Feline Injection Site Sarcoma
update July, 2018
The Feline Injection Site Sarcoma guidelines were first published in the Journal of Feline Medicine and Surgery (2015) 17, 606-613; the present guidelines were updated by Katrin Hartmann with input from Johannes Hirschberger (Medizinische Kleintierklinik of the LMU Munich).
In cats, invasive sarcomas (mostly fibrosarcomas), so called “feline injection-site sarcomas” (FISS) are the most serious adverse effect following vaccination. They develop at sites of a vaccination or injection. They have characteristics that are distinct from those of fibrosarcomas in other areas and behave more aggressively. The rate of metastasis ranges from 10 to 28%.
The pathogenesis of these sarcomas is not yet definitively explained. According to the most widely accepted hypothesis, chronic inflammatory reactions are considered a trigger for subsequent malignant transformation. Adjuvanted vaccines induce intense local inflammation and it has been suggested that they would be linked to the development of FISS. The risk is likely lower for modified-live and recombinant vaccines, but no vaccine is risk-free. Injection of cold vaccines also has been associated with a higher risk of FISS. Moreover, injections of long-acting drugs (such as glucocorticoids, and others) also have been associated with sarcoma formation.
Aggressive, radical excision is required to avoid tumour recurrence. The prognosis improves if additional radiotherapy and/or immunotherapy (such as recombinant feline IL-2) are used.
For prevention, injection of any irritating substance should be avoided. Vaccination should be performed as often as necessary, but as infrequently as possible. Vaccines should be brought to room temperature prior to administration. Non-adjuvanted, modified-live or recombinant vaccines should be preferred over adjuvanted vaccines, if available and proven equally effective. Injections should be given at sites at which surgery would likely lead to a complete cure; the interscapular region should generally be avoided. Postvaccinal monitoring should be performed.
Recently, vaccination of cats has received scientific and public attention following the supposition that a range of rare adverse effects can arise following vaccination. In cats, the most serious of these adverse consequences is the occurrence of invasive sarcomas (mostly fibrosarcomas), so called “feline injection-site sarcomas” (FISS), that can develop within the skin at sites of previous vaccination. A task force has been instituted and is regularly updated in the USA to help veterinarians to understand, mange, and prevent these tumours (Morrison and Starr, 2001; Vaccine-Associated Feline Sarcoma Task Force, 2005). Despite extensive research on the pathogenesis of these sarcomas, there is no definitive causal relationship that explains their occurrence and the direct link to vaccination. The most accepted hypothesis suggests that chronic inflammatory reaction at the site of injection provides a trigger for subsequent malignant transformation. As the pathogenesis of FISS is not yet fully understood, the following ABCD recommendations on how best to avoid their occurrence are sometimes based only on expert opinion.
Epidemiology and characterisation
In 1991, an increased incidence of tumours in cats that developed at injection sites was first reported in the United States (Hendrick and Dunagan, 1991). This observation was connected to an increased use of rabies and feline leukaemia virus (FeLV) vaccinations (Hendrick and Goldschmidt, 1991; Kass et al., 1993). As a consequence, these tumours were first called feline “vaccine-associated sarcomas”. However, the subsequent finding that also other non-vaccinal injectables can be associated with this type of tumour has led to reclassification of these neoplasms as “feline injection-site sarcomas” (FISS). These tumours seem to be unique to cats (Carroll et al., 2002), although comparable tumours have been reported in ferrets (Munday et al., 2003) and very occasionally in dogs (Vascellari et al., 2003).
FISS occur at sites typically used for vaccination and injections, such as the interscapular region (Fig.s 1-3), the lateral thoracic or abdominal wall, the lumbar regions, and in the area of the semimembranosus and semitendinosus muscles in the hind limbs. FISS are most commonly located in the subcutis, but also can occur intramuscularly (Dubielzig et al., 1993; Hendrick and Brooks, 1994). FISS can develop as early as four months and up to two to three years after an injection. They are characterized by invasive local growth in the subcutis, often with spread along fascial planes (Hirschberger and Kessler, 2001). Most FISS are fibrosarcomas (Doddy et al., 1996), but other malignancies, such as osteosarcomas (Esplin et al., 1993), chondrosarcomas (Hendrick and Brooks, 1994), rhabdomyosarcomas (Hendrick and Brooks, 1994), malignant fibrous histiocytomas (Esplin et al., 1993; Hendrick and Brooks, 1994), and myofibroblastic sarcomas (Dubielzig et al., 1993) have also been described.
In contrast to fibrosarcomas in other areas, FISS have different histological characteristics with typical perivascular infiltration of lymphocytes and macrophages at the tumour periphery, a central area of necrosis, inflammation and local infiltration of tumour cells (Fig. 4; Doddy et al., 1996; Madewell et al., 2001). FISS behave more aggressively than sarcomas at other sites (Hendrick et al., 1994). The rate of metastasis ranges from 10% to 28% (Couto and Macy, 1998; Hershey et al., 2000). The lung is the most common site of metastasis, followed by regional lymph nodes and abdominal organs, such as kidney, spleen, intestine and liver (Sandler et al., 1997; Kobayashi et al., 2002).
In the last 20 years, an epidemiological association has been demonstrated between vaccinations and the later development of FISS (Hendrick et al., 1992, 1994; Kass et al., 1993, 2003; Macy, 1995; Dean et al., 2006). The incidence of FISS has been estimated at 1 to 4 in every 10,000 vaccinated cats in USA (Coyne et al., 1997; Gobar and Kass, 2002), and the ratio of injection-site to non-injection-site sarcomas increased from 0.5 in 1989 to 4.3 in 1994 (Doddy et al., 1996). In one study in the USA, reported rates of reaction were 0.3 FISS per 10,000 vaccines and 11.8 postvaccinal inflammatory reactions per 10,000 vaccinations in cats (Gobar and Kass, 2002). If inflammatory reactions are a necessary prelude to FISS, then these rates suggest that 1 in 35 to 40 inflammatory reactions develop into FISS. In Poland, the prevalence of FISS was estimated to be 16 in 10,000 cats in general practice and 85 in 10,000 cats in practices specialising in oncology (Kliczkowska et al., 2015). In the UK, the incidence of FISS seems to be relatively low (incidence risk of FISS per year was estimated to be 1/16,000-50,000 cats registered by practices, 1/10,000-20,000 cat consultations, and 1/5,000-12,500 vaccination visits) (Dean et al., 2013). One reason for the low rate might be that rabies vaccination is not a routine procedure for cats in UK. One study in Canada compared the annual prevalence of feline postvaccinal sarcomas among 11,609 feline skin mass submissions from 1992 to 2010 and revealed no decrease in disease prevalence or increase in age of affected cats in response to change in vaccination formulation or recommended changes in feline vaccination protocols (Wilcock et al., 2012).
Despite extensive research, there is no definitive proof of the pathogenesis of FISS. The most widely accepted hypothesis suggests that a chronic inflammatory reaction at the site of an injection acts as a trigger for subsequent malignant transformation. It has been suggested that adjuvanted vaccines would be linked to the development of FISS due to the more intense local inflammation associated with such products. This idea is supported by frequent identification of adjuvants in histological or ultrastructural investigations of these sarcomas (Hendrick et al., 1992; Madewell et al., 2001).
Many data suggest an association between vaccination and FISS in cats. Alum, a vaccine adjuvant, has been found in many FISS biopsy samples (Deim et al., 2008). In most inactivated vaccines, an adjuvant is added to enhance the inflammation at the site of injection, which is intended and necessary when applying a killed agent in order to trigger the necessary immune response. However, this inflammation might potentially lead to malignant transformation. Traces of adjuvants can be seen in the inflammatory reaction, specifically accumulated within macrophages or multinucleate giant cells, and later in histological sections of FISS in the transformed fibroblasts (Hendrick et al., 1992). Intracellular crystalline particulate material was found in an ultrastructural study in five of 20 investigated FISS, and in one of the five cases was identified as aluminium-based (Madewell et al., 2001). Although no specific vaccine or adjuvant has been incriminated (Kass et al., 2003), local irritation from adjuvant is thought to potentially stimulate fibroblasts to the point that malignant transformation occurs.
At first, only rabies and feline leukaemia virus (FeLV) vaccines were identified as risk factors (Kass et al., 1993; Hendrick et al., 1994; Coyne et al., 1997), but subsequently other vaccines, including vaccines against feline panleukopenia virus (FPV), feline herpesvirus-1 (FHV-1), and feline calicivirus (FCV) also were found to be involved in the development of FISS in some cases (Hendrick et al., 1994; Lester et al., 1996; Burton and Mason, 1997; Coyne et al., 1997; DeMan and Ducatelle, 2007). In addition to vaccines, injections of long-acting drugs, e.g. glucocorticoids, penicillin, lufenuron (Esplin et al., 1999; Gagnon, 2000; Kass et al., 2003; Srivastav et al., 2012), cisplatin (Martano et al., 2012), or meloxicam (Munday et al., 2011) have been associated with sarcoma formation. In one study, the frequency of administration of long-acting corticosteroid injections (dexamethasone, methylprednisolone, and triamcinolone) was significantly higher in cats with FISS in the interscapular region than in control cats (Srivastav et al., 2012). Fibrosarcomas were also reported at the site of a deep, non-absorbable suture in one cat (Buracco et al., 2002); derived from a granulomatous inflammation caused by a foreign body in one cat; around a surgical swab in the abdomen of one cat (Haddad et al., 2010); adjacent to the site of microchip implantation in two cases (Daly et al., 2008; Carminato et al., 2011); and associated with a subcutaneous fluid port device (McLeland et al., 2013). This suggests that all inflammatory reactions, theoretically, have the potential to lead to the development of FISS through triggering uncontrolled proliferation of fibroblasts and myofibroblasts, which, in some cases, results in malignant transformation.
Although many causes of inflammation are associated with FISS development, the risk seems to be higher for vaccines compared to other injections; amongst vaccines, the risk seems to be higher when adjuvanted vaccines are used. A recent study compared associations between vaccine types and other injectable drugs with the development of FISS in a case-control study of 181 cats with soft tissue sarcomas (cases), 96 cats with tumours at non-vaccine regions (control group I), and 159 cats with basal cell tumours (control group II). There was an association between the administration of various types of vaccines and other injectable products (e.g. long-acting corticosteroids) and FISS development. Of 192 sarcomas, 101 had vaccinations at the site of tumour development during the preceding three years, and 23 had received other injections (Srivastav et al., 2012). This study also showed that adjuvanted inactivated vaccines were significantly more commonly associated with FISS development than other vaccines; of 35 vaccinated cats with sarcoma on the hind limb, 25 had received adjuvanted vaccines, seven cats had received modified live virus (MLV) vaccines (FPV, FHV-1 and FCV), and only one cat had received a recombinant vaccine. However, these findings also indicate that no vaccines were risk-free and that other factors also can be associated with the development of FISS (Srivastav et al., 2012).
The mechanism by which the inflammatory reaction causes tumour formation is not fully understood. Growth factors can promote proliferation, can induce malignant transformation, and also can be involved in the regulation of angiogenesis. Overexpression of growth factors and oncogene activation have been demonstrated in cats with FISS and are suspected to play a role in tumour development (Hendrick, 1998, 1999; Nieto et al., 2003).
As in earlier studies an epidemiologic association has been demonstrated between FeLV vaccination and a higher risk of FISS, some studies looked at a possible role of FeLV and its mutant feline sarcoma virus (FeSV) in the development of FISS, but could not detect either FeLV or FeSV in the tumours (Ellis et al., 1996). Furthermore, no other viruses, including feline immunodeficiency virus, feline foamy virus, polyomaviruses or papillomaviruses, were detected in tumour tissues (Kidney et al., 2000, 2001a, 2001b, 2002). No evidence was found for the replication or expression of endogenous retroviruses being involved in FISS formation (Kidney et al., 2001a, 2001b).
The observation that not all cats develop FISS after vaccination suggests that there might be a genetic predisposition. It has been proposed that there is a higher incidence of FISS in siblings of affected cats, and that some cats tend to develop more than one FISS. Alterations with unknown relevance, such as hyperploidy (Kalat et al., 1991), translocations (Mayr et al., 1996) and triploidy (Mayr et al., 1991) of oncogene and tumour suppressor loci have been found on extra chromosomes and monosomic chromosomes in affected cats. Mutations have been identified in the tumour suppressor gene p53, which is implicated in cancer initiation and progression in sarcoma tissue of cats with FISS (Mayr et al., 1995, 1998; Nambiar et al., 2000, 2001; Banerji and Kanjilal, 2006). A case-control study (50 domestic shorthair cats with a confirmed diagnosis of FISS and 100 disease-free matched controls) investigating a possible association between polymorphisms in the genomic sequence of the feline p53 gene and a predisposition to FISS, found a strong association between FISS and the presence of specific nucleotides at two of the polymorphic sites (Banerji et al., 2007). However, another study, conducted in Germany, could not reproduce these findings and observed no association with the polymorphisms described (Mucha et al., 2014).
Appropriate treatment should first include staging and careful planning of the surgery (Ladlow, 2013), because aggressive, radical excision is crucial to avoid tumour recurrence. The prognosis improves if, in addition to radical surgery, additional treatments such as radiotherapy or immunotherapy are used. Preoperatively, (contrast-enhanced) computed tomography (CT) or magnetic resonance imaging (MRI) should be obtained for staging and to determine the extent of the tumour and the size of the radiation field required to maximize the chance of a successful outcome (Rousset et al., 2013). CT or ultrasound can also assess peritumoral inflammation (Zardo et al., 2016). It was shown that the actual size of tumours determined by CT can be up to twice the size estimated at physical examination (McEntee, 2000; Martano et al., 2011; Ferrari et al., 2017), and the size of the tumour is considered one of the most important prognostic markers (Porcellato et al., 2017). Surgeons should attempt to achieve complete, en bloc, surgical tumour resection with at least 3 cm (better 5 cm) margins (Phelps et al., 2011; EBM grade III) and the removal of one fascial plane underlying the tumour, because incomplete resection can result in recurrence as early as two weeks after surgery (Lester et al., 1996; Scherk et al., 2013; EBM grade III). Tumour-free margins are very important to achieve a longer disease-free interval, which was 700 days when complete tumour excision was accomplished in addition to adjuvant radiation therapy, but only 112 days for incomplete resection in addition to adjuvant radiation therapy (Cronin et al., 1998; EBM grade III). However, even with clean surgical margins, the recurrence rate can be as high as 50 % (McEntee and Page, 2001; EBM grade III).
Treatment using surgical excision alone has a recurrence rate of up to 70 %, with tumour regrowth usually occurring in the first six months after surgery (Hendrick et al., 1994; EBM grade III), but preoperative or postoperative radiation therapy significantly decreases recurrence rates and prolongs remission times (Cronin et al., 1998; Kobayashi et al., 2002; Steger-Lieb et al., 2002; Eckstein et al., 2009; Mayer et al., 2009), while chemotherapy in addition to surgery is less effective. However, two studies showed some benefits of chemotherapy. In one study, a certain efficacy of three epirubicin doses before and after surgery was demonstrated, compared to outcomes of historical controls (Bray and Polton, 2016; EBM grade III). In a randomized multicenter study, liposome-encapsulated doxorubicin (LED) and doxorubicin (DOX) treatment in addition to surgery (but without radiation) led to a prolonged median disease-free interval when compared to surgery alone, with no difference in efﬁcacy between LED and DOX (Poirier et al., 2002; EBM grade III). New approaches, such as combining doxorubicin (DOX)-loaded phosphatidyldiglycerol-based thermosensitive liposomes with local hyperthermia, also hold some promise (Zimmermann et al., 2016; EBM grade II). On the other hand, the tyrosine kinase inhibitor toceranib, which is licensed for the treatment of canine mast cell tumours, did not lead to a clinical response in cats with FISS (Holtermann et al., 2017; EBM grade III). Thus, so far chemotherapy mainly remains an option for palliative treatment in cats with non-resectable FISS, when radiation therapy is not available (Zabielska-Koczywąs et al., 2017).
Additional immunotherapy appears to be a promising option (Jahnke et al., 2007; Huttinger et al., 2008; Jas et al., 2015). Results of prospective randomized controlled studies on cytokine gene transfer techniques for adjuvant-immunological treatment of FISS showed reduced recurrence rates. In cats receiving gene therapy by the peritumoural administration of histo-incompatible Vero cells expressing human interleukin-2 in addition to surgery and radiation therapy, only five of 16 FISS cats (31%) had FISS recurrence, while eleven of 16 control cats (69%) that only had surgery and radiation therapy, but no immunotherapy, had FISS recurrence within 16 months (Quintin-Colonna et al., 1996; EBM grade I). Use of neo-adjuvant gene therapy using a non-viral vector that expresses feline granulocyte-macrophage colony-stimulating factor (GM-CSF) or a combination of the feline genes GM-CSF, IL-2, and interferon-γ (IFN-γ) was well tolerated by cats (Jahnke et al., 2007; Huttinger et al., 2008; EBM grade I) and showed promising results. Recombinant feline IL-2 is now commercially available in Europe for the treatment of FISS in combination with excision and radiation therapy. In a randomised controlled clinical trial, administration of a recombinant canarypox virus expressing feline IL-2 was well tolerated and resulted in a significantly longer median time to relapse and a significant reduction in the risk of relapse at one year and two years (Jas et al., 2015; EBM grade I).
Prevention consists of three general considerations. First, injections in cats should always be given at sites at which surgery (such as amputation of a limb or excision of lateral abdominal skin) would likely lead to a complete cure with the least complicated surgical procedure. Second, general recommendations to reduce the inflammatory reaction at injection sites should be followed, such as avoiding the administration of irritating substances. And third, it is advised to vaccinate as often as necessary, but as infrequently as possible (e.g. according to the principles of current vaccination guidelines, such as avoiding FeLV vaccination in already FeLV-infected cats or feline panleukopenia vaccination in cats with pre-existing antibodies against FPV).
In general, injecting distally in a leg aids in the treatment of subsequent sarcomas (by amputation of the leg) because these tumours are very difficult to excise completely and often recur after resection (Macy, 1995). Administration of vaccines (or other injections) between the scapulae is generally contraindicated because tumour resection is almost impossible in this location. To assess the acceptance of the Vaccine-Associated Feline Sarcoma Task Force of the American Association of Feline Practitioners (AAFP) recommendation (published in 1999) by veterinarians, a study including 392 cats with FISS compared the anatomical locations of tumours between cases with FISS diagnosed before and after the publication of these recommendations (Vaccine-Associated Feline Sarcoma Task Force, 1999). Comparing the prevalence of cases arising before and after the publication of the vaccination recommendations, the proportions of FISS significantly decreased in the interscapular (53% to 40%) and right and left thoracic (10% to 4% and 9% to 1%, respectively) regions, whereas the proportions of FISS significantly increased in the right thoracic limb (1% to 10%) and the combined regions of the right pelvic limb with the right lateral aspect of the abdomen (13% to 25%) and the left pelvic limb with the left lateral aspect of the abdomen (11% to 14%). Thus, despite publication of the vaccination recommendations, a high proportion of tumours still developed in the interscapular region. There was also an increase in lateral abdominal FISS, which could be attributable to aberrant placement of injections intended for the pelvic limbs. Thus, veterinarians are complying with vaccination recommendations to some extent, but only the administration of vaccines as distally as possible on a limb would allow for complete surgical margins if limb amputation is required (Shaw et al., 2009; EBM grade III). Data in Europe show a similar situation. In a study examining the location of FISS in cats presented to the oncology service at the University teaching hospital in Munich, most FISS still occurred between the scapulae (40%), followed by the right (19%) and left thoracic walls (13%) (Haas, 2009). A cross-sectional study in the UK determined cat owners' attitudes towards surgical treatments of different anatomical regions. However, less than half of the owners (39%) would pursue surgery regardless of tumour site. One percent would not pursue surgery. Of the remainder, respondents would not allow amputation of the forelimb (20%), hind limb (15%) or tail (15%). On the other hand, the majority of respondents were willing to travel up to 100 miles for radiotherapy or chemotherapy (66 and 69%, respectively) (Carwardine et al., 2014). Thus, owner education by the veterinarian explaining optimum treatment options is important.
Unfortunately, there is still a lack of information to provide evidence-based vaccine site recommendations. The majority of safety and efficacy data comes from licensing studies in which vaccines are administered subcutaneously in the interscapular region, which should not be used for any injection in field cats. Current research indicates that radical surgical resection of injection-site sarcomas including margins of at least 3 cm, but preferably 5 cm (Phelps et al., 2011; EBM grade III), is associated with the highest response rate and long-term survival (Hershey et al., 2000; EBM grade III). With this in mind, the AAFP panel on vaccination guidelines conducted an informal survey of veterinarians whose practices focused on radiation (12), surgical (36), and medical (44) oncology for opinions on what the preferred vaccination sites should be (Scherk et al., 2013). These experts agreed that distal to the stifle followed by distal to the elbow were their preferred sites. Nearly as popular was the tail. Respondents frequently commented that vaccines should be administered as low on the leg as possible. They added that vaccination of cats resting in a crouched position often results in inadvertent injection of the skin fold of the flank, resulting in tumours that are difficult to resect (Scherk et al., 2013). This is reflected in the recent paper that found an increase in lateral abdominal injection-site sarcomas since the publication of the Vaccine Associated Feline Sarcoma Task Force vaccination recommendations in 1999 (Phelps et al., 2011). Based on this, the AAFP recommends in their guidelines, that vaccines against FPV, FHV-1, and FCV should be administered below the right elbow, FeLV vaccines should be administered below the left stifle, and rabies vaccines should be administered below the right stifle (Scherk et al., 2013). So far, vaccination in the tail was not considered a practical option. However, a pilot study demonstrated that vaccination in the tail is well tolerated by cats and that the tail-vaccinated cats developed an antibody response comparable to that observed following injection of the vaccine distally in the leg (Hendricks et al., 2014; EBM grade II), and so further studies should be performed to confirm that this would be an alternative option leading to equal protection rates.
In addition to considering appropriate injection sites, post vaccination monitoring plays an important role. Vaccination sites should be recorded (Day et al., 2016), and veterinarians should instruct their clients to monitor vaccination (or injection) sites for swelling or lumps in order to detect potential sarcomas early and at a time while they still can be removed successfully.
Practitioners and owners should follow the “3-2-1”-rule: Incisional wedge biopsies or total removal and histological examination of any mass is warranted if the mass is still present three months after vaccination, if the mass becomes larger than two cm in diameter, or if the mass is increasing in size one month after vaccination. In general, a diagnostic workup is warranted when any cutaneous mass is noted in a cat. FISS are usually firm, indolent, seemingly well-circumscribed, subcutaneous masses that are often not freely moveable.
Concerning general recommendations to prevent inflammatory reactions at injection sites, there are a few rules to follow. Generally, cats should receive as few subcutaneous injections as possible. Intramuscular injections in cats should be avoided because intramuscular tumours develop with a similar frequency, but are more difficult to detect early. Whenever feasible, cats should receive drugs orally or intravenously. The subcutaneous injection of long-acting irritating substances (such as long-acting glucocorticoids) should be avoided.
One study examined potential risk factors when administering vaccines (Kass et al., 2003b), and few factors were associated with the development of FISS. It was observed that the size of the needle and the syringe, the velocity of injection, and whether manual pressure was applied after injection or not, played no role. In contrast, the temperature of the vaccine made a significant difference, with cold vaccines being associated with a higher risk of FISS development than vaccines at room temperature (Kass et al., 2003). Thus, vaccines should be taken out of the refrigerator about 15 minutes before injection, but not much longer to avoid reduction in vaccinal efficacy.
Regarding the risk of FISS development, intranasal vaccines are to be preferred over injectable vaccines in cats. However, in most countries, only injectable vaccines are available. Therefore, vaccines are preferred that cause the least subcutaneous inflammatory reaction. Currently, there is insufficient information to make definitive recommendations on the vaccine type (Kass, 2018), however it is the consensus of the ABCD expert group that, with the current state of knowledge, vaccines without adjuvants should be preferred over adjuvant-containing vaccines, which means that MLV or recombinant vaccines without adjuvant (e.g. canarypox-vectored vaccine) should be preferred over inactivated vaccines with adjuvants, if these are available and as long as they have been proven to be equally effective.
It has been shown that recombinant canarypox-vectored vaccines cause less inflammation at the injection site by an extensive study investigating the subcutaneous tissue response following the administration of a single dose of multi-component vaccines. Three groups of 15 cats were injected with one of three vaccines or saline as a negative control; cats in group A received a non-adjuvanted recombinant canarypox-vectored FeLV vaccine; cats in group B received a FeLV vaccine with a lipid-based adjuvant; cats in group C were vaccinated with a FeLV vaccine adjuvanted with an alum-Quil A mixture. On days 7, 21 and 62 post-vaccination, significantly less inflammation was associated with administration of the non-adjuvanted recombinant canarypox-vectored vaccine. The inflammation was most severe in cats receiving aluminium-based adjuvant. Cats receiving adjuvanted vaccines had evidence of residual adjuvant material accumulated within macrophages even at 62 days post-vaccination (Day et al., 2007). As described earlier in a case-control study comparing associations between vaccine types with development of FISS, adjuvanted inactivated vaccines were significantly more commonly associated with FISS development than other vaccines; of 35 vaccinated cats with sarcoma on the hind limb, 25 cats had received adjuvanted vaccines, seven cats had received MLV vaccines (FPV, FHV-1, and FCV), while only one cat had received a recombinant canarypox-vectored vaccine (Srivastav et al., 2012; EBM grade III).
Finally, to prevent development of FISS, cats should be vaccinated only as frequently as necessary. Therefore, long vaccination intervals should be applied in adult animals where possible, vaccines (such as rabies vaccines and FPV vaccines) that are licensed for three- or even longer boosters should be preferred, no FeLV or rabies vaccinations should be administered to indoor-only cats, and immune cats should not be vaccinated (e.g. if presence of antibodies, e.g., against FPV, is detected). This confirms the necessity of individual vaccination schedules.
Vaccination of cats provides essential protection and should not be stopped because of the risk of FISS.
Vaccines are not the only injectable medical products associated with FISS.
A reasoned vaccination schedule is important. Cats should be vaccinated only as often as necessary in accordance with current guidelines.
Appropriate sites for injections should be selected. The interscapular region should generally be avoided. Vaccines should be injected at a site where a mass can be easily surgically removed, preferably distally in a limb.
Vaccines should be brought to room temperature prior to administration, but should not be kept unrefrigerated for hours.
Subcutaneous injection is preferred to intramuscular injection.
Non-adjuvanted vaccines are generally preferred over those containing adjuvant. Thus, modified-live vaccines or recombinant vaccines, that are usually without adjuvant, are preferred over inactivated vaccines that contain adjuvant, if available and proven equally effective. Vaccines with a long duration of immunity should be preferred over those with short duration of immunity.
Post-vaccination monitoring should be performed. Any lump at the site of injection that is still present three months after vaccination, that is larger than two cm in diameter, or that is increasing in size one month after vaccination should be surgically removed and submitted for histopathology.
Banerji N, Kanjilal S (2006). Somatic alterations of the p53 tumor suppressor gene in vaccine-associated feline sarcoma. Am J Vet Res 67: 1766-1772.
Banerji N, Kapur V, Kanjilal S (2007). Association of germ-line polymorphisms in the feline p53 gene with genetic predisposition to vaccine-associated feline sarcoma. J Hered 98: 421-427.
Bray J, Polton G. Neoadjuvant and adjuvant chemotherapy combined with anatomical resection of feline injection-site sarcoma: results in 21 cats. Vet Comp Oncol. 2016; 14: 147-60.
Buracco P, Martano M, Morello E, Ratto A (2002). Vaccine-associated-like fibrosarcoma at the site of a deep nonabsorbable suture in a cat. Vet J 163: 105-107.
Burton G, Mason KV (1997). Do postvaccinal sarcomas occur in Australian cats? Aust Vet J 75: 102-106.
Carminato A, Vascellari M, Marchioro W, Melchiotti E, Mutinelli F (2011). Microchip-associated fibrosarcoma in a cat. Vet Dermatol 22: 565-569.
Carroll EE, Dubielzig RR, Schultz RD (2002). Cats differ from mink and ferrets in their response to commercial vaccines: a histologic comparison of early vaccine reactions. Vet Pathol 39: 216-227.
Carwardine D, Friend E, Toscano M, Bowlt K (2014). UK owner preferences for treatment of feline injection site sarcomas. J Small Anim Pract 55: 84-88.
Couto CG, Macy DW (1998). Review of treatment options for vaccine-associated feline sarcoma. J Am Vet Med Assoc 213: 1426-1427.
Coyne MJ, Reeves NC, Rosen DK (1997). Estimated prevalence of injection-site sarcomas in cats during 1992. J Am Vet Med Assoc 210: 249-251.
Cronin K, Page RL, Spodnick G, Dodge R, Hardie EN, Price GS, et al (1998). Radiation therapy and surgery for fibrosarcoma in 33 cats. Vet Radiol Ultrasound 39: 51-56.
Daly MK, Saba CF, Crochik SS, Howerth EW, Kosarek CE, Cornell KK, et al (2008). Fibrosarcoma adjacent to the site of microchip implantation in a cat. J Feline Med Surg 10: 202-205.
Day MJ, Horzinek MC, Schultz RD, Squires RA. Vaccination Guidelines Group (VGG) of the World Small Animal Veterinary Association (WSAVA) (2016). WSAVA Guidelines for the vaccination of dogs and cats. J Small Anim Pract 57: 4-8.
Day MJ, Schoon HA, Magnol JP, Saik J, Devauchelle P, Truyen U, et al (2007). A kinetic study of histopathological changes in the subcutis of cats injected with non-adjuvanted and adjuvanted multi-component vaccines. Vaccine 25: 4073-4084.
Dean R, Adams V, Whitbread T, Scase T, Dunham S, Mellor D, et al (2006). Study of feline injection site sarcomas. Vet Rec 159: 641-642.
Dean RS, Pfeiffer DU and Adams VJ (2013). The incidence of feline injection site sarcomas in the United Kingdom. BMC veterinary research 9: 17.
Deim Z, Palmai N, Cserni G (2008). Feline vaccine-associated fibrosarcoma induced by aluminium compound in two cats: short communication. Acta Vet Hung 56: 111-116.
De Man MM, Ducatelle RV (2007). Bilateral subcutaneous fibrosarcomas in a cat following feline parvo-, herpes- and calicivirus vaccination. J Feline Med Surg 9: 432-434.
Doddy FD, Glickman LT, Glickman NW, Janovitz EB (1996). Feline fibrosarcomas at vaccination sites and non-vaccination sites. J Comp Pathol 114: 165-174.
Dubielzig RR, Hawkins KL, Miller PE (1993). Myofibroblastic sarcoma originating at the site of rabies vaccination in a cat. J Vet Diagn Invest 5: 637-638.
Eckstein C, Guscetti F, Roos M, Martín de las Mulas J, Kaser-Hotz B, Rohrer Bley C (2009). A retrospective analysis of radiation therapy for the treatment of feline vaccine-associated sarcoma. Vet Comp Oncol 7: 54-68.
Ellis JA, Jackson ML, Bartsch RC, McGill LG, Martin KM, Trask BR, et al (1996). Use of immunohistochemistry and polymerase chain reaction for detection of oncornaviruses in formalin-fixed, paraffin-embedded fibrosarcomas from cats. J Am Vet Med Assoc 209: 767-771.
Esplin DG, Bigelow M, McGill LD, Wilson SR (1999). Fibrosarcoma at the site of a Lufenuron injection in a cat. Vet Cancer Soc Newsletter 23: 8-9.
Esplin DG, McGill LD, Meininger AC, Wilson SR (1993). Postvaccination sarcomas in cats. J Am Vet Med Assoc 202: 1245-1247.
Ferrari R, Di Giancamillo M, Stefanello D, Giudice C, Grieco V, Longo M, Ravasio G, Boracchi P (2017). Clinical and computed tomography tumour dimension assessments for planning wide excision of injection site sarcomas in cats: how strong is the agreement? Vet Comp Oncol 15: 374-382.
Gagnon A (2000). Drug injection-associated fibrosarcoma in a cat. Feline Practice 28: 18-21.
Gobar GM, Kass PH (2002). World Wide Web-based survey of vaccination practices, postvaccinal reactions, and vaccine site-associated sarcomas in cats. J Am Vet Med Assoc 220: 1477-1482.
Haas J (2009). Klinik, Labordiagnostik und verwendete Impfstoffe bei Katzen mit einem Fibrosarkom: eine Übersicht über die Patienten der Medizinischen Kleintierklinik 1999-2007. Munich, Germany, Ludwig Maximilian University.
Haddad JL, Goldschmidt MH, Patel RT (2010). Fibrosarcoma arising at the site of a retained surgical sponge in a cat. Vet Clin Pathol 39: 241-246.
Hendrick MJ (1998). Feline vaccine-associated sarcomas: current studies on pathogenesis. J Am Vet Med Assoc 213: 1425-1426.
Hendrick MJ (1999). Feline vaccine-associated sarcomas. Cancer Invest 17: 273-277.
Hendrick MJ, Brooks JJ (1994). Postvaccinal sarcomas in the cat: histology and immunohistochemistry. Vet Pathol 31: 126-129.
Hendrick MJ, Dunagan CA (1991). Focal necrotizing granulomatous panniculitis associated with subcutaneous injection of rabies vaccine in cats and dogs: 10 cases (1988-1989). J Am Vet Med Assoc 198: 304-305.
Hendrick MJ, Goldschmidt MH (1991). Do injection site reactions induce fibrosarcomas in cats? J Am Vet Med Assoc 199: 968.
Hendrick MJ, Goldschmidt MH, Shofer FS, Wang YY, Somlyo AP (1992). Postvaccinal sarcomas in the cat: epidemiology and electron probe microanalytical identification of aluminum. Cancer Res 52: 5391-5394.
Hendrick MJ, Shofer FS, Goldschmidt MH, Haviland JC, Schelling SH, Engler SJ, et al (1994). Comparison of fibrosarcomas that developed at vaccination sites and at nonvaccination sites in cats: 239 cases (1991-1992). J Am Vet Med Assoc 205: 1425-1429.
Hendricks CG, Levy JK, Tucker SJ, Olmstead SM, Crawford PC, Dubovi EJ, et al (2014). Tail vaccination in cats: a pilot study. J Feline Med Surg 16: 275-280.
Hershey AE, Sorenmo KU, Hendrick MJ, Shofer FS, Vail DM (2000). Prognosis for presumed feline vaccine-associated sarcoma after excision: 61 cases (1986-1996). J Am Vet Med Assoc 216: 58-61.
Hirschberger J, Kessler M (2001). Das feline Fibrosarkom. Tierärztliche Praxis 29: 66-71.
Huttinger C, Hirschberger J, Jahnke A, Kostlin R, Brill T, Plank C, et al (2008). Neoadjuvant gene delivery of feline granulocyte-macrophage colony-stimulating factor using magnetofection for the treatment of feline fibrosarcomas: a phase I trial. J Gene Med 10: 655-667.
Jahnke A, Hirschberger J, Fischer C, Brill T, Kostlin R, Plank C, et al (2007). Intra-tumoral gene delivery of feIL-2, feIFN-gamma and feGM-CSF using magnetofection as a neoadjuvant treatment option for feline fibrosarcomas: a phase-I study. J Vet Med A Physiol Pathol Clin Med 54: 599-606.
Jas D, Soyer C, DeFornel-Thibaud P, et al (2015). Adjuvant immunotherapy of feline injection-site sarcomas with the recombinant canarypox virus expressing feline interleukine-2 evaluated in a controlled monocentric clinical trial when used in association with surgery and brachytherapy. Trials Vaccinol 4: 1-8.
Kalat M, Mayr B, Schleger W, Wagner B, Reifinger M (1991). Chromosomal hyperdiploidy in a feline sarcoma. Res Vet Sci 51: 227-228.
Kass PH (2018). Prevention of Feline Injection-Site Sarcomas: Is There a Scientific Foundation for Vaccine Recommendations at This Time? Vet Clin North Am Small Anim Pract 48: 301-306.
Kass PH, Barnes WG, Jr., Spangler WL, Chomel BB, Culbertson MR (1993). Epidemiologic evidence for a causal relation between vaccination and fibrosarcoma tumorigenesis in cats. J Am Vet Med Assoc 203: 396-405.
Kass PH, Spangler WL, Hendrick MJ, McGill LD, Esplin DG, Lester S, et al (2003). Multicenter case-control study of risk factors associated with development of vaccine-associated sarcomas in cats. J Am Vet Med Assoc 223: 1283-1292.
Kidney BA, Ellis JA, Haines DM, Jackson ML (2000). Evaluation of formalin-fixed paraffin-embedded tissues obtained from vaccine site-associated sarcomas of cats for DNA of feline immunodeficiency virus. Am J Vet Res 61: 1037-1041.
Kidney BA, Haines DM, Ellis JA, Burnham M, Jackson ML (2001a). Evaluation of formalin-fixed paraffin-embedded tissues from vaccine site-associated sarcomas of cats for polyomavirus DNA and antigen. Am J Vet Res 62: 828-832.
Kidney BA, Haines DM, Ellis JA, Burnham ML, Jackson ML (2002). Evaluation of formalin-fixed paraffin-embedded tissues from feline vaccine site-associated sarcomas for feline foamy virus DNA. Am J Vet Res 63: 60-63.
Kidney BA, Haines DM, Ellis JA, Burnham ML, Teifke JP, Czerwinski G, et al (2001b). Evaluation of formalin-fixed paraffin-embedded tissues from vaccine site-associated sarcomas of cats for papillomavirus DNA and antigen. Am J Vet Res 62: 833-839.
Kliczkowska K, Jankowska U, Jagielski D, Czopowicz M, Sapierzyński R (2015). Epidemiological and morphological analysis of feline injection site sarcomas. Pol J Vet Sci 18: 313-322.
Kobayashi T, Hauck ML, Dodge R, Page RL, Price GS, Williams LE, et al (2002). Preoperative radiotherapy for vaccine associated sarcoma in 92 cats. Vet Radiol Ultrasound 43: 473-479.
Ladlow J (2013). Injection site-associated sarcoma in the cat: treatment recommendations and results to date. J Feline Med Surg 15: 409-418.
Lester S, Clemett T, Burt A (1996). Vaccine site-associated sarcomas in cats: clinical experience and a laboratory review (1982-1993). J Am Anim Hosp Assoc 32: 91-95.
Macy DW (1995). The potential role and mechanisms of FeLV vaccine-induced neoplasms. Semin Vet Med Surg (Small Anim) 10: 234-237.
Madewell BR, Griffey SM, McEntee MC, Leppert VJ, Munn RJ (2001). Feline vaccine-associated fibrosarcoma: an ultrastructural study of 20 tumors (1996-1999). Vet Pathol 38: 196-202.
Martano M, Morello E, Buracco P (2011). Feline injection-site sarcoma: past, present and future perspectives. Vet J 188: 136-141.
Martano M, Morello E, Iussich S, Buracco P (2012). A case of feline injection-site sarcoma at the site of cisplatin injections. J Feline Med Surg 14: 751-754.
Mayer MN, Treuil PL, LaRue SM (2009). Radiotherapy and surgery for feline soft tissue sarcoma. Vet Radiol Ultrasound 50: 669-672.
Mayr B, Bockstahler B, Loupal G, Reifinger M, Schleger W (1996). Cytogenetic variation between four cases of feline fibrosarcoma. Res Vet Sci 61: 268-270.
Mayr B, Eschborn U, Kalat M (1991). Near triploidy in a feline fibrosarcoma. Zentralbl Veterinarmed A 38: 617-620.
Mayr B, Reifinger M, Alton K, Schaffner G (1998). Novel p53 tumour suppressor mutations in cases of spindle cell sarcoma, pleomorphic sarcoma and fibrosarcoma in cats. Vet Res Commun 22: 249-255.
Mayr B, Schaffner G, Kurzbauer R, Schneider A, Reifinger M, Loupal G (1995). Mutations in tumour suppressor gene p53 in two feline fibrosarcomas. Br Vet J 151: 707-713.
McEntee MC (2000). The utility of contrast enhanced computed tomography in feline vaccine associated sarcomas: 35 cases. Vet Radiol Ultrasound 41: 575.
McEntee MC, Page RL (2001). Feline vaccine-associated sarcomas. J Vet Intern Med 15: 176-182.
McLeland SM, Imhoff DJ, Thomas M, Powers BE, Quimby JM (2013). Subcutaneous fluid port-associated soft tissue sarcoma in a cat. J Feline Med Surg 15: 917-920.
Morrison WB, Starr RM (2001). Vaccine-Associated Feline Sarcoma Task Force. J Am Vet Med Assoc 218: 697-702.
Mucha D, Laberke S, Meyer S, Hirschberger J (2014). Lack of association between p53 SNP and FISS in a cat population from Germany. Vet Comp Oncol 12: 130-137.
Munday JS, Banyay K, Aberdein D, French AF (2011). Development of an injection site sarcoma shortly after meloxicam injection in an unvaccinated cat. J Feline Med Surg 13: 988-991.
Munday JS, Stedman NL, Richey LJ (2003). Histology and immunohistochemistry of seven ferret vaccination-site fibrosarcomas. Vet Pathol 40: 288-293.
Nambiar PR, Haines DM, Ellis JA, Kidney BA, Jackson ML (2000). Mutational analysis of tumor suppressor gene p53 in feline vaccine site-associated sarcomas. Am J Vet Res 61: 1277-1281.
Nambiar PR, Jackson ML, Ellis JA, Chelack BJ, Kidney BA, Haines DM (2001). Immunohistochemical detection of tumor suppressor gene p53 protein in feline injection site-associated sarcomas. Vet Pathol 38: 236-238.
Nieto A, Sanchez MA, Martinez E, Rollan E (2003). Immunohistochemical expression of p53, fibroblast growth factor-b, and transforming growth factor-alpha in feline vaccine-associated sarcomas. Vet Pathol 40: 651-658.
Phelps HA, Kuntz CA, Milner RJ, Powers BE, Bacon NJ (2011). Radical excision with five-centimeter margins for treatment of feline injection-site sarcomas: 91 cases (1998-2002). J Am Vet Med Assoc 239: 97-106.
Poirier VJ, Thamm DH, Kurzman ID, Jeglum KA, Chun R, Obradovich JE, O'Brien M, Fred RM 3rd, Phillips BS, Vail DM (2002). Liposome-encapsulated doxorubicin (Doxil) and doxorubicin in the treatment of vaccine-associated sarcoma in cats. J Vet Intern Med 16: 726-731.
Porcellato I, Menchetti L, Brachelente C, Sforna M, Reginato A, Lepri E, Mechelli L (2017). Feline Injection-Site Sarcoma. Vet Pathol 54: 204-211.
Quintin-Colonna F, Devauchelle P, Fradelizi D, Mourot B, Faure T, Kourilsky P, et al (1996). Gene therapy of spontaneous canine melanoma and feline fibrosarcoma by intratumoral administration of histoincompatible cells expressing human interleukin-2. Gene Ther 3: 1104-1112.
Rousset N, Holmes MA, Caine A, Dobson J, Herrtage ME (2013). Clinical and low-field MRI characteristics of injection site sarcoma in 19 cats. Vet Radiol Ultrasound 54: 623-629.
Sandler I, Teeger M, Best S (1997). Metastatic vaccine associated fibrosarcoma in a 10-year-old cat. Can Vet J 38: 374.
Scherk MA, Ford RB, Gaskell RM, Hartmann K, Hurley KF, Lappin MR, et al (2013). 2013 AAFP Feline Vaccination Advisory Panel Report. J Feline Med Surg 15: 785-808.
Shaw SC, Kent MS, Gordon IK, Collins CJ, Greasby TA, Beckett LA, et al (2009). Temporal changes in characteristics of injection-site sarcomas in cats: 392 cases (1990-2006). J Am Vet Med Assoc 234: 376-380.
Srivastav A, Kass PH, McGill LD, Farver TB, Kent MS (2012). Comparative vaccine-specific and other injectable-specific risks of injection-site sarcomas in cats. J Am Vet Med Assoc 241: 595-602.
Steger-Lieb A, Kostorz A, Hauser B, Sumova A, Kaser-Hotz B (2002). Einsatz der Strahlentherapie beim vakzineassoziierten Sarkom der Katze, Erfahrungen aus 18 Fällen. Tierärztliche Praxis 30: 35-40.
Vaccine-Associated Feline Sarcoma Task Force (1999). Vaccine-Associated Feline Sarcoma Task Force guidelines. Diagnosis and treatment of suspected sarcomas. J Am Vet Med Assoc 214: 1745.
Vaccine-Associated Feline Sarcoma Task Force (2005). The current understanding and management of vaccine-associated sarcomas in cats. J Am Vet Med Assoc 226: 1821-1842.
Vascellari M, Melchiotti E, Bozza MA, Mutinelli F (2003). Fibrosarcomas at presumed sites of injection in dogs: characteristics and comparison with non-vaccination site fibrosarcomas and feline post-vaccinal fibrosarcomas. J Vet Med A Physiol Pathol Clin Med 50: 286-291.
Wilcock B, Wilcock A, Bottoms K (2012). Feline postvaccinal sarcoma: 20 years later. Can Vet J 53: 430-434.
Zabielska-Koczywąs K, Wojtalewicz A, Lechowski R (2017). Current knowledge on feline injection-site sarcoma treatment. Acta Vet Scand 59: 47.
Zardo KM, Damiani LP, Matera JM, Fonseca-Pinto AC (2016). Recurrent and non-recurrent feline injection-site sarcoma: computed tomographic and ultrasonographic findings. J Feline Med Surg 18: 773-782.
Zimmermann K, Hossann M, Hirschberger J, Troedson K, Peller M, Schneider M, Brühschwein A, Meyer-Lindenberg A, Wess G, Wergin M, Dörfelt R, Knösel T, Schwaiger M, Baumgartner C, Brandl J, Schwamberger S, Lindner LH (2016). A pilot trial of doxorubicin containing phosphatidyldiglycerol based thermosensitive liposomes in spontaneous feline soft tissue sarcoma. Int J Hyperthermia 25: 1-13.