History and Epidemiology
Injection site sarcomas were first linked with the administration of rabies vaccines in 1991. This observation coincided with a switch by the American vaccine industry from modified live rabies vaccines to more heavily adjuvanted killed products, a change that was made because of concerns about vaccine-induced disease. In addition, the frequency of feline rabies vaccination was concurrently increased in some states and counties because of implementation of annual rabies vaccination laws. Strong epidemiologic support for a cause and effect relationship between vaccination and sarcoma development was published in 1993. Cats were proven to have an increased risk of sarcoma at vaccine sites; the risk increased when multiple vaccinations were administered in the same anatomic location, and a causal relationship was demonstrated for not only rabies vaccines, but FeLV vaccines as well. Rabies and FeLV vaccines have remained the products most commonly implicated in the pathogenesis of vaccine- associated sarcomas, although scattered reports exist describing tumor development associated with other vaccines as well as non-vaccine pharmaceuticals.
The estimated incidence of vaccine-associated sarcomas varies significantly from source to source, but is likely one to 10 in 10,000 vaccines administered. Based on the estimated size of the vaccinated pet cat population in the United States, this translates into an annual incidence of between 2,200 and 22,000 cases. Tumor development is usually seen within three to 12 months of vaccination, but may be delayed for as long as three years.
Pathogenesis
Vaccine-associated sarcomas appear to be the result of the chronic local inflammatory response induced by the presence of vaccine adjuvant. Lesions are characterized histologically by a pronounced inflammatory component with mononuclear cell proliferation, granulation, and fibrosis. These areas of inflammation blend imperceptibly into regions of atypical fibroplasia, as well as areas of mesenchymal tissue that have overt histologic features of malignancy. This lends indirect support to the prevailing theory that over time, a complex interaction between the vaccine adjuvant, the inflammatory cells within the lesion, and the individual cat’s genome results in tumor development. Because not all vaccinated cats develop vaccine-associated sarcomas, inherent genetic instability or the presence of specific intracellular oncogenes is believed to be ultimately responsible for malignant transformation in affected animals. Tumorigenesis could occur in direct response to the presence of vaccine adjuvant, or might be the result of cytokines and growth factors that are produced as part of the inflammatory response and released into the cellular environment where they interact with fibroblasts and myofibroblasts. Preliminary results suggest that abnormalities in the function of p53, as well as platelet-derived growth factor (PDGF) and its receptor may play roles in the pathogenesis of vaccine-associated sarcomas. However, neither the feline leukemia virus (FeLV) nor the feline immunodeficiency virus (FIV) appears to be directly involved.
Biologic Behavior and Histology
Feline vaccine-associated sarcomas are typically found in middle-aged to older cats, although cats of any age may be affected depending on their vaccination history. A specific breed or sex predilection is not reported. Lesions are typically found in anatomic locations where vaccinations are administered: the interscapular space, the paralumbar region, and the subcutaneous tissues and large muscles of the thighs. Just like spontaneous soft tissue sarcomas, vaccine-associated sarcomas appear as firm, subcutaneous masses adherent to underlying structures. While the outward appearance and texture of these tumors may suggest a well-demarcated lesion, the actual interface between tumor and normal host tissue is usually poorly defined. Vaccine-associated sarcomas seem more likely to exhibit aggressive local biologic behavior than their spontaneous counterparts: rapid growth and extensive local invasion through and along fascial planes is common. Some authors also believe that metastasis is more prevalent with vaccine-associated tumors, although this has not been definitively proven. However, cats that have extended survival are more likely to develop metastases with time.
Vaccine-associated sarcomas are most often classified histologically as fibrosarcomas, although many other soft tissue sarcomas have been reported. These include malignant fibrous histiocytomas, myxosarcomas, leiomysarcomas, rhabdomyosarcomas, and osteosarcomas. Regardless of the specific histopathologic diagnosis, certain histologic features are usually observed. The malignant mesenchymal elements of the lesion have marked nuclear and cellular pleomorphism with a high mitotic rate and large areas of necrosis. A peripheral inflammatory infiltrate is present, containing lymphocytes, histiocytic cells, and multinucleate giant cells. Most important is the presence of adjacent macrophages containing a characteristic bluish-grey material, which is comprised of aluminum and oxygen. Aluminum hydroxide is a common component of feline vaccine adjuvants and many pathologists consider this material to be the most definitive evidence that a feline sarcoma is vaccine-associated.
Diagnostic Evaluation
The diagnostic evaluation of any animal with malignant disease must be sufficiently thorough to accomplish five goals: provide an accurate diagnosis; completely define the extent of disease (clinical stage); identify potential paraneoplastic syndromes; diagnose concurrent but unrelated diseases; and establish a normal baseline for the individual patient. The minimum database for a cat with a vaccine-associated sarcoma should include a complete blood count, serum chemistry profile, urinalysis, serologic testing for FeLV and FIV, chest radiographs (3 views), and a tissue biopsy for definitive histopathologic diagnosis. Radiographs or cross-sectional imaging (CT scan or MRI) of the primary tumor are also indicated in many cats and may play a critical role in the development of an optimal therapeutic plan. The anatomic locations in which these tumors are found can make surgical resection extremely difficult; an incisional biopsy to confirm the diagnosis followed by referral to a board certified specialist is the best approach in some cases.
Treatment
Feline vaccine-associated sarcoma represents a locally confined malignant disease that is most appropriately treated with aggressive local therapy. Metastasis may occur but is infrequent early in the course of disease; thus, patient survival depends primarily on adequate local control. Systemic therapy (i.e., chemotherapy) may be administered under certain circumstances, but plays a lesser role in most cats. Two primary forms of local therapy can be considered in general for the treatment of feline cancer patients, and in specific for the treatment of vaccine-associated sarcomas: surgery, and radiotherapy.
Surgery is the single most important component of successful therapy for feline vaccine-associated sarcomas. The first surgery has the best chance of cure; studies show that the likelihood of tumor control decreases if multiple surgeries are performed. The definitive surgery should be planned in specific detail, using radiographs and cross-sectional imaging as necessary. Aggressive surgical resection is essential and the maximal potential scope of the operation, including margins, must always be carefully considered. During the surgery itself, particular attention should be paid to several factors. All previous incisional biopsy sites should be completely excised. En bloc removal of the tumor together with wide and deep three-centimeter margins of normal tissue is recommended. Surgical dissection should be undertaken through normal tissue planes only. Sarcomas should never be “shelled” or “peeled” out; residual tumor pseudocapsule will be left behind, and local recurrence is virtually certain under these circumstances. If postoperative radiotherapy is being considered, radiodense markers such as vascular clamps or stainless steel suture should be placed in the area of the primary tumor as well as at the edges of the surgical field. This will facilitate subsequent radiotherapy treatment planning. Finally, all resected tissues should be submitted to a qualified veterinary pathologist for examination. A complete history and clinical description of the lesion should be provided and suspect margins tagged with suture or marked with India ink.
Complete surgical excision of vaccine-associated sarcomas can be curative. Unfortunately, the locally invasive nature of these tumors means that incomplete resections are common. Additional local therapy is indicated for cats that are confirmed to have residual local disease based on the results of histopathology. A second surgery completely resecting the previous surgery site will afford adequate control in some animals, and is a practical and cost-effective alternative that should be considered whenever possible. However, aggressive resection of a large, contaminated surgical field may be a technical impossibility. Radiotherapy is an additional local treatment that can improve long term local control of incompletely resected vaccine-associated sarcomas and may be applied pre- or postoperatively. The inherent resistance of sarcomas to radiotherapy means that high cumulative doses are necessary, generally between 54 and 63 Gray total dose. However, studies published to date suggest a significant improvement in disease free intervals and survival times when surgery and radiotherapy are combined. Median disease free intervals and survival times in cats with vaccine-associated sarcomas treated with surgery alone are reported at three and 19 months respectively; when adjuvant radiotherapy is administered, disease free intervals and survival times are both reported to be increased to over 28 months.
Even though responses have been reported to a variety of agents, feline vaccine-associated sarcomas are also relatively resistant to chemotherapy. Use of this systemic treatment modality alone is unlikely to provide significant benefit for the majority of cats, who suffer from local disease. However, chemotherapy may be incorporated into multimodality treatment protocols when there is proven metastatic (i.e., systemic) disease. Histologic evidence of increased malignancy with a high probability for future metastasis is also an indication for chemotherapy. Finally, certain chemotherapy drugs are used as radiation sensitizers: when given concurrently with radiotherapy they augment DNA damage, and may improve tumor response. Doxorubicin and carboplatin have both been reported to have activity against vaccine-associated sarcomas, and are radiation sensitizers. A survival benefit for cats treated with aggressive trimodality therapy (surgery, radiotherapy and chemotherapy) has yet to be convincingly demonstrated, but studies are currently underway at a number of institutions.
Prognosis
The prognosis for feline vaccine-associated sarcomas depends primarily on the surgeon’s ability to achieve a complete resection. Thus, tumor characteristics facilitating surgical excision are associated with a more favorable outcome and the possibility of prolonged survival. The prognosis is better for small, noninvasive or superficial lesions; also, location on an extremity allowing complete resection through amputation has been associated with longer disease free intervals. If complete surgical resection is not possible, the long-term prognosis is guarded; many cats will be euthanatized because of progressive disease within months of the time of diagnosis.
Prevention
Vaccine-associated sarcomas may be easier to prevent than they are to treat and many measures have been recommended to decrease the likelihood of tumor development. Veterinarians should consider switching to nonadjuvanted vaccines. If adjuvanted products are used, single dose vials are recommended so that the dose of adjuvant received by each vaccinated animal is standardized. Meticulous and detailed record keeping is essential. Information present in the animal’s medical record should include the date of vaccination; the vaccine name, manufacturer, lot or serial number and expiration date; the site of vaccine administration (rabies to be given in the right thigh, FeLV in the left); the name of the person administering the vaccine; and documentation of informed client consent. Multiple vaccines should never be given in the same site, and feline leukemia virus vaccines should only be administered to those cats truly at risk. Clients should be encouraged to monitor vaccine sites through regular palpation, and any mass detected should be treated as malignant until proven otherwise. Complete surgical resection is recommended for injection site masses that persist for longer than two to three months after vaccination, are increasing in size over one month after vaccination, or are greater than 2 centimeters in diameter. Finally, histologically confirmed vaccine-associated sarcomas should be reported to the vaccine manufacturer as well as appropriate oversight agencies, i.e., the United States Pharmacopeia Veterinary Practitioners’ Reporting Program (800-4-USP-PRN).
References
1. Bregazzi VS, LaRue SM, McNeil E et al. Treatment with a combination of doxorubicin, surgery, and radiation versus surgery and radiation alone for cats with vaccine-associated sarcomas: 25 cases (1995-2000). J Am Vet Med Assoc 2001; 218:547-550.
2. Hendrick MJ, Goldschmidt MH. Do injection site reactions induce fibrosarcomas in cats? (Letter to the Editor). J Am Vet Med Assoc 1991; 199:968.
3. Hershey AE, Sorenmo KU, Hendrick MJ et al. Prognosis for presumed feline vaccine-associated sarcoma after excision: 61 cases (1986-1996). J Am Vet Med Assoc 2000; 216:58-61.
4. Kass PH, Barnes WG, Spangler WL et al. Epidemiologic evidence for a causal relation between vaccination and fibrosarcoma tumorigenesis in cats. J Am Vet Med Assoc 1993; 203:396-405.
5. Mauldin GN. Soft tissue sarcomas. Vet Clin N Amer Small Anim Pract 1997; 27:139-148.
6. Morrison WB, Starr RM et al. Vaccine-associated feline sarcomas. J Am Vet Med Assoc 2001; 218:697-702.