Incidence

Many anecdotal reports exist of immune-mediated hemolytic anemia (IMHA), thrombocytopenia, and joint disease being brought on by vaccinations. Recently, a study did show the first clinical evidence of a temporal relationship between vaccination and IMHA in dogs. (Duval and Giger, JVIM, 1996,10:290-295) In this retrospective study, 58 dogs presenting with IMHA over a 27 month period were compared to a random control group of 70 dogs presenting for other reasons. 26% of the IMHA dogs had been vaccinated within 1 month prior to presentation, versus no increase in frequency of presentation within 1 month of vaccination in the control group. DHLPP vaccination was involved in every case. As well, rabies, bordetella, coronavirus, and lyme borrelia had been given concurrently in some of the dogs.

Recommendations

In a dog with a history of vaccination within one month of development of an immune-mediated disease, assuming the patient survives the disease, I would avoid vaccinating that animal in the future. Legal requirements for rabies vaccine would need to be met.

Vaccine Associated Sarcomas in Cats

Incidence

Incidence rates range from 1/10,000 cats vaccinated to 1/1000 cats vaccinated. A prospective study with private practitioners in Philadelphia shows a rate of 5/2000 cats vaccinated (to date, only at rabies vaccine sites). In this study the tumors arose 16 to 43 months after the last vaccination (average of 26 months). Three of the cats are dead following multiple recurrences and two cats are still alive with no recurrence or metastatic disease. This tumor type has not been observed in countries that do not vaccinate regularly for rabies or FeLV (i.e. Australia, England, Japan, New Zealand, Hawaii).

These tumors are associated primarily with killed vaccine products.

• Effect of multiple vaccinations at the interscapular site: Odds of developing a tumor at the interscapular site were compared for cats receiving 0, 1, 2, or 3 vaccinations at this site in their entire vaccination history:
• 1 vaccination = 50% increase in odds of developing a tumor
• 2 vaccinations in one site = 127% increased risk (over no vaccine)
• 3-4 vaccinations in one site = 175% increased risk.

Signalment

Any sex, any breed, any age.

History

Firm, irregular subcutaneous mass identified anywhere from 3 mo to 3 yr post-most recent vaccination.

Physical examination

Gross appearance

• Subcutaneous, firm, broad-based, non-painful, irregular mass
• Located at intrascapular region or hind leg (previous vaccination sites)
• Appearance of encapsulation is deceiving

Diagnostic evaluation

Cytologic evaluation of primary lesion

• Aspirates reveal mesenchymal cells: large, spindloid cells that show a wide degree of pleomorphism, with high nuclear to cytoplasmic ratio.
• May contain multinucleated giant cells.

Thoracic radiographs

• Metastasis to lungs uncommon, but two recent reports show as high as a 25% metastatic rate.

Histopathology is essential for definitive diagnosis

• Hallmarks of vaccine-associated sarcomas include:
• Spindle cells, multinucleated giant cells, and variable numbers of pleomorphic polygonal to histiocytoid cells with mild to marked atypia.
• May see lymphocyte infiltration.
• May see adjuvant (foreign material).
• Histologic diagnosis of the sarcoma may vary. Fibrosarcoma is most common, but may also see: malignant fibrous histiocytoma, osteosarcoma, rhabdomyosarcoma, chondrosarcoma. The biologic behavior of all of these are similar: locally very invasive, low to moderate metastatic rate.
• Any of these tumor types at a previous injection site should be considered a vaccine-associated sarcoma.

• Tumorigenesis is believed to occur due to either or both:
• localized, highly concentrated antigen deposition
• residual adjuvant.

The 2 vaccines most commonly associated with tumor development are the rabies and the FeLV vaccines, both inactivated products with high levels of adjuvant. The nature of the adjuvant material that induces tumor formation is unknown; however, aluminum adjuvants have been associated with post-vaccinal sarcomas in humans and aluminum has been identified in a few feline vaccine-associated sarcomas. Tumor development following univalent vs. multivalent vaccines has not been evaluated. There are 3 main steps to malignant transformation: initiation, promotion, and progression. There may be an underlying abnormality within a protooncogene (initiating factor) that is promoted by the adjuvant.

• Mutagenicity studies have evaluated the effect of diluted vaccine on cells growing in tissue culture. Rabies vaccine diluted down to 1:100 has a direct mutagenic and often fatal effect on cells. Studies with vaccine adjuvant alone (aluminum hydroxide) show a similar mutagenic effect on cells.
• A study has been performed in which 6 inactivated feline vaccines (3 different rabies and 3 different FeLV vaccines) were evaluated for evidence of postvaccinal vaccine site reactions (VSR) 21 days after SQ administration. Thirty-six cats total (6 cats/group) were evaluated. Twenty-one days after rabies vaccination, the VSR was approximately twice the size of VSR following FeLV vaccination. Of the 3 FeLV vaccines, one contained an aluminum adjuvant, one contained a non-aluminum adjuvant, and one contained no adjuvant. The severity of the VSR depended on amount and type of adjuvant, with aluminum being the most severe and no adjuvant being the least severe.
• Vaccine-associated sarcomas have been compared to trauma-induced intraocular sarcomas in cats. Intraocular tumors with similar histologic variability have been described following previous and/or persistent trauma; in both tumor types myofibroblasts were identified. Myofibroblasts are believed to represent a transitional stage of fibroblasts (or potentially macrophages) during wound healing. In the case of vaccine associated tumors, adjuvant may result in malignant transformation of these myofibroblasts, with subsequent tumor formation. Areas of transition between inflammation and tumor development have been observed in vaccine-associated tumors.
• Some of the confusion as to which vaccine may be most associated with tumor development stems from poor vaccine histories (i.e. - what vaccine given where and when?). KEEP GOOD RECORDS: vaccine type, manufacturer, and location given. Give Rabies Right rear and Leukemia, if it is an outdoor cat and really needs the vaccine, Left rear. FVRCP is given over the right front shoulder.

• Injectable lufeneron (Program) has been linked to the development of sarcomas in 3 cats. On the product label, listed adverse reactions include injection site reactions (granulomas) that have the same histologic appearance as granulomas formed at vaccine sites. The sarcomas identified following lufeneron injection have the same histologic appearance as VAS.

• Interval between vaccination and tumor development reported to be 3 months to 3 years; however, the interval is reported from the most recent vaccination, and the vaccine that caused the tumor may have been a previous one!
• Locally very invasive - wide surgical margins essential!
• Metastatic (most often to lung parenchyma) late in the course of disease, > 25% metastatic disease (lungs > regional nodes)

• Highly pleomorphic or anaplastic tumors have poorer prognosis
• Affected anatomy – i.e., wide surgical excision may not be possible
• poor for head, back, proximal limb; good for distal limb

• Wide (3 to 5 cm margins) surgical excision should be attempted. Important factors to keep in mind are the migration of tumor cells along fascial planes. This occurs in spite of the formation of a pseudocapsule around the tumor.
• Chance for control is best with first surgery
• Radical excision at the first occurrence is important for increased DFI (disease free interval) and overall survival.
• In one study by Hershey, et. al., only 2 of 24 cats treated with aggressive surgery alone were long term survivors. Recurrence occurred within 400 days. In this same study, DFI was compared when the surgery was performed by a specialist vs by a general practitioner. For the first 2 excision attempts, longer DFI were documented for surgeries performed at a teaching hospital. By the third attempt, there was no difference in DFI.

• A second study compared DFI and survival for cats treated with one (group 1) or more (group 2) surgeries, or surgery plus radiotherapy (group 3). If the cat had 1 surgery, it had been treated at a teaching hospital. Cats with 2 or more surgeries had at least the most recent surgery performed at a teaching hospital. Group 1 cats had median DFI and survival times of >16 months. Group 2 cats had a 5 month median DFI and a 13 month median survival. Group 3 cats had a 4.5 month median DFI and a 9 month median survival. Cats with ‘clean’ surgical margins had longer median DFI (>16 vs 4 months) and survival times (>16 vs 9 months) than cats with incomplete resections (p = 0.008).

• Cronin et al. 33 cats treated with radiation prior to surgery. Median DFI=398 days, median survival=600 days. 19 treatment failures, with 11 local recurrences, 4 metastatic disease, and 4 both recurrence and distant metastasis. 2 died without evidence of disease. The only predictor of treatment success was evidence of tumor cells at the margin of the excised tissue. 5 cats with 'dirty' margins had a median DFI=112 days, vs. 26 cats with clean margins DFI=700 days. This is a concern, as the theory behind radiation is that the cells left behind will be sterile and not able to multiply. Thus, did the radiation actually gain these cats more time that the surgery alone would have? That answer remains to be seen. Certainly, some of the cats with margins assessed as clean may have had some areas of tumor cells left behind, as histologic margin examination cannot evaluate every single mm of the excised tissue.
• Theoretically, radiation should be a good treatment option for microscopic disease. The true efficacy of radiotherapy against vaccine associated sarcomas in cats remains unknown. It is likely that radiation will be a necessary adjuvant to surgical treatment of these tumors.

Chemotherapy