as deep) of the dissection can aid in the treatment planning. The second concern is the induction of hypoxic regions within the surgical site. Hypoxic tissues and cells are resistant to radiation. This is a normal change following tissue disturbances, but can be decreased by gentle tissue handling, appropriate hemostasis and tension-free closure. If surgery is performed prior to radiation, preplanning the surgical excision is important, keeping these concerns in mind. In addition, less aggressive surgery may be indicated, to avoid detrimental changes, if radiation is planned postoperatively.
The primary disadvantage of performing surgery following radiation therapy is related to the tissue changes encountered. Irradiated tissues are compromised, especially in vascular supply. These tissues are slow to heal and less resistant to infection and tension. With this in mind, the surgeon also needs to have gentle tissue handling, appropriate hemostasis and strive for a tension-free closure. If it is possible to excise all the irradiated tissue and repair the defect with a vascularized graft, this may be preferred. The use of vascularized omental grafts may also greatly aid healing. Another concern regarding post-radiation surgery is the lack of discernable margins. If the tumor has decreased in size from the radiation, margin measurement becomes difficult. The recommendation at this point is to plan the margins based on the original tumor size and tissue involvement. This will require some method of documentation of the original tumor, either with skin markings, photographs or CT/MR images.
Although the rate of distant metastasis is low for VAS, combination treatment protocols including chemotherapy have been suggested and trials are being conducted using adjuvant chemotherapy. The reasons for chemotherapy are based on the theoretical increase in metastasis secondary to improved local disease control as well as the potential benefit in local disease control. In studies conducted thus far, improvement in survival has been small, yet present using doxorubicin either at the same time as radiation therapy or beginning after recovery (approximately one month following radiation therapy). The impact of chemotherapy may be diluted due to case selection bias in choosing chemotherapy for more advanced disease or high-risk patients. Further studies may help to elucidate the true efficacy of adjuvant chemotherapy.4
Follow-up for VAS cases must focus on local disease control. Most failures are within the treatment site and most will occur within 6-9 months of the completion of therapy. Diligent palpation by the owner is the cornerstone, with further evaluation of suspicious changes by the veterinarian. Masses which show progressive growth should undergo biopsy. The need for periodic staging measures is unknown, but they are likely indicated prior to further major interventions for recurrent disease. The options for recurrent disease are dependent on prior treatment. Re-irradiation has not been evaluated, but is likely to result in unacceptable normal tissue complications due to the high doses used in primary therapy. Radiation could be considered for new growth outside of the original treatment field. Surgical removal may be an option for recurrence, the surgical dose being dependent on prior surgery, local tissue involvement and the impact of irradiated tissues. Following aggressive first-line therapy, options for recurrent disease may be limited to palliative surgical resection of the mass.
Due to the many concerns surrounding VAS, the AVMA formed the Vaccine Associated Sarcoma Task Force (VASTF). This task force is charged with assessing the impact of this disease, the responsibilities of owners, veterinarians and vaccine manufacturers, establishing research directions and funding as well as making recommendations for treatment and prevention. A number of clinical and bench research projects have been sponsored by the VASTF, through funding from vaccine manufacturers and veterinary associations, in the areas of incidence and impact, etiology, prevention and treatment. Recommendations of disease prevention and treatment have also been made through the American Association of Feline Practitioners and pamphlets are available. In summary, these organizations recommend avoiding overvaccination and aggressive diagnostics for injection site reactions as well as aggressive treatment strategies. Vaccine site recommendations have been variable, but attempts been made to improve treatment options, especially surgical control. The details of all of these recommendations are evolving as more is learned about the disease and treatment response. In addition, adverse reactions to injectable agents should be reported through the Veterinary Practitioners Reporting Program of the US Pharmacopeia.
References
Hendrick MJ: Feline vaccine associated sarcomas. Cancer Invest 1999;17:273-277.
McEntee MC, Samii VF, Madewell BR: Contrast-enhanced computed tomography for treatment planning of feline vaccine-associated sarcomas; preliminary findings. Proc Vet Cancer Soc 1999;62 (abstract).
Kuntz CA, Powers BE. Modified wide local excision for vaccine associated sarcomas in cats. Vet Surg 2000;29:481 (abstract).
Poirier VJ, Kurzmann ID, Vail DM. The role of chemotherapy in vaccine associated sarcoma: Doxil versus doxorubicin. Proc Vet Cancer Soc 2000;43 (abstract).