+ Feline Vaccine-Associated Sarcomas

• Strong association between inactivated vaccines (i.e., FeLV and rabies) and STS at injection-sites
• Prevalence: 0.010%-0.036%, but may be as high as 0.1%
• Non-vaccine associated STS are uncommon in cats
• VAS develop in areas of inflammation induced by adjuvanted vaccine products
• VAS is histologically similar to traumatically-induced ocular sarcoma
• VAS odds increase by 50% after 1 vaccination, 127% after 2 vaccinations, and 175% after 3 vaccinations, but others have found no association with multiplicity of vaccinations
• VAS also reported at injection sites for anything that can cause local inflammation such as non-adjuvanted killed feline vaccines, lufenuron, corticosteroids, antibiotics, and microchips (due to hair follicles)
• VAS reported in series of cats receiving killed adjuvanted panleukopenia, rhinotracheitis, and calicivirus vaccine in Canada
• Interval between vaccination and VAS between 3 months and 3 years
• 2 proposed causes:
• Adjuvant rabies and FeLV vaccines have immunogenic adjuvants causing local and persistent inflammatory responses resulting in fibroblast and myofibroblast proliferation and neoplastic transformation
• Deposition of a high concentration of antigen

+ Vaccine Adjuvants

• Vaccine adjuvant is most commonly implicated as the cause of local tissue inflammation
• Aluminium (hydroxide or phosphate) is a common component of vaccine adjuvants and has been identified in post-vaccination granulomas and VAS
• Specific role of aluminium, other adjuvants, adjuvant components, and vaccine antigens is unknown
• Aluminium may only be a marker of previous vaccination and other vaccine components may induce or enhance inflammatory process resulting in sarcoma development
• Post-vaccination inflammatory reactions are common (80%-100%) although size of inflammatory lesions twice as large for rabies compared to 3 FeLV vaccines
• Adjuvant FeLV containing aluminium most consistently produces post-vaccination vaccine-site inflammation, whereas no inflammation is observed with non-adjuvanted FeLV vaccinations

+ Vaccination Site Inflammation

• Degree of inflammation is not reduced by administering vaccines intramuscular
• Post-vaccination inflammation resolves by 3 months
• Incisional biopsy is recommended for inflammatory mass > 2 cm in diameter or persisting > 4 months
• VAS and lymphocytes in VAS have a mild to strong reaction to PDGF and strongly express c-jun whereas non-VAS are not associated with either PDGF or c-jun
• Neoplastic cells in VAS closest to lymphocytes stain strongest for PDGF implying that lymphocytes in VAS may secrete PDGF, recruit macrophages, and cause myofibroblast proliferation
• No apparent association with FeLV or FeSV or papillomavirus or polyomavirus antigen and DNA

+ Pathology

• VAS have increased necrosis, inflammatory cells (lymphocytes and macrophages in particular), and mitosis compared to non-VAS
• VAS are mesenchymal in origin and can be FSA, malignant fibrous histiocytoma (or myofibroblastic sarcoma), OSA, CSA, leiomyosarcoma, undifferentiated sarcoma, lymphangiosarcoma, or rhabdomyosarcoma
• VAS are histologically similar to trauma-induced ocular mesenchymal tumors suggesting a similar pathologic mechanism of inflammation and wound healing

+ Vaccination-Associated versus Non-Vaccine-Associated Sarcoma

• VAS sites: interscapular, dorsolateral thoracic and flank, paralumbar, and femoral regions
• non-VAS sites: head (including oral cavity), limbs, bone, tail, and other
• VAS is diagnosed in 55% (94/170) cats with STS
• VAS, and not non-VAS, are associated with overexpression of PDGF, EGF, and TGF-β

+ Prevention

• Recommendations for prevention of VAS are controversial:
• Change vaccination sites
• Minimize use of polyvalent vaccines
• Use of non-adjuvant vaccines
• Avoid aluminium-based adjuvants
• Avoid over-vaccinating cats
• National Feline Vaccine-Associated Sarcoma Task Force states that no vaccine to be administered in the interscapular area with
• Rabies in the distal right pelvic limb
• FeLV in the distal left pelvic limb
• Other vaccines in the distal right thoracic limb
• Subcutaneous and intramuscular injections cause similar degree of inflammation and tumor production
• Subcutaneous sites are recommended as they are more easily detected

+ Signalment

• Mean age 8-12 years
• No sex or breed predilection

+ Clinical Signs

• Firm swelling at or near previous vaccination injection site < 3 years after vaccination
• Lymphadenopathy or respiratory distress due to metastatic disease is a rare presentation

+ Diagnosis

• FNA will differentiate abscess, granuloma, foreign body, and neoplasia
• Vaccine granulomas have reactive fibroblasts which can be difficult to differentiate from VAS
• Needle-core or incisional biopsy should be planned so biopsy tract can be removed with definitive procedure
• VAS have increased necrosis, inflammatory cells (especially lymphocytes, macrophages, and non-degenerate neutrophils ± reactive fibroblasts, eosinophils, mast cells, plasma cells, and multinucleate giant cells) and cycling cells compared to non-VAS
• Injection reaction is characterized by basophilic to azurophilic, amorphous, or globular intracytoplasmic material with macrophages or multinucleated giant cells

+ Imaging Studies

• Regional and thoracic radiographs for evidence of local invasion and metastatic disease
• Ultrasound, CT, or MRI is useful for determination of surgical margins or radiation field
• Tumor volume based on contrast-enhanced CT scans is approximately twice volume detected using palpation

+ General Considerations

• Treatment options can be based on tumor size
• Small to medium-sized tumors: surgery (± adjunctive chemotherapy or immunotherapy)
• Large-sized tumors: radiation therapy or chemotherapy can be used to downsize tumor prior to surgical resection or, alternatively, surgery can be used to downstage VAS to microscopic disease for postoperative radiation therapy

+ Surgical Management

• Excisional biopsy is not recommended as seldom curative and recurrence results in more difficult 2nd surgery
• Interscapular location and infiltration makes surgical resection difficult even with partial scapulectomy and excision of epaxial muscles and dorsal spinous processes
• Amputation has a higher cure rate than surgery in the interscapular region
• Aggressive surgical resection is associated with recurrence rates of 30%-70% (despite complete excision)
• Local tumor recurrence usually observed within 6 months
• However, radical surgery with 3-5 cm lateral margins and 2 fascial layers deep (or body wall resection) has been reported in 30 cats with no evidence of local tumor recurrence with a mean follow-up time of 17.2 months

+ Radiation Therapy

• Radiation therapy is recommended because of difficulty in achieving complete excision and durable tumor control
• Adjuvant protocol: 3 Gy fractions Monday-Wednesday-Friday for 7 weeks with total 63 Gy or 2.7 Gy fractions Monday-to-Friday for 19-25 fractions
• Brachytherapy involves placement of radioactive sources into or near the tumor and results in high dose of radiation to the tumor bed while minimizing exposure and toxicity to surrounding tissue

+ Chemotherapy

• Chemotherapy has some beneficial effects in cats with VAS
• Doxorubicin, mitoxantrone, vincristine, and paclitaxel have in vitro activity against VAS-cell lines
• Doxorubicin (25 mg/m 2 or 1 mg/kg), carboplatin (200-240 mg/m 2), mitoxantrone, and cyclophosphamide have occasionally resulted in either PR or CR in cats with gross disease
• Doxorubicin alone is associated with a 39% overall response rate in cats with gross disease with 15% CR, 24% PR, and median response duration of 84 days
• Median DFI is significantly longer when cats with microscopic VAS are treated with doxorubicin (388 days v 93 days)
• Doxorubicin and cyclophosphamide result in 50% PR, but response duration is not durable with a median 125 days, however, MST for responders is significantly longer than non-responders (242 days v 83 days)
• However, doxorubicin did not improve survival time in cats treated with surgery and radiation therapy (674 days v 842 days)

+ Immunotherapy

• Non-specific immunomodulation (i.e., mixed bacterial vaccine or levamisole) has no effect on DFI or MST
• Acemannan may have some effect although small number of cats and used in combination with radiation therapy
• Acemannan causes macrophages to secrete more TNF-α, IL-1, PgE 2, and IFN, enhances macrophage phagocytosis and, through inhibition of glucosidase activity, may effect tumor cell adhesion and metastasis
• IL-2, combined with surgery and brachytherapy, significantly improves MST (16 months v 8 months), however, anaphylaxis is a problem with IL-2 administration

+ General Considerations

• 0%-25% metastatic rate to lungs and other organs including skin, subcutaneous tissue, regional lymph nodes, mediastinum, liver, and pelvis
• p53 mutations are present in 20% (2/10) VAS and Mab-240, an anti-p53 antibody, was positive in 81% and cats with cytoplasmic expression of p53 have a significantly shorter DFI than those with nuclear expression of p53
• MMP 2 expression and lack of MT-MMP 16 expression and survival time are significantly correlated with a MST 822 days v 261-400 days if MMP 2 is not expressed or MT-MMP 16 is expressed
  • poor prognostic factors include:
• Castrated male
• Large tumor size

• 1 surgery

• Incomplete excision
• Long interval between surgery and radiation therapy
• ± site (extremity longer survival time due to amputation and ability for complete resection)
• MST 345-576 days

+ Surgery

• Local tumor recurrence rate 25%
• Metastatic rate 25%
• Median DFI 10 months
• MST 345-576 days with a 1-year survival rate of 36.0% and 2-year survival rate 13.8%
• DFI is significantly influenced by VAS location, surgeon, completeness of histologic resection, and number of surgeries:
• Median DFI is significantly longer with tumors on the extremity than other sites (325 days v 66 days)
• Median DFI is significantly longer if 1st surgery is wide rather than marginal (325 days v 79 days)
• Median DFI for complete histologic resection is significantly longer than incomplete resection (> 16 months v 4 months)
• Median DFI is significantly longer following 1 surgery than ≥ 2 surgeries (> 16 months v 5 months)
• Median DFI 94 days if treated by general veterinarian or 272 days if referral surgeon
• MST is significantly influenced by surgeon, completeness of histologic resection, and number of surgeries:
• MST for complete histologic resection is significantly longer than incomplete resection (> 16 months v 9 months)
• MST is significantly longer following 1 surgery than ≥ 2 surgeries (16 months v 13 months)

+ Surgery and Radiation Therapy

• Local tumor recurrence rate 41%-45% and is significantly higher with > 1 surgery (31% v 55%)
  • metastatic rate 12%
  • median DFI 398-405 days
• Median DFI depends on the number of surgeries prior to radiation therapy and complete surgical resection:
• Median DFI is significantly greater with 1 surgery before radiation therapy (469 days v 345 days)
• Median DFI is significantly decreased with incompletely resected tumors (112 days v 700 days)
• MST 600-842 days with:
• 1-year survival rate 86%
• 2-year survival rate 44%
• 3-year survival rate 28%
• 4-year survival rate 24%
• 5-year survival rate 12%
• MST depends on sex and tumor size:
• Castrated males have a significantly shorter survival time than spayed females (638 days v 735 days)
• Large tumors prior to the 1st surgery have a significantly shorter survival time