Soft-tissue sarcomas are common mesenchymal tumours of the cat, representing approximately 7% of all skin and subcutaneous neoplasia reported in this species. Two distinct clinical presentations are classically observed, a multicentric form occurring in young cat less than five years old associated with the feline sarcoma virus (FeSV), and a solitary tumour development in cats usually older than eight years (average 12 years) that are typically feline leukaemia (FeLV) negative, and therefore is non-FeSV associated. However, more recently there has been a reported increase in solitary sarcomas affecting cats at a younger and in a wider age range and developing at the site of previously administered vaccinations. The vaccines involved have been primarily killed adjuvanted rabies and feline leukaemia products, although inactivated feline viral rhinotracheitis / calicivirus / panleukopaenia (FVRCP) vaccines have also been implicated. These tumours have been variously referred to in the literature as feline post-vaccinal, post-vaccination, vaccination - induced and vaccination-site (VS) sarcomas. Vaccines that have been associated with tumorigenesis are not of a specific brand nor from any particular manufacturer. While epidemiological evidence supports a causal relationship between sarcomatogenesis and killed adjuvanted vaccines, there have been no reports statistically linking sarcomas to modified-live or recombinant vaccines, nor of canine post-vaccinal sarcomas associated with usage of killed adjuvanted rabies vaccines. Neither has association between sarcoma formation and non-vaccinate injections has been demonstrated.
The most frequently reported feline post-vaccinal tumour is the fibrosarcoma, but are other tumour types have been reported. Chondrosarcomas, rhabdomyosarcomas, myofibroblastic sarcomas, osteosarcomas, malignant fibrous histiocytomas, undifferentiated sarcomas and multiple histopathological sarcomatous tumours have also been reported. Histopathological assessment alone is considered supportive rather than diagnostic of post-vaccinal sarcomas, and a physical and temporal relationship to the vaccination site is needed. The estimations of incidence of post-vaccinal sarcoma formation range from 1 to 2 per 10,000 cats vaccinated to 13 per 10,000 total vaccinations administered.
Soft-tissue sarcomas are mesodermal tumours of connective tissue, named after their cellular origins i.e. fibrosarcomas originate from fibroblastic connective tissues, histiocytomas may emerge from more primitive mesenchymal tissue capable of either fibroblastic or histiocytic differentiation, and malignant schwannomas arise from Schwann (nerve sheath) cells. Whilst the initiating cause of most sarcomas is unknown, a causal relationship has been confirmed between multicentric sarcomas and FeSV in younger cats, and foreign implants and single-event or chronic trauma with subcutaneous, musculoskeletal and ocular sarcomas. In 1991, a rise in the incidence of feline soft-tissue sarcomas was reported, the trend coinciding with legislation mandating compulsory rabies vaccination of cats in Pennsylvania, USA. Subsequently, the increased frequency of neoplasia was demonstrated to be occurring at vaccination sites, and an epidemiological relationship between vaccination, vaccination-site and tumour occurrence established.
The pathogenesis of post-vaccinal sarcoma is as yet unknown. No breed, sex or age predisposition has been demonstrated. Although the tumours are generally well demarcated, they are locally invasive, and reoccurrence after surgical excision is frequent. Metastases, however, are rarely reported. The cellular composition of the tumours is variable, but typically spindle cells, multinucleated giant cells and pleomorphic histiocytic / polygonal cells with some degree of atypia, focal areas of necrosis, peripheral infiltration of lymphocytes and histiocytes, and granulation tissue and fibrosis are seen. A number of factors have been implicated as potential causes of tumorigenesis, and the aetiology may be multifactoral and involve cocarcinogenic interaction. Possible causes proposed and under investigation include chronic inflammation and proto-oncogenic induction at the vaccine site by vaccine adjuvants, especially aluminium, vaccine antigens, cytokines and the presence of exogenous and endogenous feline retroviruses e.g. FeLV, FeSV, feline syncytium forming virus and endogenous feline leukaemia virus (en-FeLV).
Preceding the increased incidence of feline sarcomas was the release of killed, aluminum - adjuvant rabies and FeLV vaccine products to the veterinary profession. These products were, and are currently, in extensive use in especially North America. Adjuvants are utilised to augment and prolong the immune response to the inoculated antigen(s) likely through macrophage activation and cytokine production. Aluminium is a common component of adjuvants used in inactivated feline vaccines. Allergic foreign body granuloma formation has been reported in humans following use of aluminium-based adjuvants, and aluminium has been implicated in the pathogenesis of a human soft-tissue sarcoma following total hip replacement and linked to the development of local chronic inflammation and granuloma development at vaccine sites in dogs and cats. Histological reviews of post-vaccinal inflammatory reactions and fibrosarcomas in cats found well-demarcated foci of granulomatous panniculitis with lymphocyte and macrophage infiltration. Foreign material composed of aluminium and oxygen was detected within macrophages at these sites, and suspected of causing aberrant fibrous connective tissue repair due to resultant persistent inflammatory and immunological reactions. However, as post-vaccinal sarcomas have been reported following use of vaccines not containing aluminium-based adjuvants, its is possible that aluminium may simply be a "marker" verifying the vaccine site or a promoter of a marked chronic inflammatory response allowing action of cocarcinogenic factor(s).
Inflammation may be an important catalyst of post-vaccinal tumorigenesis. Sarcomas at vaccination sites are morphologically and immunohistochemically similar to feline ocular sarcomas that occur following trauma, with fibroblasts and myofibroblasts involved in the fibrous repair of wound healing and chronic inflammation. Myofibroblasts may represent a transitional stage of development of fibroblasts or other primitive mesenchymal cells of capillary adventitial origin stimulated by the growth factors (cytokines) produced during the wound healing process. The proliferation of these cells in response to the inflammation initiated by adjuvants or other vaccine components increases the possibility of neoplastic transformation due to proto-oncogenic activation, whether due to chromosomal mutation or retroviral integration or activation in the cell genome. Fibrosarcomas are known to occur at injury sites in FeSV positive cats. Cytokines have a significant role in tissue repair, and transforming growth factor-b (TGF-b) released during the wound healing response has been shown to stimulate sarcoma formation in chickens infected with Rous sarcoma virus (RSV). No such effect was shown by other growth factors of inflammation (epidermal growth factor, platelet-derived growth factor, insulin-like growth factor, TGF-a). Research directed at identifying growth factors and their receptors in both normal and post-vaccinal altered (panniculitis and sarcomatous) feline skin and panniculus is currently being pursued. However, FeLV vaccines usually produce less injection-site inflammation than rabies products and yet epidemiological studies have shown a decreased risk of post-vaccinal tumour formation with rabies when compared with FeLV vaccination. It has been proposed that certain vaccine antigens alone or in combination may potentiate or enable cocarcinogens resulting in oncogenic expression, especially when multiple antigens are administered or monovalent products are routinely injected at the same vaccination site.
The role of the oncornaviral subfamily of exogenous and endogenous retroviruses in post-vaccinal sarcoma formation remains uncertain. The feline sarcoma virus is a replication-defective variant of FeLV. These are acute transforming viruses that incorporate endogenous feline retroviral sequences that exist as part of the feline genome (proto-oncogenes) forming potent initiators of tumorigenesis. Oncogene activation itself does not lead to tumour development in the absence of promoting cofactors such as host inflammatory factors, foreign body reactions or chemical carcinogens. A recent immunohistochemical and polymerase chain reaction study of 130 feline post-vaccinal fibrosarcomas failed to detect the presence of exogenous FeLV and FeSV. However it was noted that this did not preclude a role for these viruses, particularly in light of the rapid onset of these sarcomas (often within three to nine months post-vaccination), a situation more likely with viral oncogenesis than the extended prodromal interval seen with tumours associated with chronic inflammatory reactions. Exogenous retroviruses may reside in bone marrow, leading to a neoplastic transformation of fibroblast precursors, whose proliferation is stimulated by cytokines present at the site of vaccine-induced inflammation. Further, defective endogenous proviral sequences or insertions may result in the in vivo expression of oncogenes due to the presence cocarcinogens in exogenous FeLV and FeSV negative animals.
Due to its aggressive nature, no single treatment regime has proven routinely effective in control of feline post-vaccinal sarcoma. Surgical resection with wide (3 cm) and deep (fascia and muscle up to full-thickness body wall) margins is recommended as the principal form of clinical management of soft-tissue sarcoma. Due to microscopic neoplastic infiltration beyond the fibrous pseudocapsule that is formed as the tumour compresses surrounding tissue, en bloc excision is essential. However, post-vaccinal sarcomas are significantly more likely to redevelop than spontaneously arising sarcomas with greater than 62% tumour reoccurrence reported. This may be due not only to their invasive nature, but also to the difficulty of adequate resection in the inter-scapular region, the most commonly recorded site of these tumours. Mesenchymal tumours such as malignant histiocytoma and neurofibrosarcoma are considered radioresistant, partially due to the presence of hypoxic areas within the tumour parenchyma. However, radiotherapy may be of assistance in cases of regrowth and non-resectable post-vaccinal neoplasia, especially if performed after surgical debulking to the level of microscopic disease to lessen the degree of tumour hypoxia. Preoperative radiation has also been recommended to reduce the tumour to a size compatible with surgical removal, but as yet there have been no published reports on the efficacy either method as an adjunct therapy for post-vaccinal sarcoma, nor of comparison between megavoltage and orthovoltage regimes. Chemotherapy with doxorubicin, cyclophosphamide, methotrexate and vincristine has proved of limited benefit, in part caused by high connective tissue content and poor vascularity of the tumours. The chemotherapeutic use of carboplatin or adriamycin may be more promising.
More recently immunotherapy with acemannan, an antiviral and immunomodulating b -(1,4)-linked mannan from the plant Aloe barbadensis has produced partial and complete tumour regression in recurrent canine and feline fibrosarcomas. Acemannan is administered by intraperitoneal and intralesional injection, and enhances macrophage production of the cytokines TNF-a (tumour necrosis factor-a ), interferon-g (INF-g ), and interleukin-1 and 6 (IL-1, IL-6). It has been shown to stimulate cytotoxic T-lymphocyte function in vitro (via IL-1) and macrophage phagocytosis and cytotoxicity against tumour cells. Acemannan has therefore been suggested as an adjunct to surgical and radiation therapy, and clinical trials are ongoing.
Due to the high rate of tumour recurrence, the prognosis in cases of post-vaccinal sarcoma is generally regarded as poor, with a reported median survival of 9 months (range 6 to greater than 12 months) with a 45% survival rate at one year after en bloc surgical resection and radiotherapy. Staging of the tumour is recommended prior to initiating a definitive course of therapy particularly if extensive surgery or adjunct radiation therapy is being considered. Mitotic index and tumour site have been shown to have a direct correlation with prognosis, while size, histological appearance, and duration of growth have not been statistically linked with survival times.
The issue of post-vaccinal sarcomas has generated much discussion within the veterinary community in the United States, and has lead to the establishment of the Vaccine-Associated Feline Sarcoma Task Force (VAFSTF), a joint body composed of veterinary researchers and clinicians, and representatives of the USDA (Department of Agriculture) and Animal Health Institute. The objectives of this group are to establish the true incidence of post-vaccinal sarcoma, determine causal and prognostic factors and to heighten the awareness of the disease in the veterinary profession and the public. The initial VAFSTF recommendations include recording vaccine site, type and lot number as part of the permanent medical record, strict adherence to the manufacturers' recommendations, use of alternative vaccination routes (e.g. nasal, topical) if available, and standardising vaccination site protocols. The latter recommendation is the subject of some debate. The task force advises vaccination as far distally as possible on the hind leg (right for rabies, left for FeLV), the unstated intention being to allow amputation of the limb if necessary to ensure adequate tumour resection. As the prevalence of post-vaccinal sarcomas is perceived as low, and due to technical and practical problems that may arise (difficulty in vaccine administration, paucity of skin for surgical closure following wide margin resection, owner resistance to limb amputation) this recommendation has not met with universal acceptance. This protocol may also be ill-advised as by standardising the vaccination site, it ensures repeated localised exposure to vaccinal components of possible carcinogenic nature.
As inflammation appears to be a necessary precursor and moderator of post-vaccinal tumour development, it is therefore prudent to minimise the post-vaccinal inflammatory response. This may be achieved by avoidance of adjuvant vaccines, especially those utilising aluminium, and instead using modified-live, recombinant or monovalent products if available and efficacious, varying and recording vaccination sites whilst avoiding the inter-scapular region, and avoiding unnecessary vaccination altogether. Owners should also be advised to monitor and report any lump persisting after vaccination. The optimal time for excision of post-vaccination granulomas has not been determined. Most masses present at vaccination sites three or more weeks after inoculation are granulomas, and only a small number progress to a neoplastic stage. It is advisable to biopsy any mass that evidences signs of continuing growth or that is not spontaneously resolving to differentiate between these two entities as the treatment regimes and prognostic outlooks vary significantly.