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- The most recent studies suggest that in the genetically predisposed cat the injection of many substances may contribute to sarcoma development.
- Remember to record in the medical record where vaccinations were injected—this information could be critical in the future.
- Client education may translate into earlier diagnosis; talk with clients at various points throughout a patient’s life about what to look for when concerned about sarcoma development.
- Heredity may be a factor in determining risk for these sarcomas.
The Feline Sarcoma Controversy: Where Do We Stand?
Dr. Sparkes: In 1991, pathologists at the 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.
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.
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 vaccination study conducted at the University of Florida, 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 percent is not terrible. If you look at herd immunity, you want 80 percent 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.
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.
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.
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.
Maximizing Prevention, Minimizing Risk
Dr. Sparkes: The profession has been searching for a magic bullet to prevent feline injection-site sarcomas (FISS). At least one journal has looked at the recommendations for prevention and management—do the guidelines give us direction to better prevent them?
Dr. Vawter: I think general practitioners will still see the recommendations as controversial. If every cat were sedate and nice, we could follow the standard protocols easily. A lot of veterinarians have to be retrained on how to handle a cat to induce less stress. The newer low-stress practice strategies recommend more sedation and more anti-anxiety methods. We may need to start considering these as crucial to the practice of medicine.
Dr. Welborn: Cats have been the forgotten species, and thankfully that’s changing. Understanding how a cat feels when it comes in and trying to make the environment better are really important.
Dr. Vawter: The low-stress practice is becoming more and more popular. General practitioners have to put aside their bias that it’s something they can’t do. The general practitioner also has a lot going on. There needs to be a shift to retrain technicians and assistants to get more history. Does this cat go outside? Is it running around with other cats? Depending on the answers, we need to be customizing treatment plans. If they don’t need a certain vaccine, then we don’t give it. We also have to retrain ourselves and re-evaluate the way we treat cats. Should we or shouldn’t we vaccinate below the hock or the stifle? Or in the tail? But the distal limb—there’s no controversy to that. It’s just a matter of establishing a mindset that each cat is an individual.
Dr. Sparkes: We need to examine our approach to handling cats as a starting point. Otherwise trying to inject in the tail or very distally in the limb is going to be a disaster for both cat and owner.
Dr. Fenimore: In the Shaw et al. study discussing temporal changes in characteristics of injection-site sarcomas in cats, many cats still developed sarcomas in the interscapular space despite the revised recommendations of vaccinating as distally on the limb as possible.7 Are veterinarians compliant in vaccinating the distal limbs, or did those cats get other injectable medications there?
Dr. Vawter: There are some data to support that veterinarians as a whole are trying to move toward limbs since those recommendations were released.
Dr. Sparkes: Do you think that applies to other injectables as well?
Dr. Boston: For longer-acting injectables, probably yes. It would be nice to have a movement to at least try to record where we inject. If you get used to vaccinating lower on the limb, that’s where you’ll be giving your subcutaneous injections: It’s just part of your practice. You get the cat in a towel, pull out its limb, and give your injection. Your technicians are used to holding cats that way. There are going to be cats that are almost feral and ready to rip everyone apart—unless you sedate them. But most cats you can work with.
Dr. Fenimore: Vaccine companies have been responsive to the sarcoma issue, reducing the volume of vaccines. If this is a tough area to vaccinate, it’s helpful that there isn’t a lot of volume to inject. Some injectable medications seem to cause significant irritation, so perhaps we should be administering these more distally.
Dr. Sparkes: Some clinicians suggest that it’s negligent to give vaccines interscapularly.
Dr. Boston: I think it’s negligent to vaccinate anywhere except distal limb or tail. The hip is no better than interscapular. With amputation, if the cat doesn’t get metastatic disease, most will survive if you catch it early and resect along with 5 centimeters of normal tissue.
Dr. Sparkes: Does injecting more distally in the limb also help with monitoring cats afterward for injection-site reactions?
Dr. Vawter: There is a lot of loose skin up toward the top. A small sarcoma is going to be noticed on the distal limb a lot faster. If you’re depending on the owner to notice something, it may help them see things faster.
Dr. Boston: Another component is telling clients, “this is what you need to look for and this is when to call me.” Tell every single client.
Dr. Welborn: Many owners do not retain all of the examination room conversation, so we write it down in self-explanatory handouts with appropriate photographs or diagrams. I describe how owners should monitor the vaccination area. Many will note the small swelling immediately after vaccination. I tell them to compare any later swelling to that starting point. My goal is to have every owner monitor every vaccine site on a daily basis. If we can do that, we might catch disease much earlier.
Client Education & Compliance
Dr. Sparkes: Owners aren’t expecting you to inject a cat in its limb. Is that in itself helpful in reinforcing the importance of monitoring?
Dr. Welborn: I think so. Again, that goes into the conversation we have with the owner. We aren’t doing a good job informing owners about how to monitor.
Dr. Sparkes: Owners now come in with information from the Internet. Do they have a realistic appreciation of the risks?
Dr. Welborn: Probably 50 percent of what they read is not accurate, but it’s an opening for a dialogue. I tell owners it is not black and white—this is what we know right now. We always do a risk assessment. Not all cats need all vaccines. We have to follow state law about rabies vaccination, but if we can decrease the number of vaccines, that’s certainly beneficial.
Dr. Fenimore: Owners are very receptive to education about the consequences of certain infectious diseases: like rabies—we know it’s fatal and preventable, and that the benefits of vaccinating outweigh the risks. When you present it to them as such, they are receptive to vaccinating.
Dr. Boston: Do you continue to vaccinate a cat that has had an FISS? I wouldn’t if it was my own cat. I would transition it to be an indoor cat and hope that it has developed enough immunity over the years.
Dr. Sparkes: Rabies adds a complication with the legal requirements, but what about using other injectable products?
Dr. Vawter: You have to start thinking where and when. If you have a patient with a vaccine sarcoma, do you microchip that cat and risk it? Do you give it methylprednisolone? No, probably not.
Dr. Sparkes: Do veterinarians follow the 3-2-1 rule: intervening if there is swelling at the injection site for over 3 months or if it’s greater than 2 centimeters in diameter or increasing in size 1 month or more after vaccination?
Dr. Vawter: A limiting factor in the 3-2-1 rule is owner compliance. Will clients monitor a barn cat that they let out the door as soon as they get home?
Dr. Boston: Even some vets can’t remember what 3-2-1 means. Is the 3 for centimeters or months? There could just be a 1 rule: if your cat has 1 mass for more than 1 month, you need to come back.
Dr. Fenimore: The 3-2-1 rule was drawn up by the Vaccine-Associated Feline Sarcoma Task Force and it has been published.8 Although these guidelines are familiar to and understood by many practitioners, translating them for the client and emphasizing the importance of monitoring is another area of work.
Dr. Boston: The current recommendations are based on the Phelps paper—cut with 5-centimeter radial margins and 2 fascial planes deep.9 Should you resect in a general practice? I would argue not. The size of the defect that you need to create really dictates a referral center for surgery and the care needed postoperatively.
Dr. Fenimore: Would an oncologist say radiate them first and see if we can get these masses smaller prior to cutting?
Dr. Boston: The debate about that rages on. Surgeons like to cut first to avoid surgery in a radiation field and its increased risk for complications. But then you create a hypoxic scar, and radiation doesn’t work as well. Veterinarians need information about how to handle that. With aspiration, you aren’t going to be able to distinguish a granuloma with inflammation from a sarcoma. An incisional biopsy is needed to avoid disrupting the structure of the mass with a punch or a wedge biopsy until we get a histologic diagnosis. Doing it after a month might be too reactive, but I wouldn’t wait for 3 months. You will probably end up biopsying some granulomas, but that’s acceptable. Clients sometimes push veterinarians to do what they can to save money: They don’t want a referral. We need to reinforce that this isn’t necessarily appropriate.
Dr. Fenimore: If we biopsy masses early and only inflammation is noted on histopathology with no suspicious cancerous cells, what are current recommendations in moving forward?
Dr. Boston: I would leave it up to the owner to either monitor or do a very marginal excision of the inflammatory tissue. I would be inclined to remove it, but the incisional biopsy will guide you as far as how. If owners just want to watch it closely, we need to ask them to come back in 3 weeks so we can measure it again. Measure it with calipers and take pictures so it’s well documented and you know in 3 weeks whether it’s a problem.
Dr. Sparkes: How realistic is it to expect owners to participate in monitoring their cats?
Dr. Vawter: You’re doing well to get them in more than once a year to get a vaccine; getting them to return for rechecks is a challenge.
Dr. Welborn: It’s so owner dependent, too. Some owners have an outside cat that they only see when they feed it.
Dr. Boston: It’s good to give owners a choice. No one is going to spend $10,000 to treat a barn cat for a sarcoma; but there are also clients who weigh kibble to know exactly how much their cat eats. Not everyone needs to treat cancer in their pet either, but good information and early monitoring give people options.
Dr. Sparkes: How do we get clients engaged in monitoring?
Dr. Welborn: Communication. Engage the client from the beginning—we have a thorough questionnaire every client fills out every year. That is the start of the process of risk assessment. Most owners are appreciative when they realize we are truly tailoring vaccine protocol to their pet. When we speak about post-vaccine monitoring, that owner is truly engaged because he/she now understands this is something easy to do to help protect their cat. And you make it simple: This is what you need to feel, and this is what you need to look for. Almost all of our owners have been very proactive.
Dr. Sparkes: How do we have a meaningful conversation in a short period of time?
Dr. Boston: Most new puppy or kitten appointments are longer, so I think that’s a good time to introduce the topic. Usually you’re providing a lot of information that’s important to being a good pet owner. You dedicate more time to that appointment because you’re bonding with clients and getting them started on the right foot.
Dr. Vawter: We’ve adopted a fear-free protocol. We designed a cat room and taught the technicians to make the cat burrito, and don’t grab them by the scruff. Treat them in the carrier. Clients who never experienced this started asking why. Then they realize you’re trying to make their cat more comfortable, that you care. They become more open to listening to you. Building a fear-free practice opened the door for me to start having real conversations about risk development in cats.
Dr. Boston: It helps to put the risks in writing. Something catastrophic happens with spays/neuters in probably 1 in 10,000 cases. But clients still spay and neuter their pets. People will still vaccinate their cats when appropriate. Explaining why you’re doing it and the risk and engaging them in the process is important.
Dr. Fenimore: Providing written material is really helpful for owners. The AAFP has client brochures about vaccinating cats, the importance, and associated risks. Having worked in a shelter and appreciating infectious disease, I know the importance of vaccinating cats while being respectful of the frequency at which we vaccinate. Feline duration of immunity articles and vaccine guidelines from various organizations provide veterinarians with information to help prevent over-vaccination, but to omit vaccination is not an option.
Dr. Welborn: We shouldn’t stop vaccinating, but we have to concentrate on client education and be more vigilant with monitoring. Keeping better records potentially provides more information for oncologists to help us pinpoint other triggers that might be involved.
Dr. Vawter: Don’t jump off the deep end and stop vaccinating, but treat every cat as an individual. Try to assess each patient’s risk and take steps to mitigate that risk. Use a towel around a cat so you can get down low or try a tail vaccine. There’s no reason not to.
- Gobar GM, Kass PH. World Wide Web-based survey of vaccination practices, postvaccinal reactions, and vaccine site-associated sar-comas 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.
- Shaw SC, Kent MS, Gordon IK, et al. Temporal changes in characteristics of injection-site sarcomas in cats: 392 cases (1990-2006). JAVMA. 2009; 234(3):376-380.
- Hartmann K, Day MJ, Thiry E, et al. Feline injection site sarcoma: ABCD guidelines on prevention and management. J Feline Med Surg. 2015; 17(7):606-613.
- Phelps HA, Kuntz CA, Milner RJ, Powers BE, Bacon NJ. Radical excision with five-centimeter margins for treatment of feline injection-site sarcomas: 91 cases (1998-2002). JAVMA. 2011; 239(1):97-106.
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