What are Feline Injection-Site Sarcomas (FISS)?
Maigan Espinili Maruquin
I. Characteristics / Epidemiology
The feline injection-site sarcomas (FISS) were first reported on 1991 (Hendrick and Goldschmidt 1991). With the implementation of stricter vaccination and development of vaccines for rabies and FeLV, the increased incidence of vaccine reactions was recognized (Hendrick and Dunagan 1991, Kass, Barnes et al. 1993, Hartmann, Day et al. 2015, Saba 2017). With this, recommendations were to use the term ‘vaccine-associated sarcomas’, however, studies show that aside from vaccines are other non-vaccinal injectables in the subcutis or muscle can also cause chronic inflammatory response which led to reclassification as ‘feline injection-site sarcomas’ (FiSSs) (Martano, Morello et al. 2011, Hartmann, Day et al. 2015).
The FISS develops in 1–10 of every 10,000 vaccinated cats wherein malignant skin tumors of mesenchymal origin develops (Zabielska-Koczywąs, Wojtalewicz et al. 2017). It has been described as secondary to inflammation in different organs like eye (PEIFFER, MONTICELLO et al. 1988), uterus (Jelínek 2003) and muscle or skin after placement of non-absorbable suture or microchips (Buracco, Martano et al. 2002) (Bowlt 2015). Between three months to 10 years after vaccination, the development of FISS can occur (Hendrick, Shofer et al. 1994, McEntee and Page 2001) (Esplin, D. G., et al., 1993). Whereas, a study reported that the younger cats developed tumor at the vaccination site as compared to the older ones with similar tumors in other body areas with bimodal distribution of age with a peak at 6–7 years and a second at 10–11 years (Kass, Barnes et al. 1993, Martano, Morello et al. 2011).
Fig. 01. Saba, C. F. 2017 shows the occurrence of FISS.
II. Pathogenesis / Clinical Signs
After investigations, the hypothesis suggests that secondary to chronic and inflammatory response to vaccine or injection, having ultimate malignant transformation of surrounding fibroblasts and myofibroblasts triggers the tumors (Hendrick and Brooks 1994, Hartmann, Day et al. 2015, Saba 2017)( Hendrick MJ., 1999).
Fig. 02. (Cecco, B.S., et al., 2019) The sites where FISS occurs
Reports show significant correlation between the rabies and/ or FeLV vaccinations in the development of FISS (Hendrick, Goldschmidt et al. 1992, Kass, Barnes et al. 1993, Hendrick, Shofer et al. 1994). Despite many causes are associated with what triggers the tumor, higher risks are seemed to be coming from vaccines, specifically adjuvanted (Hartmann, Day et al. 2015). Discovered were traces of adjuvants in the inflammatory reaction and later in histological sections (Hendrick and Brooks 1994, Hartmann, Day et al. 2015).
Particles of grey- brown material in the necrotic centre and within the cytoplasm of macrophages were reported consistent with an inflammatory reaction (Hendrick and Dunagan 1991, Hendrick and Brooks 1994, Martano, Morello et al. 2011). The infiltrates reported includes macrophages often having cytoplasmic material, giant cells, lymphocytes and mixed neutrophils and eosinophils. Further, identified in the tumors were cytokines, growth factors and mutations in tumor suppressor genes (Ladlow 2013, Carneiro, de Queiroz et al. 2018).
While fibrosarcoma is commonly diagnosed, some histological types were also reported to include: malignant fibrous histiocytoma, rhabdomyosarcoma, myxosarcoma, liposarcoma, nerve sheath tumor, poorly differentiated sarcomas, and extraskeletal osteosarcoma and chondrosarcoma (Esplin, McGill et al. 1993, Hendrick and Brooks 1994, Hershey, Sorenmo et al. 2000, Dillon, Mauldin et al. 2005, Saba 2017). According to Saba. C, 2017, any sarcoma that develops within the vicinity of vaccination or injection site should be considered an FISS and thus, should be treated aggressively.
While tumors are invasive and variable in size, Martano M.E., et al, 2011 reported that large sized may be due to rapid growth. On the other hand, there could also be delayed in appearance due to its interscapular or deep location (Bowlt 2015). The mass can also be mobile or intensely adherent to the underlying tissue which is usually not painful, but solid and may be cystic (Bowlt 2015). These tumors that develop commonly in sites of injection can reach several centimetres in diameter within a few weeks (Martano, Morello et al. 2011).
Since not all cats develop this tumor after vaccination, suggestions are due to genetic predisposition, with higher case of FISS occurrence in siblings of affected cats. Further, some cats may develop more than one FiSS (Hartmann, Day et al. 2015).
III. Staging / Diagnosis
To properly react with the tumor, proper staging shall be performed. Once a histological diagnosis has been confirmed (Bowlt 2015), it requires complete blood count, a serum biochemical panel, urinalysis, 3-view thoracic radiography, lymph node examination by palpation, and ultrasonography of the abdominal cavity and cytology when applicable (Séguin 2002, Zabielska-Koczywąs, Wojtalewicz et al. 2017). Abdominal ultrasound may be required, depending on the location of the tumor. Computed tomography (CT) or magnetic resonance imaging (MRI) of the lesion and the thorax is required to see the actual size and evaluate the extent of the tumor (Cronin, Page et al. 1998, McEntee and Page 2001, Martano, Morello et al. 2011, Rousset, Holmes et al. 2013, Travetti, di Giancamillo et al. 2013, Saba 2017, Zabielska-Koczywąs, Wojtalewicz et al. 2017). Thoracic radiography is then performed to exclude metastatic deseases, which has 10- 24% chances (Saba 2017, Zabielska-Koczywąs, Wojtalewicz et al. 2017). Whereas, there is as high as 45% for the recurrence rate even after performing surgical excision (Cronin, Page et al. 1998)
Considering the possibility of misdiagnosing the tumor as a granuloma from small tissue samples, and the fact that these can be heterogeneous, incisional biopsy can be done at sites that can be easily excised (Martano, Morello et al. 2011). The indications for a biopsy are based in 3-2-1 rule (Vaccine-Associated Feline Sarcoma Task Force, 2005; Vaccine-Associated Feline Sarcoma Task Force guidelines, 1999; (Morrison and Starr 2001). This incisional biopsy is strongly recommended for masses that has persisted for >3 months, is >2 cm, and/or is growing over the course of 1 month post injection in the site (Saba 2017).
Radical surgery or wide excision may be recommended. Surgery will be performed with at least 3 cm margins peripherally and one fascial plane deep into the tumor wherein completeness of surgical margins is then considered the most important predictive factor for the FISS treatment. (Zabielska-Koczywąs, Wojtalewicz et al. 2017).
Radiotherapy is recommended often due to the high urate of recurrence, as high as 70% if the radical surgery is insufficient, and to have a disease- free survival (Hendrick and Brooks 1994). When the radiotherapy was performed before the surgery, metastatic seeding during surgery is less likely (Zabielska-Koczywąs, Wojtalewicz et al. 2017). Having both the radical surgery and radiotherapy might be the most efficient way to treat FISS but short- and long-term side effects shall be considered, too (Zabielska-Koczywąs, Wojtalewicz et al. 2017). The side effects of the radiation can be mild and primarily include dry desquamation of the skin, however, the healing of the wound may also be delayed (Saba 2017).
Having chemotherapy is not used as monotherapy, but may serve as neoadjuvant setting in a multimodal approach and cytostatic drugs were used in FiSS treatment (Zabielska-Koczywąs, Wojtalewicz et al. 2017). Further, additional immunotherapy has also promising reults (Jahnke, Hirschberger et al. 2007, Hüttinger, Hirschberger et al. 2008, Hartmann, Day et al. 2015, Jas, Soyer et al. 2015). Studies of cytokine gene transfer techniques as adjuvant-immunological treatment has showed less recurrence rates (Hartmann, Day et al. 2015).
For patients that has FISS, the age, sex, breed, of the FeLV status don’t seem to affect the survival time (Bowlt 2015). After the surgery, recurrence of tumor or metastasis significantly affects survival (Phelps, Kuntz et al. 2011, Bowlt 2015).
To prevent the occurrence of the FISS, few things must be considered. The choice of injection site should be assessed. It is recommended to have the site recommended for monitoring (Hartmann, Day et al. 2015).
The inflammatory reactions shall also be avoided in the injection sites. It is recommended to give subcutaneous injections as few as possible. Intramuscular tumours develop with a similar frequency, but are more difficult to detect early, thus must also be avoided. Oral drugs or intravenous must be given if needed. In addition to, long-acting irritating substances of injections must be avoided. And finally, cats should be vaccinated no more than necessary (Hartmann, Day et al. 2015).
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