Vaccine-Induced Sarcoma Reading LIst

[Bill and I are college profs, have access to MedLine … which links us to the 6 major veterinary journals. I have read more than 200 articles, covering the past 20 years of professional debate. The following have been the most useful to us for the history, pathology, interventions, and prognosis. Would be happy to have Bill send pdf files to anyone from school. Our home connection is simply too slow.]

Starter Bibliography: [see http://www.avma.org/vafstf/bibrefs.asp] “Vaccine-Associated Feline Sarcoma Task Force.”

This gives a reference beginning: key journals in the profession, key parameters for disease, essential researchers (*No one is more important than Mattie Hendrick at UPenn … if you can, read all of her articles), and conference proceedings (these are of interest because it suggests what has been available to local vets in the way of continuing education).

Chronology of Key Articles with Highlights Noted:

1991: Hendrick, MJ and MH Goldschmidt. “Do injection site reactions induce fibrosarcomas in cats” (letter). JAVMA, 1991: 199:968.

Hendrick, MJ and CA Dunagan. “Focal necrotizing granulomatous panniculitis associated with subcutaneous injection of rabies vaccine in cats and dogs (1988-1989)”. JAVMA, 1991: 198: 304-305.

1992 [This is 8 years after Mattie Hendrick began her tireless research into vaccine induced sarcoma in cats. 1985, Pennsylvania mandated rabies vaccine for cats and Hendrick noted the appearance of a new, probably chemically-induced soft tissue tumor in cats. Coincidentally, 1985 was when leukemia (killed vaccine/adjuvanted) became an annual option. This was also a time when raccoon rabies from NJ and fox rabies from central Canada swept the northeast, prompting an increase in the annual vaccination rate.]

Dubielzig, RR et al. “Myofibroblastic sarcoma associated with rabies vaccination in a cat. Veterinary Pathology 1992: 29: 438.

Goldschmidt, MH et al. Skin tumors of the dog and cat. 1^st edition. Tarrytown, NY: Pergamon Press, 1992:162-7.

· I do not have this … but it is important to note the appearance of VAS in a textbook this early. Anyone seeking more than a journal article as reference should find this important.

·

Hendrick, M et al. “Vaccine-induced sarcomas in the cat: identification and localization of aluminum by electron probe x-ray microanalysis.” Veterinary Pathology 1992: 29: 439.

Hendrick, M et al. “Post vaccinal sarcomas in cats: epidemiology and electron probe microanalytical identification of aluminum.” Cancer Research 1992: 52: 5391-4.

• The above two articles are the confirmation of the adjuvant role in the inflammatory process thought to incite carcinogenesis.

1993

Esplin, D. Glen et al. “Postvaccination sarcomas in cats.” JAVMA, 1993: 202: 1245-47

• Useful contact addresses
• Commentary endorses vaccination [“Information would seem to indicate that the risk of death and disease from failing to vaccinate is considerably greater than the risk of a sarcoma.”]
• Since it is under “Special Commentary,” it is fair to say that this represents the “official story” as of 1993.

Kass, PH et al. “Epidemiological evidence for a causal relation between vaccination and fibrosarcoma tumorigenesis in cats.” JAVMA 1993: 203:396-405.

• Kass joins Hendrick as a key figure in the documentation of VAS. All of his articles are worth noting.

1996

Lester, Sally et al. “Vaccine Site-Associated Sarcomas in Cats: Clinical Experience and a Laboratory Review (1982-1993).” Journal of the American Animal Hospital Association. 1996: 32: 91-95.

• Overview of type of vaccine, location of vaccine—and incidence of neoplasm.
• 1^st article that I located to claim epidemiological experience in much higher incidence than professionally reported.
• Open rebutting of the American Association of Feline Practitioners suggestion that “variation of the injection site may help decrease the incidence of neoplasia.”
• Authors note: “However, in the authors’ practice,” the change in vaccination protocols which resulted in an abrupt decline in the number of vaccine site-associated sarcomas was a switch from killed to modified-live virus vaccines.”
• Conclusion: “Until the exact etiology is known, it would seem prudent to use the fewest killed vaccine products possible in cats.” [* So Natty has been given killed vaccines his entire lifetime … and all that time, the profession has been discussing the dramatic risk of killed vaccines.]

Macy, Dennis W. and Mattie Hendrick. “The potential role of inflammation in the development of postvaccinal sarcomas in cats.” Veterinary Clinics of North America: Small Animal Practice. 26: #1: January 1996: 103-109.

• Essential reference for local vets. No vet in practice should have missed this key article.
• Several aspects make this an important article. 1] It highlights the utter lack of hard statistics (opening paragraph cites a range of “10 cases in 100,000 vaccinations” or “1 in 1000” or “increased numbers of sarcoma cases—‘between 21% and 61%” (what use of such numbers? and what do they tell us about the state of science in veterinary practice? ; 2] It notes “The increased incidence of fibrosarcomas in cats parallels the introduction and widespread use of two killed adjuvanted vaccines note previously used in the cat.” 3] Implicates the adjuvant in the intensified inflammatory process perhaps guilty of causing the cancerous changes. 4]Emphasizes the need to use nonadjuvanted products.

1997

Coyne, Michael et al. “Estimated prevalence of injection-site sarcomas in cats during 1992.” JAVMA 1997: 210/2:249-251.

• This is a highlighted “Scientific Reports” in the central professional journal. All practicing vets should have read it.
• Startling in what it reveals re: practicing vets—and their accountability. Soliciting VAS incidence from all current members of the American Association of Feline Practitioners (1993), these researchers designed a questionnaire re: vaccination protocols (brands, types, sites, injection protocol). Of the 1,112 AAFP members surveyed, 235 (21%) “returned responses sufficiently complete for inclusion in the study.”
• Response rate was low (21%) even after “additional request for participation.”
• At no point could the “method of diagnosis” be determined.
• This article confirms the under reporting, the lack of current knowledge, as well as the fear of litigation surrounding VAS.

1998

Al-Sarraf, Reneé. “Update on feline vaccine-associated fibrosarcomas.” Veterinary Medicine, August 1998, 729-35.

• Useful contact addresses
• Overview historically and clinically
• Histological and biological behavior
• Photos (surgical, incisional)
• Recommendations of note (esp. given date). Informed consent, issues of granulomas turning into sarcomas, and “Moral questions also arise secondary to vaccination.”
• Cautionary note re: labeling of vaccinations “A three-year rabies vaccine should not be used yearly. Note that some three-year products are labeled as one-year products.” [see Couto note below]
• Additional key references cited.

*Vaccine Associated Feline Sarcoma Symposium” (JAVMA special issue)

Bergman, Philip J. “Etiology of feline vaccine-associated sarcomas: history and update.” JAVMA, 1998: 213: 1424-25.

• 2 key questions: “do postvaccinal granulomas inevitably lead to sarcoma”

and “do all VAFS start as palpable granulomas”?

• “We know that postvaccinal reactions to some rabies and FeLV vaccines may be more common than previously reported”
• “In the last 24 months, only 180 cases of the VASF have been reported … likely representing a gross under-representation of the number of cases of VAFS in the United States.”

Hendrick, Mattie J. “Feline associated sarcomas: current studies on pathogenesis.” AJVMA, 213:1425-1426.

• Useful in interpreting pathology reports.

------. “Historical review and current knowledge of risk factors involved in feline vaccine-associated sarcomas.” AJVMA, 213: 1422-3.

• Re: variables. “It has been speculated that orange tabby cats are more commonly affected. All of these variables [including syringe, etc.] have existed since cats were first vaccinated and it is unlikely that they have a major role in the pathogenesis of vaccine-associated sarcoma development.” [This struck home because Nat’s former vet claimed that vaccinations played no role in these tumors. She claimed it was genetic. She still persists in this view.]

Couto, C. Guillermo and Dennis W. Macy. “Review of treatment options for vaccine-associated feline sarcoma.” JAVMA, 213: 1426-27.

• Again, evidence of curiously useless statistics: “The prevalence of soft tissue sarcomas after vaccination varies between 1/1,000 and 1/10,000.”
• Key assertion: “The most important recommendation for prevention of vaccine-associated tumors would appear to be not overvaccinating. Kass et al clearly documented that the “risk of vaccine-associated tumors increases with the number of vaccines administered.”
• “With respect to rabies vaccination, annual vaccination against rabies by use of a 3-year rabies product should be discouraged (i.e., for fear of malpractice).”
• “The indiscriminate use of FeLV vaccine should be stopped because epidemiologic data suggest that it is the number 1 case of vaccine-associated sarcomas.”
• What may be the most astonishing admission (I cannot believe how it is put): “In 1985, we traded a modified live rabies virus vaccine that caused problems in 1/500,000 cats for a killed virus adjuvanted vaccine that induced tumors in 1/1000 cats (boy, were we smart!)”
• More suspect statistics: “Even attempts at aggressive wide-surgical excision are often incomplete and result in a 30 to 70% failure rate.” [What are we to make of these useless statistical spreads?]

Starr, Robin. “Vaccine-associated feline sarcoma task force: a new model for problem solving in veterinary medicine.” AAVMA, 213: 1428-29.

• This strikes me as a classic “putting the lid on” article. It blankets dissent, dismisses disagreement as counter-productive. Its conclusion speaks for itself: We have funded 6 excellent studies and averted a national public relations crisis by presenting balanced news features and press releases. We demonstrated that the profession is concerned and seeking solutions.”

Richards, James. “Education/communication: history and current status.” JAVMA, 213: 1429-30.

• Familiar with Richards from the Cornell cat newsletter, I was disappointed by the “extremely rare,” “wait and see” advice re: VAS in same.
• This brief capsule shows that Richards was primarily concerned with warding off any suspicion on the part of the cats’ families. He notes” Even though the ideal way for a cat owner to receive information about vaccine-associated sarcomas is from his or her veterinarian, the high profile necessitated a public response.”
• His final note “Requests for information and interviews were all directed to a single person (the chairperson of the education/communication subgroup) to ensure an accurate response.” Control of the message is essential in such instances.
• “The proactive, profession-wide effort to inform veterinarians and cat owners has increased veterinary awareness of the issue and minimized the appearance of alarmist messages in the media, which are essential to ensuring that cats continue to receive vaccinations appropriately.” The point of almost 10 yrs of research has been that cats have not been receiving vaccinations appropriately.
• Richards’ role as communications officer led me to review tenured professorships as well as conference sponsors: overwhelmingly, they are endowed/sponsored by pharmaceutical companies.
• PS: a follow-up note in JAVMA 213: 785: “Dr. James R. Richards of the Cornell Feline Health Center used the occasion to proclaim how successful the campaign to educate veterinarians and cat owners about this problem has been so far.” What can this mean? Given the circumstances we find ourselves in 9 yrs later, do any of us feel successful?

2000

Hershey, A. Elizabeth and Mattie Hendrick, et al. “Prognosis for presumed feline vaccine-associated sarcoma after excision: 61 cases (1986-96).” JAVMA, 216:58-61.

• Best summary of time to first recurrence [TFR].
• Many variables … single modality of therapy … combination … qualification of surgeon, etc. Extreme underreporting.
• Confirms the signature aspects of VAS: “Compared with sarcomas that are not associated with vaccination, VAS are more commonly characterized by anaplasia, rapid growth, ulceration, and necrosis, and are often poorly encapsulated and infiltrate along fascial planes.”
• Useful citations for additional pathological journals.

2001

Atlantic Coast Veterinary Conference.

McEntee, Margaret. “Vaccine-Associated Sarcomas: Diagnosis and Treatment Strategies.” [http:www.vin.com/VINDBPub/SearchPB/Proceedings/PRO5000/PROO389.htm]

• Excellent overview of history, treatment
• Essential summary of the task force materials [useful to send to someone as a primer to the disease]

2002

Couto, S.S., et al. “Feline Vaccine-associated fibrosarcoma: morphologic distinctions.” [http://www.vetpathology.org/cgi/content/full/39/1/33]

• Excellent guide to pathology reports. Staging, grading, cell morphology discussed.
• Useful additional references … and key figures to contact.

27 WSAVA Congress: Annual Symposium. “Update on Feline Fibrosarcoma.” [http://www.vin.com/proceedings/Proceedings.plx?CID=WSAVA2002&PID=2635]

• Primarily an update … but suggests what local vets should be aware of as of 2002. Readily available to caretakers online; many should have attended their professional conference.

Gobar, GM and Philip Kass. “World wide web-based survey of vaccination practices, postvaccinal reactions, and vaccination-site associated sarcomas in cats.” JAVMA, 2002:220:1477-1482. [Note: I have ordered this but do not yet have it.]

2003

Kass, Philip et al. “Multicenter case-control study of the risk factors associated with development of vaccine-associated sarcomas in cats.” JAVMA, 2003: 223:1283-1292.

• VAS = “an emerging epidemic problem in the United States.”
• “Even conservative estimates of disease incidence lead to projections that thousands of new cases will develop each year.”
• “Although research efforts are underway to determine the mechanism, of oncogenesis and roles of the inflammatory and immune responses following vaccination, avoidance of vaccination altogether currently remains the only way to prevent the development of FVASs.”
• “That vaccines played a causal role in the increase in the number of soft tissue sarcomas identified in cats during the 1990s is no longer in question.”
• “An abundance of evidence consistently points to a heightened risk among cats receiving FeLV, rabies virus, and possibly other vaccines.”
• History /review of adjuvant issues
• History of single manufacturer’s FVRCP as causative agent.
• Genetic variables? “One source of . . . variability is genetic propensity, although there is no a priori reason to suspect a genetic propensity in unrelated cats treated at individual practices.”
• Local practice protocols that may impact risk.
• “The frequency of routine vaccine administration could be important if the number of vaccines a cat receives over its lifetime somehow sensitizes the cat to the point that a final vaccine leads to tumorigenesis.”
• Case method review … quite useful in tracking individual responses.
• Essential chart comparing administration of FVRCP, Rabies, FeLV.
• Caution re: latest vaccines: “Although newer and purportedly less inflammatory vaccines (e.g., recombinant vaccines) reached the market after this research began, they were not used frequently enough in our study population to allow us to make any claims about their relative safety.”
• Failure of study to seek complete vaccination histories of animals.
• “As new products, perhaps purporting to be safer than their predecessors, achieve market penetration, thorough and exhaustive epidemiologic studies (i.e., case-control studies) will remain the only pragmatic strategy in verifying that such biologics will ultimately do more good than harm.”

Jelinek, František. “Postinflammatory sarcoma in cats.” Exp Toxic Pathology, 55:167-172.

• Useful graphics and pathology assessments.
• Extensive additional references.

Brearley, Malcolm. “Vaccine-associated feline sarcoma” [letter to editor]. The Veterinary Record, 12April03:478.

• UK journal … gives a British vet’s perspective on the issue professionally … clarifies terminology issues.

2004

Madewell, Bruce R et al. “Vaccine site-associated sarcoma and malignant lymphoma in cats: a report of six cases [1997-2002]” Journal of the American Animal Hospital Association. Jan/Feb 2004:40:47-50.

• Useful cases studies in that article provides pathology assessment, review, and considers questions of metastasis.
• To brief to be useful in determining additional modalities of treatment.
• Emphasizes signature aspects of vaccine associated sarcomas.

World Small Animal Veterinary Association [2004]: 29^th convention.

Ogilvie, Gregory K. , “Injection Site and Vaccine Associated Sarcomas: New advances for a new millennium.”

• Reviews literature and treatment.
• Emphasizes “the 1^st surgery should be considered definitive rather than relying on a 2^nd or 3^rd for salvage.”
• “More recent studies suggest that the treatment of choice for this tumor type is aggressive surgery in combination with high doses of pre- or post-op radiation therapy.”
• Extensive current references … and speaker contact information.
• *Available online (as all these conference papers are).

2005

VAFSTF. “The current understanding and management of vaccine-associated sarcomas in cats.” JAVMA, 226:1821-1842.

• These roundtables represent the professional orchestration of the issue. While they represent some of the best researchers, they also control the message. Considering the pharmaceutical sponsorship of these events and the pharmaceutically-endowed chairs that many of these vets hold, the discussion format may still be the best way for the cautious reader to glimpse the future of practice.
• Contradictions abound, attempts to silence disputes are evident.
• Full contact information is given for the 16 participants. Useful for any who wish to forward case studies of their animals. Find the participants who might be interested in your cat’s circumstance—send documentation as complete as possible.

World Small Animal Veterinary Association [2005]: 30^th convention.

Ford, Richard. “Infectious disease change is in the wind.”

• Review of VAS
• Consideration of recombinant DNA (modified live) vaccines.
• Discussion of Duration of Immunity (DOI) … consideration of overvaccination: [bold print in the original]: “At issue is the fact that a protective immune response is likely to persist for several years following vaccination and, for selected vaccines, routine administration of annual boosters is not necessary.”

Hershey, A.E. et al. “Aberrant p53 expression in feline vaccine-associated sarcomas and correlation with prognosis.” Veterinary Pathology, 2005: 42: 805-811.

• Extremely technical immunohistological review.
• Very extensive references pertinent to our needs.
• Slides of path specimens may offer clues to pathology reports.
• More contact information

2006

Dean, Rachel et al. “Study of feline injection site sarcomas.” [letter to editor] The Veterinary Record, 4nov2006: 641.

• UK contact information
• Review of UK clinical information

Chang, H.W. et al. “Vaccine-associated rhabdomyosarcoma with spinal epidural invasion and pulmonary metastasis in cat.” Veterinary Pathology, 2006: 43: 55-58.

• Additional key references [authors are Taiwanese]
• Highly technical, but illustrated discussion of metastasis.

The 2006 American Association of Feline Practitioners Feline Vaccine Advisory Report [available on list]

Kirpensteijn, Jolle. “Feline injection site-associated sarcoma: is it a reason to critically evaluate our vaccination policies?” Veterinary Microbiology, 2006: 117: 59-65.

• Additional practice references
• Review of history, protocols
• Emphasis in individualized vaccination
• Stressed ethical issues as well as informed consent.

Banerji, Nilanjana et al. “Somatic alterations of the p53 tumor suppressor gene in vaccine-associated feline sarcoma.” AJVR, 2006:67:1766-1772.

• Research case study of cats referred to University of Minnesota for evaluation and/or treatment.
• While the genetic discussion is highly technical, the surrounding discussion of treatment, outcome, subsequent treatment is highly informative.
• References again stress materials easily available to local vets.

2007

Guy, Bruno. “The perfect mix: recent progress in adjuvant research.” “Focus on Vaccines—Progress and Pitfalls.” Nature Reviews/Microbiology. 2007:5:505-527.

• While focusing on human vaccination protocols, this article illuminates many issues concerning the safety of animal vaccines.
• Exhaustive and highly technical references.