Sponsored by an educational grant from Boehringer Ingelheim Vetmedica, Inc.
- The most recent studies suggest that in the genetically predisposed cat the injection of many substances may contribute to sarcoma development.
- It is difficult to assess increased risk for sarcoma formation in susceptible cats among different types of injectables.
- Chronic inflammation at the site of injection is speculated as one contributory factor, but cause and effect have not been established.
- Heredity may be a factor in determining risk for these sarcomas.
- Sarah Boston, DVM, DVSc, DACVS, University of Florida, Associate Professor Surgical Oncology, Gainesville, FL
- Audra Fenimore, DVM, DACVIM, Veterinary Specialty and Emergency Hospital, Englewood, CO
- Shannon Vawter, DVM, MS, Munford Animal Hospital, Munford, TN
- Nancy Welborn, DVM, Louisiana State University, Associate Professor Veterinary Clinical Sciences, Baton Rouge, LA
- Andrew Sparkes, Moderator, BVetMed, PhD, DECVIM, MRCVS
The Feline Sarcoma Controversy: Where Do We Stand?
Dr. Sparkes: In 1991, pathologists at University of Pennsylvania alerted veterinarians to a potential association between vaccination and sarcomas. What was the evidence?
Dr. Boston: During my internship, we called them vaccine-associated sarcomas, and we definitely thought there was an association with rabies or feline leukemia vaccines. They were all interscapular.
Dr. Fenimore: There was speculation that the increase in injection-site sarcomas was linked to Pennsylvania’s mandatory rabies vaccination and the introduction of killed vaccines.
Dr. Welborn: In 1990, rabies vaccinations were intramuscular. Within 3 years of first getting the subcutaneous injection, I saw 2 interscapular vaccine sarcomas. At the time, it was accepted that the sarcomas were caused by rabies or feline leukemia vaccines.
Dr. Vawter: I was introduced to feline vaccine sarcomas from public health and epidemiology studies. Pennsylvania had an outbreak of rabies in raccoons and started a mandatory rabies vaccine protocol to get every cat vaccinated.
Dr. Sparkes: After the creation of the Vaccine-Associated Feline Sarcoma Task Force, did your understanding of the link between sarcoma risk and rabies/leukemia vaccination change?
Dr. Boston: Rightly or wrongly, everyone says these cases are injection related. The most common injection these cats are receiving is a vaccination—and that is the reasoning.
The most common injection these cats are receiving is a vaccination—and that is the reasoning for the association. —Dr. Boston
Dr. Fenimore: Aluminum-adjuvanted vaccines have gotten a bad rap. But for human vaccines, aluminum adjuvant has been used for 70 years to protect against many conditions. In earlier studies investigating the association of these vaccines and feline injection-site sarcomas, aluminum was found in macrophages of some sarcomas. But we can’t be definitive that aluminum-adjuvanted vaccines cause every sarcoma. The understanding of which vaccines have caused sarcomas is constantly changing. Rabies and FeLV vaccines have been thought to be causes, but more recent studies suggest that some modified-live vaccines may be associated with sarcoma formation and that non-vaccine injectables (steroids, long-acting penicillins) may be contributing factors.
Dr. Sparkes: A 2012 epidemiological study reported a higher proportion of cats that received inactivated versus recombinant rabies vaccine developed an injection-site sarcoma in the hind leg. Some have suggested that this study links inactivated rabies vaccination with a 10-fold higher risk for sarcoma formation.
Dr. Vawter: You have to distinguish between odds ratio and relative risk. If the odds ratio is interpreted as relative risk, you will always overstate any effect.
Different Vaccines, Different Risks?
Dr. Sparkes: Have we gained any clarity in terms of the risks associated with different vaccines?
Dr. Vawter: I have more questions than answers. Many clinicians don’t keep records for many years, and some don’t even document which side they give the vaccine on. Without documentation that a rabies shot was given in the same location, you have to be careful assuming it’s a vaccine sarcoma.
Dr. Welborn: If we can come up with some form of universal record keeping, just think of all the information we’d gain.
Anything injected that causes chronic inflammation in a predisposed cat probably could cause an injection-site sarcoma. —Dr. Boston
Dr. Sparkes: As better studies challenged a link with any specific vaccine—adjuvanted versus nonadjuvanted—they became very complex. Does the complexity contribute to the continuing association between adjuvanted vaccines and sarcoma?
Dr. Welborn: I believe it does.
Dr. Vawter: Small samples are a huge limitation. Dr. Kass’ epidemiological studies (2002/2003)1,2 are the best I’ve seen, and neither could target a specific vaccine or injectable. There’s no absolute evidence as to what causes these sarcomas.
Dr. Fenimore: In Kass’ later (2012) study,3 few cats received recombinant vaccines compared to inactivated, so we can’t conclude that certain vaccines are safer than others. There’s probably some risk with any injectable.
Dr. Boston: I agree. There is a common misconception that a nonadjuvanted vaccine can be administered anywhere. We need to continue to vaccinate distally. In the tail University of Florida vaccine paper, only one of 20 cats didn’t mount a response to rabies.4 I vaccinate my own cat in his distal tail. I think most surgical oncologists vaccinate very distal in the tail, and I’d be happy if this became a general practice.
Dr. Sparkes: Is anybody else using tail vaccination?
Dr. Welborn: When I teach students about appropriate vaccination areas, we always talk about the distal limbs and following the AAFP guidelines. When I first mention the tail, students are surprised. But it isn’t difficult, even with fractious cats.
Dr. Fenimore: What happened to the cat that didn’t seroconvert? We don’t know if there is equal protection, so more information is needed.
Dr. Sparkes: Would that make you hesitate to recommend tail vaccination?
Dr. Fenimore: For rabies, I worry about the implications of having a failed immune response.
Dr. Boston: Do we know the seroconversion rates with other sites? Because 95% is not terrible. If you look at herd immunity, you want 80% of your population vaccinated.
Dr. Sparkes: Sarcomas in cats are scary, so it’s difficult to be objective. Better studies probably put the risk at one in 10,000 or 20,000 vaccines—a lot lower than was first thought.
Dr. Welborn: One in 10,000 is the University of Florida number and the one I tell my students.4 But I always try to reiterate that the risk potential for diseases we vaccinate against is so much higher than the risk for sarcoma.
I always try to reiterate that the risk potential for diseases we vaccinate against is so much higher than the risk for sarcoma. —Dr. Welborn
Analyzing Adverse Reactions & Responses
Dr. Sparkes: George Moore’s study followed a large number of vaccinated cats for up to 2 years.5 None with injection-site lumps after vaccination had a sarcoma.
Dr. Vawter: The biggest hypothesis for the trigger to injection-site sarcoma is inflammation, from vaccines or anything else. There were 500,000 cats in that study, and about 2,000 had adverse reactions. The most significant reaction was swelling or inflammation, but inflammation did not equal sarcoma development.
Dr. Sparkes: How prevalent is the use of inactivated, adjuvanted vaccine versus modified live vaccine and how does this affect data on sarcoma formation?
Dr. Vawter: In the last report, more nonadjuvanted vaccines were reported with regard to sarcoma formation than adjuvanted. The adjuvant may be a component but not the sole reason.
Dr. Fenimore: It’s difficult to assess how many veterinarians are using killed products versus modified live versus recombinant to gauge increased risk for sarcoma formation among the vaccines.
Dr. Sparkes: Studies also show cats that have a sarcoma at a vaccination site but have never been vaccinated. What’s your understanding of the relative risk of vaccine versus other injectables?
Dr. Vawter: Mainly long-acting drugs are associated with sarcoma formation, so there’s probably an inflammatory response to many injectable products.
Dr. Fenimore: In Srivastav/Kass et al, among 15 cats with interscapular sarcomas, 7 had never received vaccines in this region.3 They did, however, receive other injectables such as steroids and long-acting penicillins. I question if I should also be administering these other injectables on the distal limb or intravenously versus subcutaneously or into the muscle.
Dr. Welborn: It’s made me think about the placement of any injection in a cat, not just long-term drugs or vaccines.
Dr. Sparkes: Several studies have looked at the inflammatory response at the site of different types of vaccinations.
We do not understand what type of inflammation plays a role in formation of these sarcomas. —Dr. Fenimore
Dr. Fenimore: These studies seem to conclude that different vaccines evoke different inflammatory responses. It was previously thought that inactivated, adjuvanted vaccines might induce more of an inflammatory response than a modified live, but then Schultze’s study showed that some non-aluminum-based feline leukemia vaccines may induce an inflammatory histologic score similar to an aluminum-based adjuvanted rabies vaccine. Yes, inflammation may be a trigger, but we do not understand what type of inflammation.
Dr. Boston: If vaccines are equivalent in immunity, it makes sense to lean toward those that don’t create a chronic inflammatory response. I believe in the Day study aluminum-based adjuvanted vaccines caused a more prolonged inflammatory response—62 days.
Dr. Fenimore: No cats in the Day study developed sarcomas,6 even if some developed a more prominent inflammatory response. Maybe the adjuvanted vaccine induced more inflammation than the others, but none of the cats developed sarcomas in the 62 days. Would the inflammation resolve if you followed them another 3 or 4 months? In a previous study, inflammation sites resolved by 4 or 5 months after injection.1
We cannot conclude cause and effect between vaccines that induce more inflammation and sarcoma formation. Inducing inflammation at vaccine sites to mount an appropriate immune response isn’t necessarily a bad thing.
Multiple injections given over a period of time, especially at the same spot, increase the risk for a sarcoma at that site. —Dr. Vawter
Dr. Vawter: Studies have shown sarcomas form anywhere from a month to 3 years later. Multiple injections over time, especially at the same spot, increase the risk for a sarcoma at that site. You would think a sarcoma would develop quickly, but the papers don’t always support that. How do you get a sarcoma 3 years after a vaccine? Is it because of multiple injections there, or due to one vaccine?
Dr. Sparkes: How do we differentiate between naturally occurring and injection-site sarcomas?
Dr. Boston: Run-of-the-mill sarcomas not associated with injection seem to grow more slowly. Injection-site sarcomas are really aggressive—if it takes 2 weeks to get an appointment, they will grow in that time.
Injection sarcomas have lymphocytic infiltration, multinucleate cells, and macrophages—components of inflammation. On the margins, you can’t tell a difference—it merges into this inflammation.
Dr. Sparkes: What do we know about the role of genetics?
Dr. Boston: Most affected cats are not purebreds; they’re domestic shorthairs from the pound. They’re spayed and neutered. No one knows where their littermates are. It’s difficult to show a genetic predisposition, but we presume it’s there. Some studies show that these cats are predisposed genetically for one of the cancer-promoter genes.
Dr. Fenimore: A lot of anecdotal information claims appreciation of sarcomas in related cats that might have received different vaccines. Aberrancies in the tumor suppressor gene p53 have been studied, but there is conflicting literature on the exact polymorphisms that may be involved.
Dr. Boston: A test to screen individual cats could be helpful. We can test now for the MDR gene to determine if it’s safe to give ivermectin or doxorubicin. If it’s multifactorial, then it may not be helpful.
Dr. Welborn: On the practical side, I see practitioners asking “How do I work this into my 10 or 15 visits a day, and what is the cost? Will cat owners be willing to absorb this cost?”
Dr. Sparkes: The World Health Organization has classified feline adjuvanted vaccines as a class 3 or class 4 carcinogen. Things like prednisolone, furosemide, spironolactone, and ampicillin are also class 3 or class 4 carcinogens. Does that add anything to where we are with injection-site sarcomas in cats?
Dr. Vawter: If you understand what the class means, it’s not that scary. If metronidazole and some other class 3 things mentioned incited cancer, researchers induced cancer through large doses. They are not real-life scenarios.
Dr. Fenimore: And ampicillin is on that list—how many lives has ampicillin saved? The benefits outweigh the risks.
The discussion continues with Expert Views from a Roundtable on Injection-Site Sarcomas: Part 2, to be featured in an upcoming issue of Clinician’s Brief.
Gobar GM, Kass PH. World Wide Web-based survey of vaccination practices, postvaccinal reactions, and vaccine site-associated sarcomas in cats. JAVMA.2002;220:1477-1482.
Kass PH, Spangler WL, Hendrick MJ, et al. Multi-center case-control study of risk factors associated with development of vaccine-associated sarcomas in cats. JAVMA.2003; 223:1283-1292.
Srivastav A, Kass PH, McGill LD. Comparative vaccine-specific and other injectable-specific risks of injection-site sarcomas in cats. JAVMA. 2012;241:595-602.
Hendricks CG, Levy JK, Tucker SJ, et al. Tail vaccination in cats: A pilot study. J Fel Med Surg. 2014;16(4): 275-280.
Moore GE, DeSantis-Kerr AC, Guptill LF. Adverse events after vaccine administration in cats: 2,560 cases (2002-2005). JAVMA.2007;231: 94-100.
Day MJ, Schoon HA, Magnol JP, et al. A kinetic study of histopathological changes in the subcutis of cats injected with non-adjuvanted and adjuvanted multi-component vaccines. Vaccine.2007;25:4073-4084.
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