Feline injection site sarcoma (FISS) is a rare malignant tumour and appropriate surgical management provides the best long-term prognosis. The pathogenesis of FISS is unclear, but it occurs at sites commonly utilised for injections. Surgery offers the most significant improvement in survival when it is aggressive and augmented with radiotherapy.
Pathogenesis and epidemiology
A theoretical causal relationship between rabies vaccination and fibrosarcomas was first recognised in the USA in 1991, with successive studies linking increased usage of rabies and feline leukaemia virus (FeLV) vaccines and the development of these tumours. Since this time, several studies have further characterised FISS and implicated other injectable medications (antibiotics, corticosteroids, NSAIDs), suture material and microchips in their development. Though the definitive pathogenesis remains elusive, the putative mechanism is that chronic inflammation at the injection site undergoes neoplastic transformation.
Epidemiological study of FISS is challenging because the appropriate study population is difficult to select (ie all cats, cats visiting a practice or cats receiving an injection). The estimated incidence of FISS in the UK is 1 in 16,000 to 50,000 per year in veterinary registered cats. In the USA, the incidence is estimated to be 1 to 4 in 10,000 vaccinated cats; however, direct comparison cannot be made between these groups as the inclusion criteria and populations studied differed between studies.
Recommendations for prevention include vaccinating only as frequently as necessary (guidelines are available), avoiding adjuvanted vaccines (although there is no consistent evidence that formulation change alters incidence) and avoiding unnecessary injections. Vaccinating in the distal limb is advocated so that wide surgical excision can be performed, but vets in the USA and Europe still mostly inject the interscapular region. Recording the vaccination site is sensible.
Given the low incidence of FISS, vaccination still provides low-risk essential protection, but protocols tailored to individual requirements are important. Allowing vaccinations to reach room temperature prior to administration (not leaving unrefrigerated for hours) may reduce the inflammatory response. A “three, two, one” protocol has been suggested to monitor for post-vaccination masses: any mass at the site of injection three months or more following vaccination, more than 2cm in diameter, or that increases in size one month after vaccination should be investigated and surgical excision of the mass is warranted.
Histology and behaviour
The majority of FISS are fibrosarcomas, but behave very aggressively compared to other sarcomas, with faster growth, increased local invasiveness (often extending along fascial planes) and higher recurrence rates following surgery (14 to 59 percent). Metastasis is reported to occur in 10 to 28 percent, most commonly to the lungs, and therefore complete staging is essential. Contrast enhanced CT or MRI imaging allows for accurate planning and appropriate decision making; incomplete margins can result in recurrence as soon as two weeks post-operatively. A disease-free interval of approximately two years is possible with tumour-free margins, as opposed to 100 days with incomplete removal. Recurrence rates of up to 50 to 70 percent within six months are reported even with clean margins.
Radical surgical excision with follow-up adjunctive treatment offers the best prognosis. Complete en-bloc resection with a minimum of 3 to 5cm lateral margins (Figure 1) and one or two complete deep fascial planes is advised. Given that numerous reports document that surgeons achieve smaller histopathological margins than they plan or report intra-operatively for a variety of skin tumours, and given the invasive nature of FISS, it is wise to aim for 5cm lateral margins and two deep fascial planes.
A retrospective study (Phelps et al., 2011) found that a 5cm lateral margin resection can achieve a median survival time of 900 days, with 14 percent local recurrence and 20 percent distant metastasis after surgery. With no recurrence or metastasis following complete excision, survival times of 1,500 days are reported (probably surgical cure). These results should be interpreted with caution; limitations of the study included 35 percent of the cats being lost to follow-up prior to documentation of recurrence and cats which underwent preoperative radiation were excluded, which may have introduced bias.
Interscapular masses are the most common location for FISS. En-bloc resection of the dorsal spinous processes and superficial paraspinous musculature (generally limited to the trapezius, but potentially including part of the origin of the cleidocephalicus or deeper rhomboideus) can achieve the deeper fascial plane necessary. Some cats can have a wide-based stance and lameness following extensive surgery, or difficulty holding the head up; this generally improves with time, but owners should be clearly warned.
Partial scapulectomy (Figure 2) is indicated when tumour lateral margin extends over the dorsal aspect of the scapula. Resection of greater than 50 percent of the scapula may substantially compromise limb function and necessitate securing the scapula to the trunk using bone tunnels and circumcostal sutures (as per scapula luxation), but in the authors’ experience, such large resections are rarely necessary. Tumours located on the thoracic and abdominal wall may require body wall resection, and the thoracic wall can be reconstructed with various combinations of latissimus dorsi muscle flaps (Figure 3), diaphragmatic advancement and/or the use of synthetic mesh implants.
Tumours arising from the limbs (more common in the USA) can be amputated and these patients have been shown to have improved outcomes compared with masses located elsewhere. In cases where the sarcoma is invading the proximal hindlimb and pelvic soft tissues, hemipelvectomy is indicated. Iatrogenic, intraoperative seeding of soft tissue sarcomas has been reported in human literature and one should avoid breaching of the tumour. A large skin excision increases the risk of incisional dehiscence, but this is not a primary concern. Skin flaps can be used to close large defects, but these are generally avoided if follow-up radiation treatment is planned. Most dehiscence heals by second intention; this can be facilitated using negative pressure wound therapy.
Adjunctive radiation treatment can decrease recurrence and prolong remission times. Neo-adjunctive (pre-surgical) radiotherapy is also described; however, disease-free interval and survival time is reduced compared to post-surgical adjunctive radiotherapy. Chemotherapy is largely unproven and is generally used when radiotherapy is not available. The use of pre- and post-surgical epirubicin improved disease-free intervals in comparison to historical controls (Bray and Polton, 2016) and in another study (Hahn et al., 2007), doxorubicin in combination with radiotherapy and surgery was found to prolong disease-free intervals. Immunotherapy (transfected canary-pox virus, locally expressing IL-2) has recently been shown to prolong the disease-free interval when used in combination with radical surgery and radiation. Whilst immunotherapy may be a promising alternative, efficacy has only yet been shown for low grade FISS.
The management of FISS requires an aggressive surgical approach requiring thorough preoperative planning, and the use of adjunctive radiation treatment improves outcomes. There is a lack of multivariate analysis in the literature, making treatment recommendations and prognostics challenging. Though rare, the serious consequences of this disease and its association with vaccinations and other injectable medication make preventative measures paramount