Feline Injection-Site Sarcoma

Feline injection-site sarcoma (FISS) is a highly aggressive, locally invasive mesenchymal neoplasm that arises at sites of prior subcutaneous or intramuscular injection in cats. It is also known as vaccine-associated sarcoma (VAS) or vaccine-associated fibrosarcoma, though it can occur after any injectable product, including non-adjuvanted vaccines, corticosteroids, antibiotics, insulin, and microchips. FISS is characterized by its rapid growth, high local recurrence rate after inadequate excision, and a relatively low metastatic potential (approximately 10-25% at the time of death). Histologically, these tumors are typically fibrosarcomas, but can also be malignant fibrous histiocytomas, rhabdomyosarcomas, osteosarcomas, or chondrosarcomas. They are notable for the presence of a dense lymphocytic and plasmacytic inflammatory infiltrate at the tumor periphery, which is a hallmark feature. The tumor arises from perivascular or perimuscular connective tissue, often within the panniculus muscle layer or between muscle fascicles. The biological behavior is characterized by infiltrative growth along fascial planes, making complete surgical excision challenging. The tumor is graded based on histologic features (mitotic index, necrosis, cellular pleomorphism) and staged using the TNM system, with local tumor control being the primary determinant of outcome.

The primary etiologic factor in FISS is chronic inflammation at the injection site, which leads to malignant transformation of mesenchymal cells. The most well-documented cause is the administration of adjuvanted vaccines, particularly those containing aluminum hydroxide or aluminum phosphate as adjuvants. These adjuvants are believed to incite a persistent inflammatory response, with the release of growth factors and cytokines that promote fibroblastic proliferation and genetic mutations. Other injectable products, including long-acting corticosteroids, non-steroidal anti-inflammatory drugs, antibiotics (e.g., tetracyclines), insulin, and even microchips, have been implicated. The latency period between injection and tumor development ranges from 3 months to 3 years, with a median of 10-12 months. The inflammatory response is characterized by a foreign-body reaction, with macrophages and lymphocytes infiltrating the site. Over time, this chronic inflammation can lead to the activation of oncogenes (e.g., c-myc, ras) and inactivation of tumor suppressor genes (e.g., p53), resulting in uncontrolled cellular proliferation. The exact molecular mechanisms are not fully understood, but there is evidence of dysregulation of the p53 pathway and overexpression of platelet-derived growth factor (PDGF) and its receptor. The tumor often arises in the interscapular region, which was historically the preferred site for vaccine administration, but can occur at any injection site, including the hindlimbs (distal to the stifle) and the tail. The anatomical vulnerability of the interscapular region is due to the presence of loose connective tissue and the panniculus muscle, which allows for tumor spread along fascial planes.

FISS is a disease of domestic cats, with no breed predilection, although some studies suggest a higher incidence in Siamese and domestic shorthair cats. The median age at diagnosis is 8-10 years, but cases have been reported in cats as young as 2 years and as old as 15 years. There is no sex predilection. The incidence of FISS is estimated to be 1 in 1,000 to 1 in 10,000 vaccinated cats, with a higher risk associated with adjuvanted vaccines. The risk of developing FISS increases with the number of vaccine doses administered at the same site, and with the frequency of vaccination. Cats that receive multiple vaccines in the interscapular region are at higher risk. The incidence has decreased since the adoption of the Vaccine-Associated Feline Sarcoma Task Force (VAFSTF) guidelines, which recommend vaccination at specific sites (e.g., distal to the stifle for rabies and FeLV vaccines) and the use of non-adjuvanted vaccines when possible. However, FISS continues to occur, and the incidence is estimated to be 1-2 cases per 10,000 cats vaccinated. The disease is more common in cats that are vaccinated annually, and the risk is higher for vaccines that contain adjuvants. There is no known genetic predisposition, but certain feline leukemia virus (FeLV) and feline sarcoma virus (FeSV) infections have been associated with fibrosarcomas in young cats, though these are distinct from FISS.

The pathophysiology of FISS involves a cascade of events initiated by the injection of an irritant substance, leading to chronic inflammation and subsequent neoplastic transformation. The inflammatory response is characterized by the recruitment of macrophages, lymphocytes, and plasma cells to the injection site. These cells release pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukins (IL-1, IL-6), and growth factors, including transforming growth factor-beta (TGF-β) and platelet-derived growth factor (PDGF). These factors stimulate fibroblast proliferation and collagen deposition, leading to the formation of a fibrous capsule around the injected material. Over time, the chronic inflammatory milieu can induce DNA damage in proliferating fibroblasts, leading to mutations in oncogenes and tumor suppressor genes. The tumor arises from the perivascular or perimuscular connective tissue, often within the panniculus muscle layer or between muscle fascicles. The tumor is highly infiltrative, with finger-like projections extending along fascial planes, making it difficult to achieve clean surgical margins. The tumor is typically firm, poorly circumscribed, and may be fixed to the underlying muscle or bone. Histologically, the tumor is composed of spindle-shaped cells arranged in interlacing bundles, with variable degrees of pleomorphism and mitotic activity. A characteristic feature is the presence of a peripheral inflammatory infiltrate, often with a perivascular distribution. The tumor can invade local blood vessels and lymphatics, but metastasis is relatively uncommon, occurring in approximately 10-25% of cases, with the lungs being the most common site of metastasis. The tumor can also spread to regional lymph nodes, but this is rare. The aggressive local behavior is the primary cause of morbidity and mortality, as the tumor can invade vital structures such as the spine, trachea, or major vessels, depending on the location.

Intrinsic factors include age (middle-aged to older cats), with a median age of 8-10 years. There is no clear breed or sex predisposition, but some studies suggest a higher risk in Siamese and domestic shorthair cats. Genetic factors may play a role, as some cats may have a genetic predisposition to develop sarcomas in response to chronic inflammation. Extrinsic factors are the most significant, with the primary risk factor being the administration of injectable products, particularly adjuvanted vaccines. The risk increases with the number of injections and the frequency of vaccination. The use of adjuvanted vaccines, especially those containing aluminum hydroxide, is strongly associated with FISS. Other injectable products, such as long-acting corticosteroids, antibiotics, and insulin, have also been implicated. The site of injection is a risk factor, with the interscapular region being the most common site due to the historical practice of administering vaccines there. The risk of FISS is higher in cats that receive multiple vaccines at the same site. Additionally, the use of vaccines that are not properly warmed or that are administered too superficially may increase the risk. There is also a potential association with the presence of feline leukemia virus (FeLV) or feline sarcoma virus (FeSV), but this is rare and distinct from FISS. Management factors, such as the frequency of vaccination and the choice of vaccine, can be modified to reduce the risk.

The most common clinical sign is a palpable mass at the site of a previous injection. The mass is typically firm, poorly circumscribed, and may be fixed to the underlying tissues. It can be solitary or multiple, and may be painful on palpation. The overlying skin may be alopecic or ulcerated in advanced cases. The mass may grow rapidly, with a doubling time of 1-2 months. Depending on the location, the mass may cause lameness (if on a limb), dysphagia or dyspnea (if in the cervical region), or neurological signs (if it invades the spinal canal). Systemic signs such as weight loss, lethargy, and anorexia are uncommon but may occur in advanced cases. On physical examination, the mass may be located in the interscapular region, the lateral thorax, the abdomen, or the limbs. The mass may be mobile or fixed, and the overlying skin may be normal or inflamed. Regional lymph nodes may be enlarged, but this is uncommon. The tumor can be locally invasive, and in some cases, it may invade the underlying bone, leading to bone lysis. The clinical stage is determined by the size of the tumor, the presence of lymph node involvement, and the presence of distant metastasis. The tumor is staged using the TNM system, with T1 being less than 2 cm, T2 being 2-5 cm, and T3 being greater than 5 cm. N0 indicates no lymph node involvement, and N1 indicates regional lymph node metastasis. M0 indicates no distant metastasis, and M1 indicates distant metastasis.

Differential diagnoses for FISS include other soft tissue sarcomas, such as fibrosarcoma (non-injection site), malignant fibrous histiocytoma, rhabdomyosarcoma, and osteosarcoma. Other differentials include benign tumors such as lipoma, fibroma, and neurofibroma. Inflammatory lesions such as abscesses, granulomas, and foreign body reactions can also mimic FISS. Additionally, other malignant tumors such as mast cell tumor, lymphoma, and adenocarcinoma (e.g., mammary gland adenocarcinoma) should be considered. Key clinical features that help differentiate FISS from other conditions include the history of a prior injection at the site, the rapid growth rate, and the characteristic histologic findings of a peripheral inflammatory infiltrate. Imaging findings, such as the presence of a soft tissue mass with invasion into underlying muscle or bone, can also be helpful. Definitive diagnosis requires histopathology, which will show the characteristic spindle cell proliferation with a peripheral inflammatory infiltrate. Immunohistochemistry can be used to differentiate FISS from other sarcomas, with positive staining for vimentin and negative staining for cytokeratin, desmin, and S-100. In contrast, lipomas are typically soft, well-circumscribed, and slow-growing, and histologically show mature adipocytes. Abscesses are typically painful, fluctuant, and associated with systemic signs such as fever, and cytology will show septic suppurative inflammation. Foreign body reactions may have a history of a foreign body, and histology will show granulomatous inflammation with foreign body giant cells. Mast cell tumors are typically erythematous, pruritic, and may have a positive Darier's sign, and cytology will show mast cells. Lymphoma is typically a soft, diffuse swelling, and cytology will show a monomorphic population of lymphocytes.

The diagnostic algorithm for FISS begins with a thorough history and physical examination, with particular attention to the presence of a mass at a previous injection site. The following steps are recommended: 1. Fine-needle aspiration (FNA) of the mass for cytology. FNA can help differentiate between inflammatory lesions, benign tumors, and malignant tumors. However, FNA has a low sensitivity for sarcomas, and a negative result does not rule out FISS. 2. If FNA is inconclusive or suggests a sarcoma, a biopsy is indicated. A core needle biopsy or an incisional biopsy is preferred over excisional biopsy, as excisional biopsy may compromise the ability to achieve clean margins later. The biopsy should be taken from the center of the mass, and the sample should be submitted for histopathology. 3. Staging is essential to rule out metastasis. This includes thoracic radiographs (three views) to evaluate for pulmonary metastasis, and abdominal ultrasound if the mass is in the abdominal region. 4. Advanced imaging, such as computed tomography (CT) or magnetic resonance imaging (MRI), is recommended to assess the extent of the tumor, particularly its invasion into underlying muscle, bone, or vital structures. CT is particularly useful for surgical planning, as it provides detailed three-dimensional information about the tumor and its relationship to surrounding tissues. 5. Regional lymph node aspiration or biopsy is recommended if the lymph nodes are enlarged or if the tumor is in a location that drains to a specific lymph node. 6. Once the diagnosis is confirmed and staging is complete, the tumor is staged using the TNM system, and a treatment plan is formulated. The treatment of choice is aggressive surgical excision with wide margins (3-5 cm lateral and 2 fascial planes deep). If surgical margins are incomplete, adjuvant radiation therapy is recommended. Chemotherapy may be considered for tumors with a high metastatic potential, but its efficacy is limited.

Complete blood count (CBC) and serum biochemistry profile are typically unremarkable in cats with FISS, unless there is concurrent disease. However, a CBC may show mild anemia of chronic disease, and a biochemistry profile may show elevated globulins due to chronic inflammation. Serum protein electrophoresis may show a polyclonal gammopathy. In some cases, there may be hypercalcemia, which is rare but can occur with paraneoplastic syndromes. Coagulation parameters (PT, aPTT) are usually within normal limits, but a coagulation panel is recommended before surgery to assess surgical risk. Blood type and crossmatch are essential if blood transfusion is anticipated. Inflammatory biomarkers such as serum amyloid A (SAA) and C-reactive protein (CRP) may be elevated, but they are not specific for FISS. Synovial fluid analysis is not relevant unless the tumor involves a joint. Urinalysis is typically normal. If the tumor is associated with a vaccine, there is no specific laboratory test to confirm the diagnosis. Histopathology is the gold standard for diagnosis, and immunohistochemistry may be used to differentiate FISS from other sarcomas. The tumor typically stains positive for vimentin and negative for cytokeratin, desmin, and S-100. The mitotic index and the presence of necrosis are important prognostic indicators.

Radiography: On standard radiographs, FISS appears as a soft tissue mass, which may be poorly circumscribed. The mass may be associated with underlying bone lysis if it invades the bone. Thoracic radiographs are essential to rule out pulmonary metastasis, which appears as well-defined nodules. Radiographs are not sensitive for detecting the extent of soft tissue invasion, so advanced imaging is recommended. Ultrasonography: Ultrasound can be used to evaluate the mass, particularly if it is in the abdominal or thoracic wall. It can help determine the depth of invasion and the involvement of underlying structures. Ultrasound-guided FNA or biopsy can be performed. Computed Tomography (CT): CT is the imaging modality of choice for surgical planning. It provides detailed three-dimensional information about the tumor, including its size, extent, and invasion into underlying muscle, bone, and vital structures. CT is particularly useful for evaluating the interscapular region, where the tumor can invade the spine. CT can also be used to plan radiation therapy. Magnetic Resonance Imaging (MRI): MRI provides superior soft tissue contrast compared to CT and is useful for evaluating the extent of tumor invasion into muscle and neurovascular structures. MRI is particularly useful for tumors in the cervical or thoracic regions. However, MRI is more expensive and requires general anesthesia. Arthroscopy: Not typically used for FISS, but may be used if the tumor involves a joint. Angiography/Fluoroscopy: Not routinely used, but may be helpful in selected cases to assess vascular invasion.

Cytology: Fine-needle aspiration of FISS often yields a paucicellular sample with spindle-shaped cells, which may be arranged in clusters or individually. The cells may show moderate to marked anisocytosis and anisokaryosis, with prominent nucleoli. However, cytology is often nondiagnostic, as the tumor is highly desmoplastic and the cells may not exfoliate well. Inflammatory cells, including lymphocytes and plasma cells, may be present at the periphery of the tumor. Histopathology: The histologic features of FISS are characteristic. The tumor is composed of spindle-shaped cells arranged in interlacing bundles or herringbone patterns. The cells have variable amounts of eosinophilic cytoplasm and elongated nuclei with coarse chromatin. There is variable pleomorphism, and mitotic figures are often numerous. A hallmark feature is the presence of a dense inflammatory infiltrate, composed of lymphocytes, plasma cells, and macrophages, at the periphery of the tumor. The tumor often invades the surrounding muscle and adipose tissue, with finger-like projections extending along fascial planes. The tumor may be graded based on the degree of differentiation, mitotic index, and the extent of necrosis. Well-differentiated tumors have a low mitotic index and minimal necrosis, while poorly differentiated tumors have a high mitotic index and extensive necrosis. Surgical margins should be evaluated for the presence of tumor cells, and the margins should be reported as clean, close, or dirty. Immunohistochemistry can be used to confirm the diagnosis and differentiate FISS from other sarcomas. The tumor is typically positive for vimentin and negative for cytokeratin, desmin, and S-100. Some tumors may express smooth muscle actin (SMA), indicating myofibroblastic differentiation.

The treatment of choice for FISS is aggressive surgical excision with wide margins. The recommended margins are 3-5 cm lateral to the tumor and at least 2 fascial planes deep. This often requires a radical resection, which may include the removal of the underlying muscle, bone, or other structures. For tumors in the interscapular region, this may involve the removal of the spinous processes of the vertebrae and the epaxial muscles. For tumors on the limbs, amputation may be necessary. Preoperative planning with CT is essential to determine the extent of the tumor and to plan the surgical approach. The surgical technique involves making an elliptical incision around the tumor, with the long axis oriented along the direction of the fascial planes. The tumor is removed en bloc, with the overlying skin and the underlying muscle. The surgical site is closed with a tension-relieving technique, such as a walking suture or a skin flap. If the surgical margins are incomplete, adjuvant radiation therapy is recommended. Radiation therapy can be administered preoperatively or postoperatively. Preoperative radiation therapy can shrink the tumor and make it more resectable, but it may increase the risk of wound complications. Postoperative radiation therapy is more common and is initiated after the surgical wound has healed. Chemotherapy may be considered for tumors with a high metastatic potential, but its efficacy is limited. Doxorubicin is the most commonly used chemotherapeutic agent, but it has significant cardiotoxic effects. Other agents, such as carboplatin and ifosfamide, have been used, but with limited success. In cases where surgery is not possible, radiation therapy alone may be used for palliative treatment. The prognosis for cats with FISS is guarded, with a median survival time of 2-3 years after aggressive treatment. The most important prognostic factor is the completeness of surgical excision. Cats with clean surgical margins have a significantly longer survival time than those with incomplete margins.

The prognosis for FISS is guarded to poor, depending on the stage of the disease and the treatment modalities used. The most important prognostic factor is the completeness of surgical excision. Cats that undergo aggressive surgical resection with clean margins have a median survival time of 2-3 years, with a 1-year survival rate of approximately 70% and a 2-year survival rate of approximately 50%. Cats with incomplete margins have a median survival time of 6-12 months, with a high rate of local recurrence. The local recurrence rate after surgery alone is reported to be 30-70%, but it is significantly reduced with the addition of radiation therapy. The metastatic rate is approximately 10-25%, with the lungs being the most common site of metastasis. Negative prognostic indicators include tumor size greater than 5 cm, a high histologic grade, the presence of necrosis, and the presence of metastasis at the time of diagnosis. Cats that receive adjuvant radiation therapy have a lower rate of local recurrence and a longer disease-free interval. The use of chemotherapy has not been shown to significantly improve survival, but it may be considered for cats with high-grade tumors or those with metastasis. The overall median survival time for cats with FISS is approximately 2 years, but this can vary widely depending on the individual case. Cats that are treated aggressively with surgery and radiation therapy have the best chance of long-term survival.

Postoperative follow-up is essential to monitor for local recurrence and metastasis. The surgical site should be examined regularly, and any new masses should be evaluated with FNA or biopsy. Thoracic radiographs should be repeated every 3-6 months for the first 2 years, and then annually thereafter, to monitor for pulmonary metastasis. The surgical wound should be monitored for signs of infection, dehiscence, or seroma formation. Suture removal is typically performed 10-14 days after surgery, depending on the location and the type of sutures used. Restricted activity is recommended for 2-4 weeks after surgery to allow for wound healing. Physical therapy, such as passive range of motion exercises, may be recommended for cats that have undergone limb amputation. If radiation therapy is administered, the skin should be monitored for radiation dermatitis, and the cat should be evaluated for side effects such as lethargy, anorexia, and myelosuppression. The cat's overall health should be monitored with regular physical examinations and blood work. The owner should be educated about the signs of local recurrence and metastasis, and should be encouraged to seek veterinary care if any new masses or clinical signs develop. The long-term prognosis is guarded, but with aggressive treatment and close monitoring, some cats can enjoy a good quality of life for several years.

Pearls: 1. Always obtain a thorough history of prior injections, including vaccines, corticosteroids, and other medications. 2. Use CT for surgical planning, as it provides the best assessment of tumor extent and invasion. 3. Perform a wide surgical excision with margins of at least 3-5 cm lateral and 2 fascial planes deep. 4. Consider referral to a surgical oncologist for complex cases. 5. Use a tension-relieving closure technique to minimize wound complications. 6. Consider adjuvant radiation therapy for all cats with FISS, even if surgical margins are clean, to reduce the risk of local recurrence. 7. Monitor for metastasis with regular thoracic radiographs. Pitfalls: 1. Do not perform an excisional biopsy without prior planning, as it may compromise the ability to achieve clean margins. 2. Avoid the use of adjuvanted vaccines in cats, and follow the VAFSTF guidelines for vaccine administration. 3. Do not underestimate the extent of the tumor, as it often extends beyond the palpable mass. 4. Avoid the use of drains, as they may increase the risk of tumor seeding. 5. Do not delay surgery, as the tumor can grow rapidly. 6. Avoid the use of non-steroidal anti-inflammatory drugs in cats, as they can cause renal and gastrointestinal toxicity. 7. Do not rely on cytology alone for diagnosis, as it is often nondiagnostic.

Perioperative antimicrobial prophylaxis: Cefazolin 22 mg/kg IV at induction, repeated every 90 minutes during surgery. Postoperative antimicrobials are not routinely indicated unless there is contamination. Analgesia: Preoperative: Buprenorphine 0.02 mg/kg IV or IM, or Methadone 0.2 mg/kg IV or IM. Intraoperative: Fentanyl CRI at 5-10 mcg/kg/hr IV. Postoperative: Buprenorphine 0.02 mg/kg IV or IM q8-12h, or Methadone 0.2 mg/kg IV or IM q4-6h, or a fentanyl patch (25 mcg/hr) applied 12-24 hours before surgery and left in place for 72 hours. NSAIDs: Not routinely recommended in cats due to the risk of renal and gastrointestinal toxicity, but if used, meloxicam 0.05 mg/kg PO q24h for a maximum of 3 days, or robenacoxib 1-2 mg/kg PO q24h for up to 3 days. Local anesthesia: Bupivacaine 1-2 mg/kg (maximum 2 mg/kg) as a local block at the surgical site, or a regional block (e.g., brachial plexus block for forelimb tumors). Chemotherapy: Doxorubicin 1 mg/kg IV every 3 weeks, or carboplatin 200 mg/m² IV every 3 weeks. These protocols are based on Plumb's Veterinary Drug Handbook and should be adjusted based on the individual patient's renal and hepatic function.

The literature on FISS is extensive, with landmark studies establishing the association between vaccination and sarcoma development. Hendrick and Goldschmidt (1991) first described the association between rabies and FeLV vaccines and fibrosarcoma development in cats. The Vaccine-Associated Feline Sarcoma Task Force (VAFSTF) was formed in 1996 to address the issue, and their guidelines recommend vaccination at specific sites (distal to the stifle for rabies and FeLV vaccines) and the use of non-adjuvanted vaccines when possible. A study by Kass et al. (1993) found that the risk of sarcoma development was 50% higher in cats that received vaccines containing aluminum adjuvants. A more recent study by Srivastav et al. (2012) reported an incidence of 1-2 cases per 10,000 vaccinated cats. Regarding treatment, a study by Hershey et al. (2000) reported that cats treated with surgery alone had a median survival time of 16 months, while those treated with surgery and radiation therapy had a median survival time of 24 months. A study by Kobayashi et al. (2002) found that the local recurrence rate was significantly lower in cats that received radiation therapy (30%) compared to those that did not (70%). The role of chemotherapy is less clear, with a study by Martano et al. (2005) showing no significant survival benefit with doxorubicin. A meta-analysis by Phelps et al. (2011) concluded that aggressive surgical excision with wide margins is the most important factor in achieving long-term control. The use of CT for surgical planning is supported by a study by Travetti et al. (2013), which found that CT accurately predicted the extent of tumor invasion in 90% of cases. Overall, the evidence supports a multimodal approach with aggressive surgery and radiation therapy for the best outcomes.