Associated Sarcomas: Are They All Caused By Vaccines?
Dennis W. Macy, DVM, MS
VACCINE ASSOCIATED SARCOMAS
Epidemiologic evidence has now been published in the United States showing a strong association between the administration of inactivated feline vaccines (feline leukemia virus (FeLV) and rabies) and subsequent soft tissue sarcoma development at sites where these vaccines have been administered. The prevalence of soft tissue sarcoma development at sites of vaccination has been reported as 3.6 cases/10,000 to 1 case/10,000 FeLV or rabies vaccines administered. Some believe that the prevalence may be as high as 1/1,000 FeLV or rabies vaccines administered. If these prevalence rates are to be applied to the 1991 United States cat population, the following projections of the number of vaccine-associated sarcomas that occurred that year can be made. In 1991, the United States' cat population was estimated at 57 million cats. Approximately 62% of cats see veterinarians during any given year, and 64% of the visits to veterinarians include vaccination. These data indicate that 22 million cats were vaccinated in 1991. Applying the vaccine-induced tumor prevalence rate of one tumor per 10,000 vaccines administered, approximately 2,200 cases of vaccine-associated sarcomas occurred in 1991. Using the higher estimated vaccine-associated sarcoma prevalence of 1/1,000 vaccinations, a total of 22,000 vaccine-associated sarcomas occurred in 1991. Because of the relatively low incidence of fibrosarcomas in cats in general (20/100,000), the association between vaccination and subsequent tumor development was made only after millions of doses of now-incriminated vaccines (rabies and FeLV) had been given to cats for half a decade. The number of vaccine-associated sarcomas submitted to veterinary diagnostic laboratories appears to have stabilized and has not increased during the last several years.
The national increased prevalence of feline fibrosarcomas in the last 15 years paralleled the introduction and widespread use of two killed adjuvanted vaccines not previously used in cats in the United States. Vaccine-site associated sarcomas are believed to develop in areas of inflammation produced by these adjuvanted vaccine products, although they have also been reported with nonadjuvanted killed feline vaccines and modified live injectable vaccines, albeit less often. Killed adjuvanted panleukopenia/rhinotracheitis/calicivirus (FVRCP) vaccines were linked to soft tissue sarcomas in several cats in Canada and Australia and modified live FVRCP vaccines were linked to soft tissue sarcomas in 3 cats in Australia. Microscopically, areas of transition between inflammation and tumor development have been frequently observed in vaccine-associated sarcomas. The neoplasms that develop after vaccination are typically mesenchymal in origin; fibrosarcomas, malignant fibrous histiocytomas (also referred to as myofibroblastic sarcomas), osteosarcomas, chondrosarcomas, undifferentiated sarcomas, and rhabdomyosarcomas are most frequently reported. Vaccine-site sarcomas are histologically similar to mesenchymal tumors that arise in traumatized eyes of cats, suggesting a common pathogenesis of inflammation and wound healing in the development of tumors in these two syndromes. The presence of inflammatory cells, fibroblasts and myofibroblasts in and around vaccine site sarcomas supports this hypothesis.
A comparison of the morphologic features of vaccine site and nonvaccine site sarcomas found significant differences between the two groups of tumors. Vaccine site sarcomas typically have increased amounts of necrosis, inflammatory cells (mostly lymphocytes and macrophages), and increased numbers of cycling cells as determined by the presence of mitosis when compared to nonvaccine site sarcomas.
Hendrick reported preliminary findings of an immunohistochemical study of growth factors and receptors that indicated that vaccine-associated sarcomas have a mild to strong positive reaction for platelet derived growth factor (PDGF) and its receptor whereas nonvaccine-associated fibrosarcomas (NVFSA) are negative. It was also demonstrated that lymphocytes in vaccine-associated sarcomas are positive for PDGF, but lymphocytes in NVFSA and in normal lymph nodes are negative. The expression of c-jun has also been examined in vaccine-associated sarcomas. C-jun was found to be strongly positive in vaccine-associated sarcomas and not expressed in NVFSA.
It is now believed that vaccines are not the only cause of sarcomas seen at injection sites. Virtually anything that produces local inflammation at the injection site may potentially be responsible for injection site sarcomas in susceptible cats, but vaccines are the only things that are given to most of the cat population with any frequency to make a good correlation. Reports of sarcomas developing at sites of antibiotic and lufenuron administration, etc. have been occasionally reported.Mechanisms other than inflammation have also been investigated. The potential role of viruses in the pathogenesis of vaccine site sarcomas has been partially studied. Ellis studied whether the feline leukemia virus or the feline sarcoma virus were expressed in vaccine-site associated sarcomas in order to determine if there might be a viral mechanism giving rise to these sarcomas. One hundred thirty vaccine site sarcomas were evaluated using PCR (polymerase chain reaction) and immunohistochemical staining but FeLV was not detected. The possible role of the tumor suppressor gene P53 in feline sarcomas has been studied in a small number of sarcomas, and mutations in P53 were detected in only 2 of 10 fibrosarcomas studied.More importantly P53 has been not only shown to be increased in the tumor but up to five centimeters from the tumor mass in histologically normal tissue.P53 is a tumor suppressor gene and is important in that it is up regulated in the presence of DNA damage and is responsible for arresting cells in G1 phase allowing time for DNA repair or in the case of excessive damage resulting in cellular apoptosis thus preventing defectives cells from further replication. The increased expression of P53 around the tumors suggests DNA damage in adjacent tissue. If P53 is defective then damaged cells will be allowed to proliferate and tumor clones to potentially develop. Abnormal P53 has been reported in some vaccine associated sarcomas. It is suggested that vaccine associated sarcomas may represent an example of field carcinogenesis similar to that observed in human with oral squamous cell carcinoma exposed to tobacco products. Further evidence of the role of this mechanism in the pathogenesis of vaccine associated sarcomas is the finding that adjuvanted feline vaccines are mutagenic in the A assay while nonadjuvanted feline vaccines do not produce mutations and cell death. Cellular mutations are though to be mediated by the formation of oxygen radical associated with the inflammatory response to the adjuvanted vaccines. Despite other possible mechanisms, inflammation remains the most accepted hypothesis in the pathogenesis of vaccine-site associated sarcomas.
The vaccine component most commonly thought to be associated with local postvaccinal inflammation is the adjuvant. Adjuvants are used in many but not all inactivated feline vaccines. Aluminum in the form of aluminum hydroxide or aluminum phosphate is a common component of vaccine adjuvants and is used in some FeLV vaccines and rabies vaccines. Because aluminum has been identified in postvaccinal granulomas and in some vaccine site sarcomas, it was considered a possible cause of tumor development. However, aluminum may be only a marker of previous vaccination, and other vaccine components may induce inflammation or enhance the inflammatory process that results in sarcoma development in some cats. The specific role of aluminum, other adjuvants, adjuvant components, or vaccine antigens in inducing sarcomas in cats remains unknown at this time.
Although local inflammation may be induced in nearly 100% of vaccinates with certain rabies and FeLV vaccines, tumors only develop in approximately 1/1,000 of these vaccinates. This fact, along with the observations that some cats develop sarcomas at every vaccine site, some treatment failure lesions distant to the primary tumor site contain adjuvant, and that many related cats have been found to be affected with vaccine-associated sarcomas, suggests an individual inherited susceptibility or genetic defect may play a role in the pathogenesis.