Sarcoma Development

The association between sites of vaccine administration and subsequent development of high-grade sarcomas and other mesenchymal tumors in cats has been well documented and accepted by the veterinary community. The association between previous vaccination and tumor at vaccination sites in cats has been observed worldwide and has a reported prevalence ranging from 1 in 1000 to 1 in 10,000 in cats. It has been estimated that up to 22,000 new cases of VAS occur annually. Vaccination site tumors also have been reported in dogs, horses, and ferrets but far less frequently. The time from vaccination to tumor development may be as short as 3 months, with 93% of tumors developing within 4 years. Sarcoma development also has been reported sporadically at the site of injection or implantation of other substances, including lufeneron, cisplatin, long-acting penicillin, long-acting glucocorticoid preparations, meloxicam, and foreign material such as suture and microchips.

Tumor genesis associated with chronic inflammation is well documented in a variety of species and potentially correlates with the amount of inflammation and the degree of fibrous proliferation in response to the foreign materials in some cats. The observed chronic inflammation after the administration of adjuvant containing rabies and FeLV fits this model. A 2002 report from the United Kingdom found that injection site sarcomas were five times more likely to develop in cats that were administered aluminum-adjuvanted FeLV vaccines than nonadjuvanted vaccines. Further supporting the role of adjuvanted vaccines in the development of sarcoma was a recent study by Shaw and colleagues (2009). In that study, the change in the location of VASs from 1990 to 2006 was studied. In 1996, there was a recommendation to change the site of administration of the most frequently adjuvanted vaccines rabies and leukemia vaccines from the intrascapular space to the rear legs. In the time since this recommendation was made, a drop in sarcomas developing in the intrascapular space was noted and more than a doubling of sarcomas reported in the rear legs was observed.

The initial reports identified only FeLV and rabies vaccines as being associated with an increased risk of sarcoma development at site of vaccination. However, an additional study in Canada (Lester et al, 1996) suggested a role for other adjuvanted killed virus vaccines, including vaccines against panleukopenia and respiratory viruses, because sarcomas were noted in cats that had not received FeLV vaccination, and the incidence of sarcoma in the population decreased after a switch was made to modified live virus vaccines. Although tumors have been reported to develop subsequent to the administration of nonadjuvanted vaccines, this is thought to be less common and may be associated with other factors such as trauma. Trauma associated with the injection process, including muscle tearing or the introduction of hair into the subcutaneous tissues at the time of injection, can result in inflammation. Although vaccines commonly contain aluminum hydroxide in suspension as an adjuvant, postvaccinal inflammation and sarcoma development also occur with vaccines using a soluble adjuvant (carbopol). It is clear that not all substances carry the same risk, and reports of sarcoma initiation following insulin administration in cats are lacking. It is thought that the risk of tumor development may relate to the reactive nature of the vaccine components or other injectable substances as well as the qualitative nature of the local inflammatory response and the various oxidative products generated by the cellular response. This is in addition to the magnitude of the fibrous response to the vaccine and its components.

Dr. Elizabeth McNiel (2001) at the University of Minnesota investigated the role of free radical damage associated with feline vaccines in producing mutations that may stimulate oncogenesis and found that cell cultures exposed to adjuvant-containing vaccines developed mutations that increased as vaccine concentration increased, whereas no mutations were found after exposure to nonadjuvanted vaccines. She further found that the mutations could be blocked by addition of a free radical scavenger. In 1999 the World Health Organization International Agency for Research on Cancer acknowledged the evidence for the potential carcinogenicity of feline adjuvanted vaccine.

Although not all veterinarians are convinced of the role of inflammation in the pathogenesis of VASs, chronic inflammation is a well-known tumor promoter in a variety of species. Cats are uniquely sensitive in this regard and frequently develop mesenchymal tumors secondary to chronic inflammation associated with ocular injury, more so than any other species. Species genetic susceptibility to foreign body inflammation–induced tumor genesis is not unique to the cat; it also has been studied in mice, and some strains are known to be resistant to foreign body sarcoma development, whereas other strains can be highly susceptible. Other potential causes such as viruses have been studied. Research appears to rule out the potential role of viral agents, including feline immunodeficiency virus, FELV, papillomavirus, and polyomavirus, as a cause of this disease in cats.

Injection site sarcomas also have been reported at sites at which only nonadjuvanted vaccines (including vectored vaccines) have been administered (Srivastav et al, 2012). These vaccines do not induce significant local inflammatory reactions, and the findings suggest that factors related to development of injection site sarcomas are more complex than inflammation alone. Genetic factors often are considered when cancers such as VAS occur in younger animals. Cats are more susceptible to oxidative injury (e.g., Heinz body formation from acetaminophen toxicity) than other species. This characteristic may be important in tumor initiation. At the University of Minnesota, Dr. Sagarika Kanjilal and her colleagues studied the role of genetic predisposition in the development of VAS. Normal p53 is up-regulated in the presence of DNA damage and suppresses tumor cell growth. Alterations in p53 were found in some cats with VAS. Mutations in p53 have been associated with initiation and progression of tumors in a variety of species. However, this link was not substantiated in a follow-up study (Mucha et al, 2012). Further studies are needed evaluating the genetic links to injection site sarcomas in cats.