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Feline injection-site sarcoma

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  • Disciplina: Oncologia
  • Specie: Gatto

Feline injection-site sarcomas are malignant tumours of mesenchymal origin that arise at the sites typically used for subcutaneous or intramuscular injections. They are characterized by a low metastatic power, but, at the same time, by a significant tendency to recur locally if not removed with a very broad and deep lateral margin. One of their distinguishing features is the latency of months or even years38,46 between the injection and the development of the tumour, followed by an extremely rapid growth, to the point of reaching a diameter of several centimetres within a few weeks.

The disease was described for the first time in the United States by two pathologists who, in a Letter to the Editor, reported an increase in diagnoses of fibrosarcoma in cats in recent years.21Initially, this increase was attributed to the obligation of vaccination against rabies and the simultaneous introduction of a vaccine against feline leukaemia. Consequently this new form of cancer became universally known as “vaccine-associated sarcoma,“ causing considerable uproar and worries in the pharmaceutical industry.

In order to thoroughly investigate the aetiology and establish the guidelines for the subcutaneous injection of drugs in cats, define the pathogenesis of this form of sarcoma, find appropriate treatment and raise the awareness of veterinarians about the problem, in 1996 a task force was established (Vaccine-Associated Feline Sarcoma Task Force - VAFSTF), again in the United States . The group was made up of the most eminent experts in veterinary oncology (AVMA).1,51 From studies conducted in the following years, it was concluded that not only vaccines, but any substance injected subcutaneously or intramuscularly and able to induce an inflammatory response could lead to tumour formation in predisposed subjects. For this reason it was decided to rename the tumour “feline injection-site sarcoma”, the name it is now recognized by. The term “sarcoma“, and not fibrosarcoma, is related to the fact that many histotypes have the same pathogenesis, although fibrosarcoma is the most common form.

 

AETIOLOGY AND PATHOGENESIS

The initial reports by Hendrick and Goldsmith21 and a subsequent study by Kass et al. attributed the increase in sarcomas and their development, in animals that were on average younger (mean 6-7 years) than the age until then reported, to vaccination against rabies and feline leukaemia, and more probably to the additives contained in these products. In addition, the risk of developing cancer increased with the number of inoculations given, rising from a 50% higher risk after a single injection to a 175% higher risk after three or more inoculations at the same site. The initial incrimination of the additives was confirmed by the finding, on histological preparations, of greyish-brown amorphous material at the necrotic centre of the lesion and in the macrophages that surrounded it.22,23 This material could trigger a foreign body inflammatory process which, over time and in predisposed subjects, led to neoplastic transformation. Current thinking is that not only the aluminium hydroxide used as an adjuvant in many vaccines, but also any substance that can stimulate a chronic inflammatory response can induce tumour formation. This is demonstrated by the sarcomas found in subjects which were never vaccinated, but treated with antibiotics or extended-release corticosteroids,29or those found at the injection site of lufenuron,17 in correspondence with non-resorbable suture material7and, perhaps, with a microchip.12

The aetiology is, however, multifactorial, since the inflammatory stimulus alone, although important, is not sufficient to cause the appearance of the tumour, as demonstrated by the low prevalence of injection-site sarcomas in the cat population. The frequency of this tumour, although highly variable depending on the author, ranges from 1/1000-1/10,00016,33 to 0,63/10,000 vaccinated cats.19 There is a lack of reliable statistics for Europe, but it is likely that the incidence is higher, at least in some countries. Genetic factors are added to physical ones, including the action of cytokines such as basic fibroblast growth factor and transforming growth factor-α,39 involved in promoting malignant transformation by stimulating the proliferation and migration of endothelial cells and activation of DNA synthesis in mesenchymal cells. Growth factors such as platelet-derived growth factor (PDGF), induced by chronic inflammation, together with the mutation or hyper-expression of oncogenes and tumour suppressor genes, can stimulate the proliferation of fibroblasts and myofibroblasts.24 These pathogenic mechanisms have also been described in other animal species, such as chickens36 and human beings,40 and in cats with regards to the development of ocular sarcomas.14

Finally, the immune system may also be involved in the process of malignant transformation, although there are still few data on the mechanisms of cancer evasion from immune vigilance in cats;8,27 the preliminary results of immunotherapy for injection-site sarcoma appear to be encouraging.20,31Factors related to the mode of administration of the injection (needle size, hand massage, the steps of administration, the temperature of the inoculated product, subcutaneous or intramuscular administration) do not seem to affect the appearance of the tumour, with the exception of the low temperature of the substance injected.29,34 Also liquids, such as physiological saline, produced no effect.43 No correlation was observed with positivity for feline immunodeficiency virus (FIV) or feline leukaemia virus (FeLV).

 

DIAGNOSIS

The diagnosis of feline injection-site sarcoma is relatively simple and is based mainly on clinical signs, taking a thorough history and a few instrumental investigations, such as fine needle biopsy and incisional biopsy if necessary. Staging is completed by a chest X-ray or, better, computed tomography (CT) of the chest and of the lesion, while a complete blood count, blood-chemistry tests and the tests for FIV and FeLV provide indications on the general condition of the animal. The average age of onset of injection-site sarcoma is lower than that of sarcomas not induced by injection, and occurs at about 6-7 years of age, with a second peak at around 10-11 years. Generally, the owners report the sudden and rapid growth of a mass, which is often found in the interscapular region or in the lateral parts of the chest or neck; however, in subjects that are not easily managed (in which injection sites are located more randomly) the mass can also develop in the buttock or rump region. The lesion may appear as a well-defined mass, with a hard or hard-elastic consistency, adherent to the deep layers of tissue, usually covered with fur and not painful or itchy (Fig. 1a and 1b). In some cases, however, there are more disseminated, granular, and poorly defined forms (Fig. 2).

The history may reveal there has been a vaccination or other inoculation, occurring on average 1 to 3 months before finding the problem, but in some cases the last inoculation may have been even several years prior to finding the mass. In general, according to the VAFSTF1,51, the‘3-2-1 rule’ applies: each nodule that appears within 1 month after injection, reaches ≥ 2 cm in size and persists for more than 3 months should undergo biopsy. Fine needle biopsy enables a diagnosis of mesenchymal tumour in 50% of cases, since these are sparsely cellular tumours and often cystic (Fig. 3), but also the finding of an inflammatory process with numerous lymphocytes and macrophages should not completely exclude the diagnosis of a neoplasm. The choice of the site to biopsy is, therefore, important, while it is useless to send a fluid sample to the laboratory. In equivocal cases, an incisional biopsy and histological examination can be used to resolve any doubts. The site chosen for sampling should be easily included in the area of the mass subsequently removed without having to increase the extension of the surgery. Nonetheless, the centre, which is often necrotic, should be avoided. Incisional biopsy, which involves the removal of an adequately sized wedge of tissue, is preferable to Tru-Cut or punch biopsies, as the tissue is quite heterogeneous and a small sample may not be diagnostic, or result in a response of panniculitis or granuloma.

 

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Once the diagnosis has been established, it is extremely useful to perform CT (or magnetic resonance imaging) of the lesion and the chest in order to determine the possibility of complete tumour excision and to look for metastases. In fact, the infiltrating nature of injection-site sarcoma means that what is observed macroscopically is often only the “tip of the iceberg”, while the contrast medium injected during CT allows the clinician to detect even microscopic areas of infiltration distant from the primary mass (Fig. 4). The proper planning of surgery, based on the true extension of the tumour is, therefore, decisive for curative purposes, since the currently reported rate of local recurrence may reach 45%, even after a correct surgical or multimodal approach.9,11,37 An ultrasound examination of the abdomen may be indicated if the tumour is located in a caudal part of the body, while chest X-rays, in at least two lateral-lateral projections, should always be performed to look for metastases if CT has not been used.

 

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Anchor(Fig. 6), perform a partial scapulectomy (Figs. 7a and 7b) or total scapulectomy (Figs. 8a and 8b), remove part of the chest wall (Fig. 9) or amputate a limb (Figs. 10a and 10b). The important thing is reconstruct the skin and muscle planes well, obliterating all the dead spaces to avoid the formation of seromas, which are one of the major complications of surgery. Functionally, recovery is rapid and complete, even in the most aggressive cases, and the only complications observed, besides seroma, are variably severe dehiscence of the wound, especially in areas of greatest tension (Fig. 11a, Fig. 11b, Fig. 11c) and the persistence of itching, sometimes for months after surgery. A seroma can be managed by applying a pressure bandage (Fig. 12), kept in place for 1-2 weeks, and by using anti-inflammatory drugs for a few days, while wound dehiscence often heals by second intention without the need for surgical revision. In all cases good analgesia in the immediate post-operative period and in the first few days after surgery is essential, and should include the local application of analgesics through small catheters introduced into the site of surgery.Anchor

All the material excised must be sent to the laboratory for confirmation of the diagnosis and assessment of the excision margins, after highlighting them with appropriate dyes (Fig. 13) or with the application of full thickness sutures on the sample so as to facilitate the orientation of the specimen for the pathologist. The information obtained from this examination is useful for prognosis as well as for planning other possible treatments  (radiotherapy, chemotherapy).

Although highly indicative, the absence of neoplastic infiltration at the margins of the wound is not always associated with the absence of local recurrence, as reported by Kobayashi et al,32 who observed a 42% recurrence rate even in cases in which histological examination showed no neoplastic infiltration at the margins. This finding was recently confirmed in a study by Giudice et al,18 who reported that although cats with incomplete excision of the tumour are 10 times more likely to develop local recurrence, this also occurred in 19% of subjects with tumour-free margins. The explanation probably lies in the particular pathogenesis of the tumour, associated with  neoplastic transformation of areas subject to a chronic inflammatory stimulus. The inflammation can persist even in remote areas, but contiguous to the tumour, and may evolve over time. The techniques for assessing the excision margins, which have not yet been standardised in veterinary medicine, need to be refined.

 

RADIOTHERAPY

Along with surgery, radiotherapy is the basis of multimodal treatment of injection-site sarcoma. The current equipment for radiotherapy makes it possible to obtain good results with both adjuvant and neoadjuvant treatment, without causing severe side effects. Both procedures have advantages and disadvantages: adjuvant radiotherapy (preferred by surgeons) allows surgery to be performed on “healthy“ tissue, with less risk of dehiscence due to skin alterations induced by the radiation therapy itself. On the other hand, the area to be irradiated is larger and must include a margin of several centimetres beyond the surgical scar, which in turn requires a margin of “normal“ tissue around the wound.  Neoadjuvant radiotherapy makes it possible to irradiate a smaller area, but entails a higher risk of subsequent dehiscence of the surgical wound. From an oncological point of view, the two alternatives are not associated with scientifically proven differences. Recent studies found a local recurrence rate of 41-45% after treatment with surgery and radiation, while the disease-free survival varied from 398 to 810 days and overall survival from 520 to 1290 days. Metastases were observed in 12-21% of patients.9,11,15,32,37

 

CHEMOTHERAPY

At present there are no studies that have evaluated the effectiveness of chemotherapy alone in the control of injection-site sarcoma. Chemotherapy is used primarily to control metastases, but it can also be considered in the context of better delineating the surgical field, if used in a neoadjuvant setting35 (without however reducing the size of the area to be removed); it may also be chosen when radiotherapy is not accepted by the animal’s owner, to try to eliminate residual cancer cells after a surgical procedure which, although aggressive, has resulted in infiltrated margins. Several authors have reported a positive prognostic effect of chemotherapy in combination with surgery, with or without radiotherapy.5,15,32,41 The drugs most commonly used are doxorubicin, carboplatin and cyclophosphamide, alone or in combination with each other. The use of vinca alkaloids has not produced any positive effects, while ifosfamide has been demonstrated to produce positive results, although it is more toxic to the bone marrow and requires a longer time of administration.42

Doxorubicin is an anthracycline. It must be administered intravenously, given its significant capacity to damage tissues. The dose in cats is 1 mg/kg or 25 mg/m2  every 3 weeks, given four or five times. The drug should be administered over about 15-30 minutes. The tolerability in cats is good and the side effects mainly involve bone marrow suppression, which can be seen 7-10 days after treatment, and nephrotoxicity (for this reason it should not be administered to patients that already have signs of kidney problems). Loss of vibrissae and (rarely) gastrointestinal problems, such as loss of appetite, have also been described. The cardiac toxicity from accumulation that has been described in dogs is extremely rare in cats, but it is still recommended that a total dose of 180-240 mg/m2should not be exceeded. Doxorubicin can be administered as a single agent or in combination with cyclophosphamide or carboplatin.

Cyclophosphamide is an alkylating agent commonly used in veterinary medicine, alone or in combination with doxorubicin, for the treatment of injection-site sarcoma. It can be given per os (50 mg/m2 for 4 days a week, adjusting the dose to avoid breaking the tablets) in the morning, or intravenously (250-300 mg/m2 every 3 weeks). It can cause myelosuppression (nadir at 7-14 days), loss of appetite and other gastrointestinal symptoms, nephrotoxicity, loss of vibrissae and haemorrhagic cystitis (rarely) in cats; treatment must be stopped if these side effects occur.

Carboplatin.Unlike cisplatin, carboplatin can be used in cats at a dose of 180-200 mg/m2 intravenously every 3 weeks, alone or in combination with doxorubicin. It is generally well tolerated but can be myelotoxic (nadir at 17-21 days after administration); it is rarely nephrotoxic but can sometimes cause depression and anorexia.

 

OTHER THERAPIES

The use of tyrosine kinase inhibitors is currently being studied in veterinary medicine for the treatment of malignant neoplasms showing abnormal protein expression or mutations of the genes encoding for the proteins. These include KIT and PDGF; the latter and its receptor are involved in the pathogenesis of injection-site sarcoma. A study published in 2004 showed that imatinib mesylate, an inhibitor of tyrosine kinases, can block the PDGF receptor in cell cultures of injection-site sarcoma and inhibit tumour growth in a murine model.30 There are currently no clinical trials demonstrating the effectiveness of the inhibitor in vivo. In 2007 a study aimed at assessing the safety of interferon-ω in the treatment of injection-site sarcoma20 was published, but unfortunately consistent data on the clinical effectiveness of this treatment are lacking. Although both of these therapies are still in the experimental stage, they may become useful adjuncts for the treatment of injection-site sarcoma.

 

PROGNOSIS

In the light of current knowledge, multimodal therapy that associates broad-based surgery and adjuvant or neoadjuvant radiotherapy, with or without the use of chemotherapy, can decrease the local recurrence rate to 41-44% at 2 years,9,37 while the rate of metastasis (mainly to the lungs) is around 12-24%.9,11,16,25 The median survival rate is 23 months, with a median disease-free survival of 13-19 months.6,9,11

 

PREVENTION

Given the “iatrogenic” aetiology of the tumour, prevention plays an important role. Initially, in order to clarify the real implications of different types of inoculation in the development of cancer, the VAFSTF guidelines recommended vaccinating against rabies in the right hind limb (Right), against feline leukaemia in the left hind limb (Left) and giving the normal polyvalent vaccine to the shoulder (FVR-CP-C). These indications have indeed borne fruit, as demonstrated by the work carried out on 392 cats and published by Shaw et al.47 In 2009, in which it was noted that since December 1996 (year of establishment of the VAFSTF) the number of injection-site sarcomas in cranial areas had gradually decreased, while they had increased in posterior areas. In 2006 the number of tumours in these two regions was more or less the same, a sign of the implementation of the aforesaid guidelines by many veterinarians. Based on these findings, and without considering the influence of other injected substances, it was determined that the rabies vaccine caused 51.7% of cancer cases, while the leukaemia vaccine caused 28.6%. The vaccine against the most common forms of feline respiratory conditions, viral rhinotracheitis (FVR), calicivirus (C), panleukopenia (P) and Chlamydia (-C) caused 19.7% of cases. This information confirms the real involvement of injections in the development of injection-site sarcoma.

Currently, the recommendation is to perform any type of subcutaneous injection (the tumour can also develop after intramuscular injection, but the diagnosis is made later) in regions which can be easily approached surgically, such as lateral parts of the abdomen, away from the spine and limbs. Alternatively, the most distal part possible of the hind limb can be used, taking into account, however, that in this case, the broad-based excision of the tumour implies amputation of the limb itself, which is certainly effective but more disabling than removing parts of the abdominal wall.

In any case, it is recommended that subjects which develop injection-site sarcoma are not re-vaccinated and that the administration of any drug by injection should be limited to those cases that are absolutely necessary. Finally, it is the responsibility of the veterinarian to assess the appropriateness of prophylactic vaccinations, according to the real risk of contagion for each animal. On this point, the final document of the VAFSTF, which was closed down in December 2004,51 provides excellent evaluation criteria, as well as information on the real duration of vaccine immunity produced by the AVMA.2,44,45

 

References

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