Mississippi State University                                                            Auburn University
               Claire M. Weigand, DVM                                                 William G. Brewer, Jr, DVM

Vaccination-site fibrosarcomas in cats were first brought to the attention of the veterinary profession by Hendrick and Goldschmidt at the School of Veterinary Medicine of the University of Pennsylvania.1  After enactment of a Pennsylvania state law requiring rabies vaccination of cats, the number of fibrosarcomas among feline histopathologic samples submitted to the University of Pennsylvania increased. The most common sites of the fibrosarcomas corresponded to sites commonly used for vaccination—the inter-scapular area, hind limb, and lumbar area. Numerous studies and case reports addressing the cause and incidence of vaccination-site sarcomas followed.

EPIZOOTIOLOGY
To investigate the epidemiologic evidence for vaccination-site fibrosarcomas, Kass and coworkers examined three sets of records: (1) 345 feline fibrosarcomas submitted to a private laboratory serving northern and central California and Hawaii between January 1, 1991 and May 15, 1992; (2) 37 feline cases of fibrosarcomas diagnosed at the University of California Veterinary Medical Teaching Hospital between 1984 and 1992; and (3) 17 Hawaiian cats that were found to have fibrosarcomas between February 1990 and October 1992.[i]  The Hawaiian cats represented a cohort that was unexposed to rabies vaccine. Because rabies has not been reported in Hawaii and because of the state's strict quarantine regulations, cats in Hawaii are rarely vaccinated against rabies.

The 1993 Kass and coworkers report found no sex predisposition for vaccination-site fibrosarcomas in cats. Cats with fibrosarcomas at vaccination sites were younger than cats with fibrosarcomas at other sites.2[ii]  The age distribution among cats with vaccination-site fibrosarcomas was bimodal, with peaks at 6 to 7 years and 10 to 11 years.2  The number of fibrosarcomas increased each year, with a 25% increase from 1987 to 1991. At the University of California, fewer than half of the feline fibrosarcomas before 1988 were at vaccination sites. Be­ginning in 1988, more than half of feline fibrosarcomas were at vaccination sites.

Kass and coworkers considered four vaccines: feline viral rhinotracheitis-calicivirus-panleukopenia (FVRCP), FeLV, rabies, and pneumonitis-chlamydia vaccines. The FeLV vaccine was most commonly associated with an increased risk for the development of fibrosarcomas at the injection site (risk ratio was 2.82). The most common site for FeLV vaccination was the interscapular area. Rabies vaccination (with a risk ratio of 1.99) came in second. The odds that fibrosarcomas would develop at the interscapular region were increased by 50% after one vaccination, 127% after two vaccinations, and 175% after three vaccinations at that site.

The data from the private laboratory in California found that Hawaiian cats had significantly fewer fibrosarcomas at vaccination sites (17.6% [3 of 17] versus 53.6% [185 of 345]). None of the Hawaiian cats with vaccination-site fibrosarcomas had received a rabies vaccine within the 5 years before diagnosis, but all of the Hawaiian cats had received FeLV vaccines within 2 years of diagnosis.

The findings of this study suggest that vaccination, particularly repeated vaccination at the same site, has led to a few cases of fibrosarcomas in cats. No particular brand of vaccine was implicated. FeLV and rabies vaccines, both of which are inactivated vaccines with adjuvants, had the highest risk ratios. It was speculated that tumorigenesis may result from an inflammatory response to localized, highly concentrated antigen deposition or from residual adjuvant.2

A study of 239 histopathologic samples of fibrosarcoma submitted to the University of Pennsylvania and Tuft’s University further characterized vaccination-site fibrosarcoma in cats.³  A questionnaire was sent to each veterinarian who submitted a histopathologic sample. The questionnaire asked about the patient's signalment and vaccination history (the date and site of injections, the manufacturer of the vaccines, and postvaccination reactions). Some of the vaccines that had been administered contained aluminum adjuvant. In many cases, information about adjuvant composition was considered proprietary and was unavailable.

The questionnaire also asked for a description of the tumor (site, size, shape and color). The cats were classified according to whether the fibrosarcoma arose at a vaccination site.

The age distribution and the lack of a sex predisposition were consistent with the findings of Kass and coworkers. In both studies FeLV and rabies vaccine were implicated most commonly.

Hendrick and coworkers also studied the size of the tumors, rate of recurrence, incidence of postvaccination inflammatory reactions, and incidence of metastasis.³ The fibrosarcomas at vaccination sites were significantly larger (48% had a diameter >4cm) than those at sites not used for vaccination (25% had a diameter >4 cm). The vaccination-site fibrosarcomas also had a higher rate (recurrence (86% within 6 months; 22% had between two and four recurrences).  In contrast, the feline fibrosarcomas at sites not used for vaccination had 14% recurrence rate in the first 3 to 8 months after excision. A documented or suspected inflammatory reaction following vaccination was seen in only two cats. In one cat, an inflammatory reaction at the vaccination site was confirmed by biopsy 1 to 2 months after rabies vaccination; a fibrosarcoma developed at that site 1 year later. In a second cat, a presumably inflammatory reaction followed administration of an FVRCP vaccine; a fibrosarcoma developed at the site 5.9 years later.

In general, vaccination-site fibrosarcomas were considered to be more aggressive. Metastasis was not confirmed in either group but was suspected on the basis of thoracic (three cats) and skeletal (one cat) radiographs of cats with vaccination-site fibrosarcomas. Nevertheless, survival time was longer if the fibrosarcoma arose at a vaccination site. Perhaps this longer survival resulted from a higher incidence of euthanasia of the older cats that had fibrosarcomas at other sites. Unlike Kass and coworkers,² Hendricks and coworkers did not find that the risk of tumor formation increased if multiple vaccinations had been given at one site.³

CAUSES
There are currently two theories about what causes vaccines to be tumorigenic. One implicates the composition of the adjuvants. The other theory involves the deposition of high concentrations of antigen.

Adjuvant Composition
Most FeLV and rabies vaccines have highly active im-munogenic adjuvants.³  This factor, coupled with the fact that many cats are given multiple vaccinations at the same site, has led to the hypothesis that adjuvants or other vaccine components cause a local and persistent inflammatory response. This inflammatory response results in a proliferation of resident fibroblasts and myofibroblasts, which may lead to neoplastic transformation.³  Because more than one vaccine has been implicated (i.e., FeLV and rabies vaccines), it has been suggested that a commonly used adjuvant may cause the lesion.[iii] Foreign material has been observed in inflammatory macrophages associated with sarcoma.⁴'⁵

In a study by Hendrick and Dunagan,[iv] 23 specimens were taken from dogs and cats that had injection-site reactions occurring over a 9-month period (between September 14, 1988 and June 26, 1989). Only five injection-site reactions had been identified in the 18 months preceding September 14, 1988 (four in the 9 preceding months and one in the 9 months preceding that). Ten of the 23 specimens (from eight cats and two dogs) were taken from animals that had received subcutaneous rabies vaccines. These animals were included in the study.

The lesions were characterized as circumscribed, subcutaneous, inflammatory reactions, often extending deep into the dermis. Central necrosis was rimmed by a zone of macrophages; a variable number of lymphocytes, plasma cells, and eosinophils were present. In some animals, lymphocytes were numerous, often with follicle formation. In 4 of 10 animals that had received rabies vaccine, a shiny, amorphous to globular gray-brown material was seen in the central necrotic zones and in macrophage cytoplasm. This material was interpreted as remnants of vaccine, adjuvant or both. This report, which was one of the first published in the veterinary literature on postvaccination reactions, attributed the increased incidence of such reactions to an increase in the number of rabies vaccines given to cats after 1987 in Pennsylvania and the fact that subcutaneous administration of rabies vaccine was uncommon before 1987.

In a study of three humans with postvaccination reactions, aluminum adjuvant was implicated as the cause of the inflammatory reaction.[v] Microscopic examination showed multiple lymphoid follicles with germinal centers and a dense surrounding cellular infiltrate consisting of lymphocytes, histiocytes, plasma cells, and eosinophils. Results of staining for aluminum were positive in two of three patients. Electron probe x-ray microanalysis has also revealed material composed of aluminum and oxygen in three feline sarcomas.5

Antigen Deposition
Deposition of high concentrations of antigen has also been hypothesized as a cause of vaccination-site sarcomas.  Kass and coworkers noted in 1993 that multiple vaccinations given simultaneously at one site were associated with fibrosarcoma development.² However, this finding was not supported by the data reported by Hendrick and coworkers.³ In addition, postvaccination inflammation was found to occur only after use of adjuvanted products—most consistently with those that contained aluminum salts.8 The two vaccines that have been most commonly associated with vaccination-site fibrosarcomas (i.e., rabies and FeLV vaccines) are inactivated products that have high levels of adjuvant. To date, no publications have focused on vaccine formulation or specifically addressed whether attenuated or inactivated viral vaccines (or univalent or multivalent vaccines) are related to vaccination-site fibrosarcomas.

RISK ASSESSMENT
         Should vaccinations be discontinued, given the evidence that some vaccines contribute to sarcoma formation? Decisions about whether to administer FeLV vaccine involve concerns about feline health. Rabies, however, is an important zoonosis; policies about rabies vaccination are driven by concerns about public health.

It is estimated that more than 22 million cats were vaccinated in 1991, and most of these cats received multiple vaccinations.⁴ Given the low incidence of fibrosarcoma in the feline population, even a doubling of that risk suggests that vaccination-sire fibrosarcomas are rare.² The risk of death and disease from failing to vaccinate high-risk animals (i.e., outdoor cats or cats in multiple-cat households) is considerably higher than risk of sarcoma after vaccination.⁴

As for public health, the low incidence of rabies in humans is the result of effective animal vaccination programs.⁴ However, cats are still recognized as potential sources for human exposure. In California in 1991, the number of reported cases of rabies in cats equaled that in all other domestic species combined.⁹  Another public health issue is the cost of human exposure treatment for rabies. In two New Jersey counties in 1990, the estimated average cost of such treatment was $1138 per exposed person.¹⁰ The emotional trauma and physical discomfort of postexposure treatment must also be considered.

The benefits of vaccination clearly outweigh the risk of vaccination-site sarcomas, but what can be done to minimize the risk? A 3-year rabies vaccine for cats (instead of yearly vaccination) is an option permitted by some States.

Public health concerns supersede clients' wishes about rabies vaccination. In contrast, clients have options related to FeLV vaccination for their cats. Consequently, accurate history taking and client education are imperative. Identification of high-risk animals and client counseling on risks versus benefits will allow the owner to make an informed decision.

Administration of killed vaccines in the interscapular space should be avoided because it is difficult to excise a tumor from that location. Administration on limbs is preferable. Survival time is longer after amputation of a tumor-bearing limb than after regional excision of a tumor in the interscapular area.

Vaccination sites should be standardized. It is suggested that the FeLV vaccine be given on the caudal half of the left side of the body and the rabies vaccine on the caudal half of the right side. Sites where the animal has previously received vaccinations should be avoided.

The site of injection, route of injection (subcutaneous or intramuscular), vaccine manufacturer, vaccine type, and vaccine serial number should be recorded in the medical record. In addition, owners should be advised to watch for postvaccination reactions, which should also be recorded in the medical record.

There is currently no clear evidence that excision of inflammatory reactions will prevent the development of sarcomas at the vaccination site. To differentiate inflammatory reactions from sarcomas, biopsy samples should be taken from all masses that develop at sites where vaccinations have been administered.

Because inactivated vaccines and adjuvants have been implicated in vaccination-site sarcomas, modified-live FVRCP vaccines should be used whenever possible (except, of course, in pregnant queens).

Caution should be exercised when making a diagnosis of vaccination-site sarcoma. Vaccination-site sarcomas are reportedly infiltrated with inflammatory lymphocytes and macrophages. Macrophages frequently contain bluish-gray material that has been hypothesized to represent aluminum or other adjuvant.  Histopathologic confirmation of the diagnosis of sarcoma and accurate documentation of the vaccine or multiple vaccines given at the site of the sarcoma are necessary. Detailed records of injection sites and standardization of vaccination sires are also required to detail the prevalence and character of these sarcomas.

TREATMENT
Treatment of sarcomas at a vaccination site does not differ significantly from that of sarcomas at other sites. Clinicians should keep in mind, however, that vaccination-site sarcomas tend to be aggressive and have a high race of recurrence. Biopsy is necessary to distinguish a postvaccination reaction from a vaccination-site sarcoma. Wide surgical excision may be inadequate.⁸ Radiation therapy should be considered before or after surgical excision. Radiation therapy may be administered by teletherapy (cobalt-60 therapy) or brachytherapy (iridium implants). Chemotherapy can be used as a palliative. Doxorubicin (alone or in combination with cy-clophosphamide) can be administered intravenously every 3 weeks to patients with metastatic disease or if surgery or radiation therapy provides inadequate results.

 REFERENCES