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Continuing Education Article
FOCAL POINT # Vaccination of cats may increase
the risk of sarcomas at the vaccination site.
Vaccination-Site Sarcomas in Cats
Mississippi State University Auburn University
Claire M. Weigand, DVM
William G. Brewer, Jr, DVM
I Rabies and FeLV vaccines are most commonly implicated in vaccination-site sarcomas in cats. I Simultaneous administration of multiple vaccinations at one site may increase the risk of vaccination-site sarcomas. I Vaccination-site sarcomas have been attributed to adjuvant composition or high concentrations of antigen. I Current recommendations are to inject rabies vaccine on the caudal half of the right side and FeLV vaccine on the caudal half of the left side of the cat’s body. I Diagnosis of vaccination-site sarcomas is based on documentation of injection sites and histopathologic diagnosis of a sarcoma.
accination-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 interscapular area, hindlimb, and lumbar area. Numerous studies and case reports addressing the cause and incidence of vaccination-site sarcomas followed (Figures 1 and 2).
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 1992.2 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.2,3 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
The Compendium August 1996
risk for the development of reactions). Some of the vacfibrosarcomas at the injeccines that had been admintion site (risk ratio was istered contained aluminum 2.82). The most common adjuvant. In many cases, insite for FeLV vaccination formation about adjuvant was the interscapular area. composition was considered Rabies vaccination (with a proprietary and was unrisk ratio of 1.99) came in available. second. The odds that fiThe questionnaire also brosarcomas would develop asked for a description of at the interscapular region the tumor (site, size, shape, were increased by 50% after and color). The cats were one vaccination, 127% after classified according to whetwo vaccinations, and 175% ther the fibrosarcoma arose after three vaccinations at Figure 1—Cat with probable vaccination-site fibrosarcoma. at a vaccination site. Note that the tumor started in the interscapular region, a that site. The age distribution and The data from the private common site for the administration of subcutaneous vac- the lack of a sex predisposilaboratory in California cines. (Courtesy of Dr. William Brawner, Department of Ra- tion were consistent with found that Hawaiian cats diology, Auburn University) the findings of Kass and had significantly fewer ficoworkers. In both studies, brosarcomas at vaccination FeLV and rabies vaccines sites (17.6% [3 of 17] versus were implicated most com53.6% [185 of 345]). None monly. of the Hawaiian cats with Hendrick and coworkers vaccination-site fibrosarcoalso studied the size of the mas had received a rabies tumors, rate of recurrence, vaccine within the 5 years incidence of postvaccination before diagnosis, but all of inflammatory reactions, and the Hawaiian cats had reincidence of metastasis.3 The fibrosarcomas at vaccination ceived FeLV vaccines within sites were significantly larg2 years of diagnosis. er (48% had a diameter >4 The findings of this study cm) than those at sites not suggest that vaccination, used for vaccination (25% particularly repeated vaccihad a diameter >4 cm). The nation at the same site, has led to a few cases of fibro- Figure 2—Same cat as in Figure 1 after hair was clipped from vaccination-site fibrosarcosarcomas in cats. No partic- area of the tumor. Note that the mass is multinodular. It is mas also had a higher rate of ular brand of vaccine was also ulcerated as can occur when fibrosarcomas become large. recurrence (86% within 6 (Courtesy of Dr. William Brawner, Department of Radiolomonths; 22% had between implicated. FeLV and rabies gy, Auburn University) two and four recurrences). vaccines, both of which are In contrast, the feline fiinactivated vaccines with brosarcomas at sites not used for vaccination had a adjuvants, had the highest risk ratios. It was speculated 14% recurrence rate in the first 3 to 8 months after exthat tumorigenesis may result from an inflammatory recision. A documented or suspected inflammatory reacsponse to localized, highly concentrated antigen deposition following vaccination was seen in only two cats. In tion or from residual adjuvant.2 A study of 239 histopathologic samples of fibrosarcoone cat, an inflammatory reaction at the vaccination ma submitted to the University of Pennsylvania and site was confirmed by biopsy 1 to 2 months after rabies Tufts University further characterized vaccination-site vaccination; a fibrosarcoma developed at that site 1 year fibrosarcoma in cats.3 A questionnaire was sent to each later. In a second cat, a presumably inflammatory reacveterinarian who submitted a histopathologic sample. tion followed administration of an FVRCP vaccine; a The questionnaire asked about the patient’s signalment fibrosarcoma developed at the site 5.9 years later. and vaccination history (the date and site of injections, In general, vaccination-site fibrosarcomas were conthe manufacturer of the vaccines, and postvaccination sidered to be more aggressive. Metastasis was not conIMPLICATED VACCINES I STUDY RESULTS I SITES OF SARCOMAS
The Compendium August 1996
firmed 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 immunogenic 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.4 Foreign material has been observed in inflammatory macrophages associated with sarcoma.4,5 In a study by Hendrick and Dunagan,6 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 graybrown 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.7 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-site 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 the risk of sarcoma after vaccination.4
ALUMINUM ADJUVANT I CONCENTRATED ANTIGEN DEPOSITION I PUBLIC HEALTH CONCERNS
The Compendium August 1996
Minimizing the Risk of Vaccination-Site Sarcomas
I Avoid unnecessary vaccinations. I Do not administer killed vaccines into the interscapular space. I Standardize vaccine sites—caudal half of the left side of the body for FeLV vaccines and caudal half of the right side of the body for rabies vaccines; limbs may be preferable. I Avoid previous vaccination sites. I Maintain detailed records about vaccinations— site of injection, route of injection (subcutaneous or intramuscular), vaccine manufacturer, vaccine type, vaccine serial number. I Instruct owners to watch for postvaccination reactions and document such reactions. I Use modified-live virus FVRCP vaccine whenever possible; do not use modified-live virus FVRCP vaccine in pregnant queens.
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 postexposure 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.
PRECAUTIONS Simple changes in the routine vaccination procedure have been suggested (see the box).8 Unnecessary vaccination should be avoided. For example, cats that receive a 3-year rabies vaccination should not have yearly rabies boosters—unless they are required by state law. Clients should be told to watch for masses forming at the site of vaccination and should return the cat for a biopsy of the mass, if needed. The current recommendation is that reactions that persist for more than 3 months should be excised and submitted for histopathologic examination.11 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.5 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 sites are also required to detail the prevalence and character of these sarcomas.
BENEFITS OF VACCINATION I SCHEDULING & SITES OF VACCINATION I RECORDKEEPING
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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 rate 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 cyclophosphamide) can be administered intravenously every 3 weeks to patients with metastatic disease or if surgery or radiation therapy provides inadequate results.8
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About the Authors
Dr. Weigand is currently affiliated with The Animal Health Center, College of Veterinary Medicine, Mississippi State University, Starkville, Mississippi. When this article was written, Dr. Weigand was with Dr. Brewer at the Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, Auburn University, Auburn, Alabama. Dr. Brewer is a Diplomate of the American College of Veterinary Internal Medicine (Oncology and Internal Medicine).
1. Hendrick MJ, Goldschmidt MH: Do injection site reactions induce fibrosarcomas in cats? JAVMA 199:968, 1991. 2. Kass PH, Barnes WC Jr, Spangler WL, et al: Epidemiologic evidence for a causal relationship between vaccination and fibrosarcoma tumorigenesis in cats. JAVMA 203:396–405, 1993. 3. Hendrick MJ, Shofer FS, Goldschmidt MH, et al: Comparison of fibrosarcomas that developed at vaccination sites and at nonvaccination sites in cats: 239 cases (1991–1992). JAVMA 205:1425–1429, 1994. 4. Esplin DC, McGill L, Meininger AC, et al: Postvaccination sarcomas in cats. JAVMA 202:1245–1247, 1993. 5. Hendrick MJ, Goldschmidt MH, Shofer F, et al: Post-vaccinal sarcomas in the cat: Epidemiology and electron probe microanalytical identification of aluminum. Cancer Res 52:5391–5394, 1992. 6. Hendrick MJ, Dunagan CA: Focal necrotizing granulomatous panniculitis associated with subcutaneous injection of rabies vaccine in dogs and cats: 10 cases (1988–1989). JAVMA 198:304–305, 1991. 7. Fawcett HA, Smith NP: Injection-site granuloma due to aluminum. Arch Dermatol 120:1318–1322, 1984. 8. Macy DW: Vaccine-induced sarcomas in cats. Proc Thirteenth Annu Vet Med Forum:842–843, 1995.
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9. Krebs JW, Holman RC, Hines U, et al: Rabies surveillance in the United States during 1991. JAVMA 201:1838–1848, 1992. 10. Uhaa IJ, Dato VM, Sorhage FE, et al: Benefits and costs using an orally absorbed vaccine to control rabies in raccoons.
JAVMA 201:1873–1848, 1992. 11. Ogilvie GK, Moore AS: Vaccine associated sarcomas in cats, in Ogilvie GK, Moore AS (eds): Managing the Veterinary Cancer Patient. New Jersey, Veterinary Learning Systems, 1995, pp 515–518.
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