Update on Feline Vaccine-associated Soft Tissue Sarcomas :

Answers To Some Commonly Asked Questions

Leslie E. Fox, DVM, MS, Dip ACVIM

Associate Professor, Department of Small Animal Clinical Sciences, University of Florida College of Veterinary Medicine.

What are the estimated risks for our cat population?

 The benefits of vaccination for preventable infectious diseases in cats still far outweigh the risks associated with vaccination. The risk of vaccine-associated sarcomas (VAS) is estimated at 1-12 cases per 10,000 vaccines. These soft tissue sarcomas typically develop between three months and three years after vaccination with feline leukemia virus (FeLV) and/or rabies vaccines. Recently, VAS have also been reported in intrascapular sites of previous FVRCP vaccinations. While most VAS look similar grossly, they are histologically diverse. Fibrosarcomas are most common, while malignant fibrous histiocytomas, osteosarcomas, chondrosarcomas, myofibroblastic fibrosarcomas, rhabdomyosarcomas, neurofibrosarcomas, liposarcomas, and undifferentiated sarcomas have been reported.

What is known about the pathogenesis of VAS?

 It is well-established that focal inflammation is associated with sarcoma development in some animal models. We also know that some vaccines induce local inflammatory reactions. What is undetermined is which vaccines used in veterinary medicine produce local inflammatory reactions and how these reactions are related to sarcoma development in cats. Vaccine-associated sarcomas appear to originate from fibroblasts or myofibroblasts that are transformed into tumor cells while making a fibrous tissue response to chronic inflammation. Tumor histology confirms the presence of inflammatory cells (ie. macrophages) in increased numbers in VAS when compared with nonvaccine-associated sarcomas.

 While we know that something in the vaccine is causing the inflammatory reaction and theorize that this causes tumor formation, the offending vaccinecomponent is as yet, unknown. Aluminum hydroxide or phosphate adjuvant found in killed FeLV and rabies vaccines has been implicated as a cause of local postvaccinal inflammation and VAS. However, the aluminum-laden macrophages may only be an indication of a previous vaccination site and may have little to do with actual tumor causation. Other vaccine components such as bacterial fractions, killed or modified live viruses, viral antigens, surface-active agents, and complex carbohydrates may make an even greater contribution to inflammation and cell transformation. Additional factors such as, the effect of giving multiple vaccines in the same site, have been associated with increased risk (127% higher after two vaccinations, and 175% higher if three or four are given simultaneously in the same location). Vaccinating with polyvalent vaccines containing multiple antigens and using multiple use vials with incompletely dispersed adjuvant may also increase risk of a postvaccinal inflammatory reaction and VAS.

How often do inactivated rabies/FeLV vaccines cause a local inflammatory vaccine reaction?

 In a recent study, Dr. Macy (1994) reported on the ability of killed vaccines to produce a measurable focal vaccine reaction. Thirty-six cats were vaccinated with six inactivated vaccines (three rabies and 3 FeLV) subcutaneously. Twenty-one days after vaccination, local reactions occurred at 80-90% of all rabies vaccination sites. The size of the lesion was independent of the type of adjuvant used. The nonadjuvanted FeLV vaccine produced no measurable vaccine reaction. The nonaluminum-adjuvanted FeLV vaccines caused a measurable inflammatory reaction in only 1/6 cats. In contrast, aluminum-adjuvanted FeLV vaccines did cause local reactions, but they were 50% smaller than the rabies vaccine reactions. Dr. Macy concluded that if post vaccinal inflammatory reaction precedes tumor development and is involved in transformation to malignancy, then rabies vaccines carry the highest risk. These findings are incongruent with previous epidemiologic studies which found a 5.5 times increased risk following FeLV vaccination and only a 2 times increase in tumor risk following rabies vaccination.  To further explore the role of rabies vaccination in local postvaccinal reactions, Dr. Macy evaluated a nonadjuvanted three year rabies vaccine in rats. Little or no inflammation was observed. So what is the bottom line? Dr. Macy recommends avoiding adjuvanted vaccines if possible and using FeLV vaccines only in cats truly at risk of acquiring the disease.

Does either intramuscular administration or massaging the vaccine site after administration decrease the incidence of a local reaction?

 Dr. Macy found that the volume of local reaction was not different when subcutaneous and IM administrations were compared. Massaging the vaccine site after administration only changed the shape of the postvaccinal reaction, not the actual reaction volume.

Are either FeLV, FIV, or feline sarcoma virus involved in the pathogenesis of VAS?

 It does not appear that the exogenous viruses FeLV and feline sarcoma virus are involved in oncogenesis of vaccine-associated fibrosarcomas when assessed by immunohistochemistry and polymerase chain reaction. The contribution of other cofactors, such as the propensity of feline fibro/myofibrocytes to undergo malignant transformation in sites of wounding and/or inflammation, is more difficult to evaluate. Feline immunodeficiency virus infection is not epidemiologically related to VAS.

Given the high incidence of localized postvaccination reactions, what is recommended for the treatment of persistent postvaccinal masses?

 Dr. Macy suggests that since most VAS occur after 3 months, lesions present for more than three months should be biopsied. The MFP\AFM guidelines are a bit more aggressive. They suggest biopsy or fine needle aspiration cytology for masses present greater than 6 weeks after vaccination. If biopsy evaluation demonstrates a histologically-confirmed inflammatory reaction, then simple lumpectomy is needed. If the mass is a sarcoma, then aggressive intervention is needed to achieve the bestclinical result.

Which treatment results in the longest survival time?

 Vaccine-associated sarcomas are locally aggressive with a moderate ability to metastasize to the lungs. Diagnosis is straightforward and based on histology. For solitary masses, early, complete surgical excision which is as aggressive as the tumor location permits, is the only known effective treatment. For obvious reasons, amputation of the affected limb is associated with the best long term survival. Because of a fibrous pseudocapsule, VAS appear to be easy to completely excise. However, numerous finger-like projections radiate along fascial planes from the primary tumor making complete excision almost impossible. En bloc resection with very wide margins of normal tissue (some surgeons say > 2 cm and other say > 3 cm) is recommended with excision of underlying bone if necessary to achieve the desired margins.

How effective is surgical excision for the treatment of vaccine-associated sarcomas?

 Sixty-one cats with vaccine-associated fibrosarcomas (Hershey, 1998) were treated with surgical excision. In the past, vaccine-associated fibrosarcomas have been thought to have a very low metastatic rate. Surprisingly, in this study, twenty-three percent of the cats had pulmonary metastasis. The median overall survival of the group was 19 months and the median number of attempted surgical excisions was 2. The median time to first recurrence of the tumors was about 3 months with most cats developing local recurrences by about 13 months after surgery. The extent of surgical excision was important for survival. The median time to first recurrence was about 2.5 months for marginal excisions versus 11 months for those cats treated with limb amputation. Twenty-five of the 61 cats had radiation and/or chemotherapy with the second attempted excision, while 36 cats did not. Unfortunately, survival data for the 25 cats was not reported. Only 5 of the 36 cats that did not have adjuvant therapy were long-term survivors with no recurrence of their fibrosarcoma suggesting that adjuvanttherapy is important for disease-free survival.

 In another retrospective study, Davidson (1997) evaluated 45 cats with vaccineassociated fibrosarcomas that were treated with either surgery alone or surgery/radiation therapy. Overall, more than one-third of the cats lived longer than one year. Eleven cats treated with one surgery had a mean relapse free interval of 16.1 months and a mean survival time of 16.2 months. Seven cats that had more than one surgery had a mean relapse free interval of 11 months and a mean survival time of 12.6 months. Seventeen cats that had more than one surgery and radiation therapy had a mean relapse-free interval of only 6.7 months and a mean survival time of 8.2 months. This suggests that cats treated with combined therapy worse than cats treated with surgical excision alone. However, they probably had less treatable disease at the outset. Again, more complete excision was associated with a better treatment outcome. Cats with complete excisions had longer mean relapse free intervals (13.4 vs 8.1 months) and mean survival times (13.4 vs 10 months) when compared to cats without complete excision. As might be expected, cats with sarcomas amenable to complete excision by limb amputation lived longer than cats with tumors on the trunk.

Does radiation therapy help achieve good local tumor control?

 There are few reports of the utility of radiation therapy for VAS. Dr. Meleo (1994) treated 9 cats with radiation therapy after surgical excision. The median time to first recurrence was 8.5 months and overall median survival was about 11 months. This probably does not represent an improvement when compared to treatment with surgery alone.

 Dr. Cronin (1998) treated 33 cats with vaccine-associated fibrosarcomas with radiation therapy (16 days of M-F 300 reds per treatment). Two weeks after radiation therapy was complete, cats underwent aggressive surgical removal of the tumor and the radiation field. Nineteen of 33 cats (57%) had tumor regrowth and/or metastasis. Eight cats developed distant metastasis (26%), while 11 cats (33%) had local regrowth.Overall, the median time to first recurrence was 14 months with a median survival time of about 20 months. Surgical margin status was important for cats treated with surgery/radiation. The presence of tumor cells at the resected margin was the only prognostic indicator ("dirty margins, 4 month median survival time vs "clean" margins, 23 month median survival time). Relapse free survival was about 2 years for cats with histologically "clean" surgical margins. Approximately one third of these cats were tumor free at 3, 4, and 5 years after treatment. Tumor size and number of surgeries prior to presentation for therapy were not statistically related to survival time or time to first recurrence.

Does chemotherapy help get achieve good tumor control?

 While not a substitute for adequate surgical excision, chemotherapy for VAS may be indicated for nonresectable tumors and control of distant metastasis. The frequency of metastatic disease noted recently is much higher (20-26% of treated cats) than previously reported. Doxorubicin is used commonly to control soft tissue sarcomas. Dr. Barber (1997) treated 10 cats with measurable nonresectable vaccine-associated fibrosarcomas with doxorubicin (1.0 mg/kg or 25-30 mg/m2 IV every 21 days) and cyclophosphamide (12.5 mg once a day by mouth on days 3, 4, 5, and 6 of each cycle). Six of 10 cats had measurable responses. All of the primary tumors became resectable after doxorubicin/cyclophosphamide protocol. Even cats (2) with pulmonary metastasis had a short term (unspecified amount of time) decrease in the size of their metastatic lesions.

Who is a good candidate for multimodality therapy?

 The patient with either recurrent tumor, large nonresectable tumor (>2 cm), incompletely removed tumor, or the potential and/or presence of metastatic disease is a good candidate for combination therapy.

Does tumor location affect treatment outcome?

 Early detection still offers the best chance for a cure. A subcutaneous mass is usually detected more easily (particularly by clients) than an intramuscular mass; therefore, the National Vaccine-Associated Feline Sarcoma Task Force (NVASTF) recommends that all vaccines are given subcutaneously. Since the treatment associated with the best outcome is complete surgical excision (limb amputation) it makes sense that vaccines be administered in an area amenable to aggressive local surgery. While sometimes perceived as undesirable by pet owners, limb amputation is a straight forward way to completely remove an aggressive soft tissue sarcoma from a location on the distal leg. To help make VAS more completely resectable, vaccine site recommendations are the following: rabies vaccine-distal right hind leg, FeLV vaccinedistal left hind leg, and FVRCP vaccine-right front shoulder area. No vaccines should be given in the intrascapular area or IM in the right hind leg.

With the inherent risks and relatively poor treatment outcome, which patients should be vaccinated and with which vaccines?

 As with any medical procedure, the needs of the individual patient are the most important factor in determining a vaccination protocol. This leaves protocol selection up to each veterinarian after making individual risk assessment. Vaccines should be administered according to the manufacturer's (and the USDA) recommendations and the immunologic needs of the patient. The MFP/AFM guidelines published in January, 1998 state that vaccines for FeLV, chlamydiosis, FIP and dermatophytosis are considered noncore vaccines and should be given only to cats at risk for contracting these diseases. Guidelines for specific vaccine administration frequency may be found on page 237, JAVMA, vol 212, no. 2, January 15, 1998.

Is documentation of vaccine injection site reactions really necessary?

 VAS is an uncommon, but devastating disease. If we are to learn anything about adverse vaccine reactions, we need to be conscientious about recording vaccine manufacturer, type and serial number, and injection location for each animal. Reactionsor vaccine-associated sarcomas should be reported directly to the vaccine manufacturer and to the US Pharmacopeia... forms can be obtained by calling 1-800-4-USP-PRN.

Is it really necessary to inform clients of potential adverse vaccine reactions?

Educating pet owners about the risks of VAS and obtaining owner consent for vaccinations has been made very easy. A client education brochure 'vaccines and Sarcomas: A concern for cat owners" is available from the Cornell Feline Health Center, the AVMA, the MHA, or the Veterinary Cancer Society. An MFP/AFM panel recommended owner consent form can be found on page 241, JAVMA, vol 212, no. 2, January 15, 1998.

How do we compensate owners for vaccine-induced sarcomas when federal and state laws mandate rabies vaccination to prevent a lethal, zoonotic disease?

 At the present time, there is no financial compensation for the owners of cats with VAS. However, Dr. Macy of the Vaccine-associated Sarcoma Task Force suggests adoption of a vaccine injury act similar to the 1986 Childhood Vaccine Injury Act in use for humans injured by mandatory vaccines. This act provides financial support for the medical care of affected children. Treatment of feline VAS is difficult and expensive ($1,000 - $3,500). Hopefully, financial assistance will be available so that all cats may be treated with the most optimal therapy.

References
Barber, et al. (1996) Effect of Combined Doxorubicin and Cyclophosphamide Therapy on
Nonresectable Feline Fibrosarcoma, Proc. 16th Ann. Conf. Vet. Canc. Soc. p 53-54.

Coyne, M.J., et al. (1997). Estimated Prevalence of Injection-Site Sarcomas in Cats During 1992. J. Amer. Vet. Med Assn. 210, 249-251.

Cronin, K., et al. (1998) Radiation Therapy and Surgery For Fibrosarcoma in 33 Cats, Vet. Rad. Ultrasound. 39:51-56.

ODavidson E.B, et al. (1996) Results of Surgical Excision of Vaccine Associated Fibrosarcomas in Cats. Vet. Surg. 25, 422.

Doddy, F.D., et al. (1996). Feline Fibrosarcomas at Vaccination Sites and Non-Vaccination Sites. J. Comp. Pathol. 114, 165-174.

Dubieizig, R.R., et al. (1993). Myofibroblastic Sarcoma Originating at the Site of Rabies Vaccination in a Cat. J. Vet Diagn. Invest. 5, 637-638.

Ellis, J.A., et al. (1996). Use of Immunohistochemistry and Polymerase Chain-Reaction for Detection of Oncornaviruses in Formalin-Fixed, Paraffin-Embedded Fibrosarcomas from Cats. J. Amer. Vet. Med. Assn. 209, 767-767.

Esplin, D.G., et al. (1996). Metastasizing Liposarcoma Associated with a Vaccination Site in a Cat. Feline. Pract. 24, 20-23.

Esplin, D.G., et al. (1995). Widespread Metastasis of a Fibrosarcoma Associated with a Vaccination Site in a Cat. Feline. Pract. 23, 13-16.

Esplin, D.G., et al. (1993). Post vaccination Sarcomas in Cats. J. Amer. Vet. Med. Assn. 202, 1245- 1247.

Hendrick, M.J., et al. (1994). Postvaccinal Sarcomas in Cats. J. Nat. Cancer lnst. 86, 341-343.

Hendrick, M.J., et al. (1994). Comparison of Fibrosarcomas That Developed at Vaccination Sites and at Nonvaccination Sites in Cats - 239 Cases (1991-1992). J. Amer. Vet. Med. Assn. 205, 1425-1429.

Hendrick, M.J., et al. (1994). Postvaccinal Sarcomas in the Cat - Histology and Immunohistochemistry. Vet Pathol. 31, 126-129.

Hendrick, M.J., et al. (1992). Postvaccinal Sarcomas in the Cat: Epidemiology and Electron Probe Microanalytical Identification of Aluminum. Cancer Res. 52, 5391-5394.

Hendrick, M., et al. (1991). Do Injection Site Reactions Induce Fibrosarcomas in Cats? J. Amer. Vet. Med. Assn. 199, 968.

Hershey, A.E., et al. (1997). Feline Fibrosarcoma: Prognosis Following Surgical Treatment: A Preliminary Report Proc. of the 16th Ann. Conf. Vet. Canc. Soc. 62.

Kass, P.H., et al. (1993). Epidemiologic Evidence for a Causal Relation Bet~veen Vaccination and Fibrosarcoma Tumorigenesis in Cats. J. Amer. Vet. Med. Assn. 203, 396-405.

Lester, S., et al. (1996). Vaccine Site-Associated Sarcomas in Cats - Clinical- Experience and a Laboratory Review (1982-1993). J. Amer. Anim. Hosp. Assn. 32, 91-95.

Macy, D.W., et al. (1996). The Potential Role of Inflammation in the Development of Postvaccinal Sarcomas in Cats. Vet. Clin. N Amer. Small Anim. 26, 103-103.

Macy, D.W. (1995). The Potential Role and Mechanisms of FeLV Vaccine-lnduced Neoplasms. Semin. Vet. Med. Surg. Small Anim. 10, 234-237.

Macy, D.W., et al. (1995). Vaccine-Associated Sarcomas in Cats. Feline Pract. 23, 24-27.

Macy, D.W., (1998) Feline Vaccine-associated Sarcomas, Proc 16th Ann. Vet. Med. Forum, ACVIM, San Diego, Calif,, p 380-382.

Macy, D.W, Bergman P.J., Powers, B. (1994) Postvaccinal reactions associated with three rabies and three leukemia virus vaccines in cats, Proc. 14th Ann. Conf. Vet. Canc. Soc. p 90-91,

Rudmann, D.G., et al. (1996). Pulmonary and Mediastinal Metastases of a Vaccination-Site Sarcoma in a Cat. Vet. Pathos. 33, 466-469.

Sandier, l., et al. (1997). Metastatic Vaccine Associated Fibrosarcoma in a 10-Year-Old Cat. Can. Vet.J. 38, 374-374.

1998 Report of the American Association of Feline Practitioners and Academy of Feline Medicine Advisory Panel on Feline Vaccines, JAVMA, Vol 212, no. 2, 227-241.    

To return to Sylvia's Cyber Kitty Condo just scratch her banner below...