Sarcoma is a malignant neoplasm of mesenchymal origin that may arise from different cell types. Although these tumors exhibit similar clinical behavior, they are traditionally classified according to their tissue of origin (Dennis et al., 2011). Fibrosarcoma is the most frequently identified histological type in FISS (Carneiro et al., 2019; Bloch et al., 2020). However, other histological subtypes, including rhabdomyosarcomas, liposarcomas, leiomyosarcomas, neurofibrosarcomas, malignant fibrous histiocytomas, undifferentiated sarcomas, and myxosarcomas, have also been described (Kliczkowska et al., 2015; Bloch et al., 2020).

The histogenesis of sarcomas is complex, and even with the aid of immunohistochemistry, difficulties may arise in precisely determining the cell of origin (Sirri et al., 2016). Due to these limitations, Dennis et al. (2011) suggested the adoption of broader terminology, such as soft tissue sarcomas or spindle cell tumors. Although histological distinction is morphologically relevant, its impact on therapeutic decision-making and prognosis has been questioned, since different cellular subtypes, despite distinct origins, tend to exhibit similar clinical behavior (Müller; Kessler, 2018; Dobromylsky; Richards; Smith, 2021; Liptak; Christensen, 2020).

Case series studies indicate that FISS frequently presents with a high histological grade, deep invasion of adjacent tissues, and a marked peri- and intratumoral inflammatory response, predominantly lymphocytic or lymphoplasmacytic. In addition, areas of necrosis, desmoplasia, and the presence of satellite nodules are common, features that contribute to the locally aggressive behavior of these neoplasms (Novaes et al., 2024).

In cats, the histological classification of sarcomas has been adapted from the system used in dogs, taking into account three main parameters: degree of cellular differentiation, mitotic index, and presence of tumor necrosis. The sum of these criteria defines the tumor’s histological grade (Dennis et al., 2011; Avallone et al., 2021). Due to the higher frequency of anaplasia, elevated mitotic rate, and extensive areas of necrosis, FISS tends to present with higher histological grades compared to sarcomas not associated with injection sites (Porcellato et al., 2017; Almeida; Pimenta; Sena, 2021), resulting in greater biological aggressiveness and a poorer prognosis.

Recently, a modification of the grading system for FISS in cats has been proposed, maintaining the parameters of mitotic index and tumor necrosis while replacing the criterion of cellular differentiation with quantification of the inflammatory response, based on the number of inflammatory and multinucleated cells. However, additional studies are still required to determine the actual impact of this modified approach on disease prognosis (Dobromylsky; Richards; Smith, 2021).

According to the Vaccine-Associated Feline Sarcoma Task Force, any nodule that develops at an injection site should be carefully monitored. Warning criteria include persistence of the mass for more than three months, a diameter greater than two centimeters, or an increase in size one month after administration (Romatowski, 1997; Morrison; Starr; VAFSTF, 2001; VAFSTF, 2005). These criteria are widely applied in clinical practice to guide early investigation of FISS.

Fine-needle aspiration cytology is considered a screening test, assisting in the identification of neoplastic lesions and in the differential diagnosis from abscesses, cysts, inflammatory processes, or granulomas (Bray; Polton, 2016; Liptak; Christensen, 2020; Almeida; Pimenta; Sena, 2021). However, studies indicate that only approximately 50 percent of FISS cases achieve a definitive diagnosis through this technique (Martano; Morello; Buracco, 2011). This limitation is related to the intense peritumoral inflammation, the presence of necrotic areas and fluid content that may compromise cytological interpretation, as well as the inability of the technique to precisely determine tumor histogenesis (Ogilvie; Moore, 2001; Kliczkowska et al., 2015). In contrast, histopathological analysis allows detailed evaluation of the neoplasm, enabling diagnostic confirmation and determination of the degree of malignancy (Avallone et al., 2021).

Imaging examinations, such as thoracic radiographs and abdominal ultrasonography, are indicated for the investigation of metastases, which occur in approximately 10 to 24 percent of cases. The lungs are the most frequently affected sites, followed by regional lymph nodes, skin, and liver (Hershey et al., 2000; Ladlow, 2013). Computed tomography and magnetic resonance imaging are particularly useful for tumor staging, allowing more precise assessment of tumor extent and degree of infiltration, in addition to contributing to appropriate surgical planning (Travetti et al., 2013; Zabielska-Koczywas; Wojtalewicz; Lechowski, 2017; Liptak; Christensen, 2020). Studies have demonstrated that measurement of FISS dimensions using these imaging modalities is superior to that obtained by manual palpation or calipers, reinforcing the need for their standardization during the clinical evaluation of these patients (Ferrari et al., 2017; Fleming et al., 2019).

Aggressive en bloc surgical resection of the neoplasm constitutes the main therapeutic modality for feline injection-site sarcomas (Phelps et al., 2011). However, due to the high rates of local recurrence and limited survival observed when surgery is used as a sole treatment, a multimodal approach is recommended. This strategy combines surgical planning with adjuvant therapies, aiming to increase the disease-free interval and, consequently, prolong the survival of affected cats (Martano et al., 2012; Ferreira et al., 2016; Almeida; Pimenta; Sena, 2021).

Surgical excision should be performed with lateral margins of at least three to five centimeters and removal of at least two adjacent deep tissue planes (Figure 2). In many cases, this approach requires resection of structures such as ribs, vertebrae, or the scapula, as well as amputation of the affected limb when indicated (Ogilvie; Moore, 2001). Although the achievement of tumor-free surgical margins does not demonstrate a direct influence on overall survival time, it is associated with reduced local recurrence rates and prolonged disease-free intervals (Giudice et al., 2010; Phelps et al., 2011; Zabielska-Koczywas; Wojtalewicz; Lechowski, 2017; Müller; Kessler, 2018; Liptak; Christensen, 2020).

Despite the performance of wide-margin surgeries, recurrence rates remain high, ranging from 50 to 86 percent, typically within four to six months. This variation is related to factors such as tumor location, histological grade, and the experience of the surgeon performing the procedure (Hershey et al., 2000; Poirier et al., 2002; Séguin, 2002; Spugnini et al., 2007; 2011).

Figure 2 Source: Silva et al. (2023).

Chemotherapy constitutes a therapeutic option used both for palliative control and as adjuvant or neoadjuvant treatment of sarcomas, particularly those with a high histological grade (Hartmann et al., 2015). Poirier et al. (2002) demonstrated a significant difference in time to tumor recurrence between animals treated exclusively with surgery and those that received chemotherapy as part of the therapeutic protocol. The combination of neoadjuvant chemotherapy with surgical resection resulted in an increased disease-free interval in the evaluated animals.

Administration of the chemotherapeutic agent prior to surgery promotes consolidation of the tumor pseudocapsule, facilitating greater drug penetration due to preservation of local microvascularization. In addition, tumor volume reduction is observed, allowing for wider surgical margins during resection (Bray; Polton, 2016).

Doxorubicin is the cytotoxic agent most frequently used in the treatment of FISS, owing to its superior therapeutic response and lower incidence of adverse effects compared to other available drugs (Ogilvie; Moore, 2001; Poirier et al., 2002; Zabielska-Koczywas; Wojtalewicz; Lechowski, 2017). In cats, however, its use may be associated with side effects such as anemia, nephrotoxicity, and myelosuppression. Therefore, patients with renal insufficiency, hemolytic anemia, or autoimmune diseases present important restrictions regarding the use of this chemotherapeutic agent (Poirier et al., 2002).

Radiotherapy may be employed either in the preoperative or postoperative period in the treatment of feline injection-site sarcomas. When used prior to surgery, its objective is to reduce tumor burden and eliminate neoplastic cells disseminated in adjacent tissues, thereby contributing to the achievement of more adequate surgical margins (Ladlow, 2013; Hartmann et al., 2015). In the postoperative context, radiotherapy acts as a strategy to control possible residual cells, reducing local recurrence rates (Ladlow, 2013).

Patients undergoing combined surgical resection and radiotherapy demonstrate lower recurrence rates and longer disease-free intervals compared to those treated with surgery alone (Cohen et al., 2001). However, this therapeutic modality is associated with relatively frequent adverse effects, including suture dehiscence, edema, seroma formation, cutaneous desquamation, alopecia, depigmentation, and, in some cases, signs of local infection (Cohen et al., 2001; Bloch et al., 2020).

The presence of metastases, large tumor volume, and a prolonged interval between surgical procedure and initiation of radiotherapy are associated with shorter survival times. These findings indicate that disease progression and early implementation of adjuvant treatment are determining factors for a more favorable prognosis (Bowlt, 2015).

Electrochemotherapy consists of the combination of a physical method, characterized by the application of electrical pulses, with a chemical method involving the administration of chemotherapeutic agents (Spugnini et al., 2008; Impellizeri et al., 2016; Plaschke et al., 2016). Exposure of cells to short, high-intensity electrical pulses induces transient alterations in the cell membrane, with reorganization of the lipid bilayer and formation of temporary hydrophilic pores, resulting in increased membrane permeability, a process known as electroporation (Giardino et al., 2006; Impellizeri et al., 2016).

Electroporation enables faster entry and higher intracellular concentrations of chemotherapeutic drugs within neoplastic cells, significantly enhancing their cytotoxicity (Cemazar et al., 2008; Plaschke et al., 2016). A relevant aspect of this technique is its cellular selectivity, as the adjacent connective tissue is preserved, reducing scar tissue formation and contributing to improved local structural preservation (Giardino et al., 2006).

Studies indicate that the efficacy of electrochemotherapy in a single session is reduced in large nodules, making more than one therapeutic session necessary (Mali et al., 2013; Plaschke et al., 2016). Systemic adverse effects, such as hematological, muscular, cardiac, or renal alterations, are rarely reported. However, mild areas of local inflammation may occur, generally resolving spontaneously within two to three weeks (Spugnini et al., 2007).

In cats with high-grade FISS undergoing combined surgical resection and electrochemotherapy, the interval to tumor recurrence ranged from twelve to twenty-two months, a value significantly higher than that observed in animals treated with surgery alone, in which recurrence occurred, on average, between four and six months (Spugnini et al., 2007; 2011). The drugs indicated for electrochemotherapy must be hydrophilic, exhibit low cellular permeability, and possess high cytotoxicity. They may be administered intravenously or intratumorally in animals presenting with single or multiple neoplasms. Bleomycin is the chemotherapeutic agent most widely used in this therapeutic modality, as it meets these criteria and is associated with low rates of adverse effects (Mir, 2006; Spugnini et al., 2017).

The prognosis of cats affected by injection-site sarcoma is variable and depends on multiple factors, including tumor location and size, histological grade, presence of metastases, choice of therapeutic protocol, and achievement of wide surgical margins, among other clinical and pathological aspects (Ladlow, 2013; Müller; Kessler, 2018; Gomes et al., 2025). Animals that do not undergo any form of treatment have a mean survival time of approximately four months (Ladlow, 2013). In contrast, the best clinical outcomes have been observed when multimodal therapeutic approaches are adopted, combining surgical resection with adjuvant therapies such as electrochemotherapy, chemotherapy, and radiotherapy (Séguin, 2002; Bray; Polton, 2016).

With regard to prevention, the primary recommendation is to vaccinate cats only when indicated, in accordance with the guidelines established by the Vaccine-Associated Feline Sarcoma Task Force, as well as to avoid the administration of substances potentially associated with exacerbated inflammatory reactions (Romatowski, 1997; Morrison; Starr; VAFSTF, 2001; Hartmann et al., 2015). Vaccination should be avoided in cats with a previous history of FISS, and, whenever possible, alternative routes of administration, such as oral or intravenous routes, should be considered. In addition, repeated multiple injections at the same site should be avoided, as these measures contribute to reducing the risk of developing this neoplasm (Ladlow, 2013).

The selection of injection sites that allow wide surgical resection, including the possibility of limb amputation, is also considered a relevant strategy to improve patient prognosis should FISS develop (Morrison; Starr; VAFSTF, 2001). Furthermore, studies indicate that the administration of vaccines at very low temperatures may be associated with an increased risk of FISS development, and it is therefore recommended that immunobiological products be kept at room temperature for a few minutes prior to administration (Ladlow, 2013; Hartmann et al., 2015).