Veterinary Society of
Surgical Oncology

GENERAL CONSIDERATIONS

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

CLINICAL FEATURES

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

TREATMENT

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

PROGNOSIS

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

VACCINE-ASSOCIATED AND SOFT TISSUE SARCOMAS

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