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A causal relationship has been reported between vaccination and the development of STS at injection sites in cats. Most vaccine‐associated sarcomas are categorized as FSA, but other histologic variants include rhabdomyosarcoma, myxosarcoma, chondrosarcoma, undifferentiated sarcoma, and malignant fibrous histiocytoma. Many of these sarcomas are associated with inflammation (Couto et al. 2002). The initial reports of a possible relationship between vaccination and STS began in the late 1980s and early 1990s (Hendrick and Goldschmidt 1991). Kass et al. reported that in cats receiving FeLV vaccination within two years of tumorigenesis, the time between vaccination and tumor development was significantly (P = 0.005) shorter for tumors developing at sites where vaccines are typically administered than for tumors at other sites. Univariate analysis, adjusted for age revealed associations between FeLV vaccination, rabies vaccination at the cervical/interscapular region and at the femoral region, with STS development at the vaccination site within one year of vaccination. In a large, prospective, case‐controlled trial, neither a specific vaccine brand nor a manufacturer was found to be associated with sarcoma development. Interestingly, there was evidence to suggest that certain long‐acting injectable drugs may also be associated with the formation of sarcoma (Kass et al. 2003). STS developing adjacent to the site of microchip implantation has been reported in a cat (Daly et al. 2008), and dog (Vascellari et al. 2006).

Most often younger cats are affected (6–7 years), with a second peak at 10–11 years. FISAS usually occur in the subcutis. In contrast, non‐injection site‐associated FSAs are often dermal in origin (Kass et al. 1993). One case has been reported suffering from hypertrophic osteopathy with concurrent FISAS (Salgüero et al. 2015). The reported prevalence in Poland differs between 0.1 and 0.85% in general and referral clinics, respectively (Kliczkowska et al. 2015). The incidence risk of FISAS per year in the UK has been estimated to be 1/16 000–50 000 cats registered by practices, 1/10 000–20 000 cat consultations, and 1/5000–12 500 vaccination visits (Dean et al. 2013). Early in the new millennium, the risk of developing a sarcoma in North America was evaluated at 0.63 sarcomas/10 000 cats and 0.32 sarcomas/10 000 doses of all vaccines (Gobar and Kass 2002). The number of vaccines administered increases the risk of developing FISAS. The risk for a cat to develop a sarcoma after administration of a single vaccine is 50% higher than the risk of a cat not receiving any vaccine. The risk for a cat given two vaccines is approximately 127% higher, and the risk for a cat given three to four vaccines is 175% higher (Kass et al. 1993).

FISAS are best diagnosed by biopsy as cytology is not reliable. A wedge or punch biopsy must be taken from a part of the mass that later will be included in the surgical resection.

MRI and/or CT of the tumor and thorax is indicated to look for pulmonary and skip metastases and evaluate size and extent of the tumor as these masses often have tendrils extending to or into underlying muscles and other tissues like bony structures (spinous process, scapula). In 10–25% of cases, pulmonary metastases are found. The lungs are the most common site for FISAS metastases, although they can also occur in the subcutaneous tissue, liver, and lymph nodes. Therefore, draining lymph nodes should be palpated and assessed by cytology and diagnostic imaging (Kuntz et al. 1997; Romanelli et al. 2008; Rousset et al. 2013). Skip metastases are highly correlated with tumor recurrence (P = 0.001) (Zardo et al. 2016).

Dual‐phase CT angiogram and MRI identify a similar number of peritumoral lesions. The extensive overlap between imaging features of neoplastic and nonneoplastic lesions precludes definitive identification of neoplastic peritumoral FISAS lesions using CTA or MRI (Nemanic et al. 2016).

STS grading system used in canines, depth of infiltration, surgical margins, and Ki‐67 index did not relate to recurrence. Instead, the size of the tumor, measured after formalin fixation, with an optimal cutoff of 3.75 cm, and the mitotic count, with an optimal cutoff of 20 mitoses/10 HPF were prognostic for recurrence and survival time (Porcellato et al. 2019). In another study, grade using the canine criteria was prognostic for metastasis but no local recurrence (Romanelli et al. 2008). In a study of cats with soft tissue sarcomas that included FISAS and non‐FISAS, modification of the criteria used to grade soft tissue sarcomas in canines was applied and was prognostic for survival time: median survival time for cats with low‐grade tumors was 900 days, with intermediate grade 514 days, and high grade 283 days (Dobromylskyj et al. 2021). In this modified system, mitotic score and tumor necrosis score were the same as in canine tumors, but inflammation score was used instead of tumor cell differentiation score (Dobromylskyj et al. 2021).

Aggressive first surgical excision with wide (Figure 4.8) to radical (3–5 cm) margins results in the best tumor‐free interval and survival time in cats with soft tissue FSA. Cats with complete excisions have significantly longer median tumor‐free interval (>16 vs. 4 months) and survival time (>16 vs. 9 months) than those with incomplete excisions (Davidson et al. 1997). Marginal excision is the major reason that high recurrence rates (up to 70%) have been reported (Davidson et al. 1997; Hershey et al. 2000). Advanced imaging of the tumor is recommended (McEntee and Samii 2000; Morrison and Star 2001) for appropriate treatment planning. Median time to recurrence was significantly longer when a cat was operated by a specialist surgeon (274 days) compared to a referring veterinarian (66 days) (Hershey et al. 2000). Other prognostic factors for survival time that are significant include local recurrence, presence of distant metastasis, and the number of surgeries (Cohen et al. 2001; Eckstein et al. 2009; Romanelli et al. 2008). Overall reported median survival time after surgical treatment has been 11.5–20.3 months (Davidson et al. 1997; Dillon et al. 2005), and median survival time after complete excisions (>16 months) has been significantly longer compared to incomplete excisions (9 months) (Davidson et al. 1997).

Figure 4.8 (a) Wide excision of a feline injection‐site‐associated sarcoma. The skin incision has been performed around the subcutaneous tumor. (b) En bloc resection of tumor mass and surrounding tissue barrier. (c) Visible dorsal spinous processes (arrows) of cervical vertebrae after tumor removal. (d) Closure in layers with simple interrupted suture patterns. Blue nylon skin sutures are visible.

The most important prognostic factor for local recurrence, and subsequent survival time, is the achievement of clean surgical margins (Banerji and Kanjilal 2006; Cronin et al. 1998; Hershey et al. 2000; Kobayashi et al. 2002). Cats undergoing limb amputation for FISAS did better than local excision anywhere else on the body (Hershey et al. 2000). Size of the tumor has been reported to influence survival time after surgery (Cohen et al. 2001; Dillon et al. 2005; Spugnini et al. 2007b). To achieve wide tumor resection, resection of the dorsal portion of interscapular vertebral spinous processes, partial scapulectomy (Trout et al. 1995), lateral body wall resection (Lidbetter et al. 2002), and hemipelvectomy (Barbur et al. 2015; Straw et al. 1992) may be necessary (Davidson et al. 1997; Davis et al. 2007; Hershey et al. 2000; Romanelli et al. 2008). Some surgeons promote using wider surgical margins than the commonly recommended 2–3 cm lateral margins with one tissue plane in depth, because of the high recurrence rate of FISAS. Fifty‐seven cats with FISASs were treated by wide resection using 4–5 cm lateral margins and one fascial plane deep to the tumor, including partial scapulectomy and removal of dorsal spinal processes if indicated. Histologically complete resections were reported for 95% of the tumors; 5% had tumor cells in the margins. Local tumor recurrence developed in 39%, with distant metastasis in 21%. About 51% of the cats were alive at an overall median follow‐up period of 366 days (median follow‐up period for the alive cats was 600 days) (Romanelli et al. 2008).

Phelps et al. (2011) reported in a case series on 91 cats treated by radical excision with five‐centimeter margins including 2 muscle planes or bone deep to the tumor (Figure 4.9). Any anatomic structures that fell within the determined margins were excised, including thoracic wall, abdominal wall, dorsal spinous processes, ilial wing, and scapula. If the tumor was subcutaneous and could be elevated away from underlying structures with 5‐cm margins, the underlying structures were not excised. Although excision of FISAS resulted in a metastasis rate similar to rates reported previously, the local recurrence rate appeared to be substantially less than rates reported after less aggressive surgeries. Overall median survival time was 901 days. Out of 91, 13 (14%) cats had local tumor recurrence, 18 (20%) cats had evidence of metastasis after surgery. The median survival time of cats with and without recurrence was 499 and 1461 days, respectively. The MST of cats with and without metastasis was 388 and 1528 days, respectively. Tumor recurrence and metastasis were significantly associated with survival time, whereas other examined variables were not. Major complications occurred in 10 cats, including 7 with incisional dehiscence. The best predictor for the development of wound healing complications after wide excision of FISAS is an increased duration of surgery (Cantatore et al. 2014).

Figure 4.9 Radical excision of a feline injection‐site‐associated sarcoma. (a) Five cm margins are measured and marked with sterile marker on the skin. (b) The radical excision required abdominal body wall excision and excision of facias in the pelvic limb and over the epaxial muscles, en bloc with the tumor. (c) It was possible to close the skin defect primarily, without the use of reconstructive techniques, which is often the case in cats after radical excision.

It is important to consider that the margin size will alter directly after removal of the specimen. Significant decreases in surgical margin length in FISASs specimens occur immediately following excision (prior to formalin fixation). Median tumor volume decreases significantly between in vivo and ex vivo assessments regardless whether measurements are obtained from 2‐D or 3‐D CT images. Subgross evaluation of tumor‐free margins from on‐slide grossly normal surgical margins to pathologist‐reported histologic tumor‐free margin overestimates the actual (histologic) tumor‐free margins (Terry et al. 2016, 2017).

Radical surgery is easier with the guidance of advanced imaging in the form of CT or MRI compared to manual palpation. Preoperatively the skin is marked as required for sufficient margins. Available amount of skin for closure has to be assessed preoperatively. If insufficient, a skin flap can be used (Montinaro et al. 2015), or skin stretcher can help to recruit extra skin in two to three days. Changes in the muscular form according to the forelimb positioning must be appreciated. It is important to have an in‐depth anatomical knowledge of the interscapular region of the feline patient to approach the study of any pathology located there and, in particular, to set up an appropriate therapy for the FISASs (Longo et al. 2015).

Adjuvant radiation therapy can improve outcomes. Median DFIs after complete resection combined with radiation therapy were 405–1110 days. Survival times after complete resection combined with radiation therapy were 476–1290 days. DFIs after resection with contaminated margins combined with radiation therapy were 112–600 days. Median survival times for contaminated margins combined with radiotherapy were 502–900 days (Cohen et al. 2001; Cronin et al. 1998; Eckstein et al. 2009). According to Eckstein et al. (2009), radiation therapy of residual microscopic tumor improves median DFI and survival time (20 and 30 months, respectively) compared to residual macroscopic tumor (4 and 7 months, respectively). However, even with neoadjuvant radiation therapy and complete margins after surgical excision, local recurrence has been reported to be 42% (Kobayashi et al. 2002).

In a study of 76 cats with vaccine‐associated sarcomas, 26 cats were treated with chemotherapy in addition to surgery and radiotherapy. Neither recurrence rates, rate of metastasis, nor survival times were improved in the chemotherapy group (Cohen et al. 2001). Neoadjuvant and adjuvant chemotherapy with epirubicin (25 mg/m²) combined with anatomical resection of FISAS resulted in local tumor recurrence in 3 cats (14%) at days 264, 664, and 1573 after surgery (Bray and Polton 2016), according to the authors these results demonstrate superior rates of tumor‐free survival and disease‐free interval when compared to historical controls.

Of 11 cats treated by stereotactic radiation for FISAS, 8 responded. The median DFI was 242 days, and an MST of 301 days (Nolan et al. 2013).

No significant effect of chemotherapy only in the treatment of FISAS in clinical settings has been reported yet, although the high metastatic rate is an indication for systemic treatment (Bregazzi et al. 2001; Cohen et al. 2001). Possibly the tyrosine kinase inhibitor, imatinib, will have an effect on FISAS. It inhibited the growth of FISAS in a murine xenograft model (Katayama et al. 2004) and could affect FISAS due to the presence of platelet derived growth factor receptor which is a receptor tyrosine kinase. In one phase 1 clinical trial of imatinib, 4/9 cases trialed had FISAS. In these four cases, a response to treatment was noted and consisted predominantly of short‐term tumor stabilization (Lachowicz et al. 2005).

In vitro doxorubicin and etoposide alone and in combination differentially alter FISAS cell viability and cycle (Hill et al. 2014).

Although masitinib did not directly enhance FISAS cell radiosensitivity under normal in vitro conditions (Turek et al. 2014), combined chemo/radiation therapy has been reported to result in a significant reduction in tumor growth compared to the respective mono‐therapies with either doxorubicin or radiation. These results support the use of the concomitant chemo/radiation therapy for adjuvant treatment of FISS, particularly in advanced or recurrent disease where surgery alone is no longer feasible (Petznek et al. 2014).

Immunotherapy has been reported successful in xenogeneic cells secreting human interleukin‐2 (IL‐2). Totally, 16 cats with FISAS were treated, two of which had local recurrence and three had metastatic disease. MST was 16 months in IL‐2 treated cats vs. 8 months for nontreated cats (Quintin‐Colonna et al. 1996).

A second study conducted with human and feline IL‐2 resulted in a lower tumor recurrence rate compared to control cats not receiving immunotherapy after surgery and iridium‐based radiotherapy (39% and 28% vs. 61% for the controls) (Jourdier et al. 2003).

Despite the recommendation for vaccine administration to be on the distal aspect of a limb to facilitate the attainment of clean surgical margins via limb amputation, a high proportion of tumors still developed in the interscapular region in a recent study evaluating the demographics of VAS. For prevention, administration of any irritating substance should be avoided. Vaccination should be performed as often as necessary, but as infrequently as possible. Nonadjuvanted, modified‐live, or recombinant vaccines should be selected in preference to adjuvanted vaccines. Injections should be given at sites at which surgery would likely lead to a complete cure; the interscapular region should generally be avoided. Postvaccination monitoring should be performed (Hartmann et al. 2015; Shaw et al. 2009). However, these current feline vaccine site recommendations may not be appropriate for cat owners as was concluded by Carwardine et al. (2014) based on an anonymous internet‐based cross‐sectional study in the UK wherein cat owning respondents would not allow amputation of their cats’ forelimb (20%), hindlimb (15%), or tail (15%).