Equine Sarcoids. A therapeutic challenge

Authors

  • Nikolaos Diakakis DVM, MSc, PhD, MRCVS - Companion Animal Clinic, School of Veterinary Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece https://orcid.org/0000-0002-4826-641X
  • Panagiota Tyrnenopoulou DVM, PhD, MRCVS - Clinic of Surgery, School of Veterinary Medicine, University of Thessaly, Karditsa, Greece

MeSH keywords:

horses, sarcoidosis, therapeutics

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Introduction

Equine sarcoids are the most common skin tumors of horses, representing 12.5% to 67% of all neoplasms (Taylor & Haldorson 2013). They are found in horses worldwide but also a wide variety of other Equidae including zebras, donkeys, and mules are affected (Jackson 1936, Reid et al. 1994, Martens & DeMoor 1996, Scott & Miller 2003, Lohr et al. 2005, Valentine 2006, Kidney & Berrocal 2008). The term “sarcoid” was first used to describe these tumors in 1936, in South Africa, to distinguish them from other fibroblastic skin tumors such as fibromas, fibrosarcomas, and papillomas (Jackson 1936). These tumors do not metastasize, but they can be invasive, are regarded as cosmetic defects, can become ulcerated and infected and, when occurring near the eyes or on the eyelids, can impair vision (Wobeser et al. 2010, Semik‐Gurgul 2021). The treatment of horses for equine sarcoids can represent a considerable expense for horse owners (Nasir & Campo 2008, Wobeser et al. 2010).

Equine sarcoids are associated with the presence of 2 types of bovine papillomaviruses (BPV), BPV-type 1 (BPV1) and BPV-type 2 (BPV2) (Teifke & Weiss 1990, Otten et al. 1993, Teifke et al. 1994, Carr et al. 2001, Wobeser et al. 2010, Semik‐Gurgul 2021).

Although there may be some pathological reasons why the name, “skin cancer” does not necessarily fit the equine sarcoid, there are several features that are consistent with the clinical principles of a genuine neoplastic disease. These include:

  • the behavior of the tumors,
  • the difficulties encountered in treatment,
  • the tendency to recurrence,
  • the spread across the body from site to site (Knottenbelt 2005).

The sarcoid is a tumor of fibroblasts (Taylor & Haldorson 2013). However, the sarcoid cell does not survive in organs other than the skin and the adjacent subcutis -it is restricted to fibroblasts in the skin itself (Yuan et al. 2010).

The basic recognized types are (Knottenbelt 2005, Taylor & Haldorson 2013:

  1. Occult. There are flat and alopecic with mild scaling (Figure 1).
  2. Verrucous. There are wart-like and have a raised, scaly, lichenified appearance with epidermal thickening (Figure 2).
  3. Nodular. There are firm, well defined, subcutaneous lesions (Figure 3).
  4. Fibroblastic. There are fleshy and ulcerated with local infiltration (Figure 4).
  5. Mixed sarcoids may include any, or all, of the aforementioned types and often become progressively more aggressive as fibroblastic transformation occurs (Figure 5).
  6. Malignant sarcoids are the most infrequent form and are aggressive, invasive tumors that proliferate rapidly and may spread along fascial planes and vessels (Figure 6).

It is worth mentioning that affected horses frequently have multiple types of sarcoids at the time of biopsy (Torrontegui & Reid 1994, Martens et al. 2001).

Figure 1. Occult sarcoid.

Figure 2. Verrucous sarcoid.

Figure 3. Nodular sarcoid.

Figure 4. Fibroblastic sarcoid.

Figure 5. Mixed sarcoid.

Figure 6. Malignant sarcoid.

Figure 7. Ligation at the base of a nodular sarcoid.

Treatment options and considerations

The various types have different treatment options and different long and short-term prognoses. In general, sarcoids are difficult to treat. Currently, there are around 40 different treatments that are used world-wide, which suggests that no single method is universally effective (Tamzali et al. 2012, Taylor & Haldorson 2013). Furthermore, the various treatments have variable effects; some can be very successful on some occasions and ineffective on others.Moreover, not all horses respond in the same way either to the presence of sarcoid tumors or to the treatment modalities. Some horses respond better to individual types of treatment and even some lesions on a particular horse respond differently to the same treatment. Treatment that may be well tolerated by one sarcoid may cause severe reactions on another. This means that treatment responses are entirely unpredictable with all treatment methods with the possible exception of radiation (Knottenbelt 2019). To make things worse, failure of any treatment method is usually accompanied by the reappearance of a more aggressive tumor -and often in increased numbers (Taylor & Haldorson 2013). It is therefore important to select the best possible alternative as the first treatment method.

As a rule, the treatment goal would be to destroy every single sarcoid cell, which is seldom achieved; therefore, prognosis is usually poor (Knottenbelt 2019). However, leaving sarcoids alone makes the prospect of treatment even less feasible so the philosophy should be to try to treat when they are small and few in numbers.

The most common treatments are:

Surgical removal

Tumors that are easily accessible and in a location such that skin closure is possible are often treated with conventional surgical excision. It is critical that wide margins (2-3 cm) are removed to prevent recurrence due to inadequate removal of all extensions of the sarcoid into surrounding tissue (Carstanjen et al. 1997, McCauley et al. 2002). Because this is often difficult to achieve, conventional surgical excision alone has yielded success rates of 30-50%, with most tumors recurring within 6 months (Genetzkyet al. 1983, McConaghy et al. 1994, Knottenbelt & Kelly 2000). Laser resection has a positive post-operative prognosis (Compstonet al. 2016), however, it is not simple to perform and is not widely available (Carstanjen et al. 1997).

Ligation (tying off wit h string / tail hair / rubber bands etc.)

This method is performed by applying a strangulating band around the base of the sarcoid (Figure 7). It could be applied to conveniently sized and situated nodular lesion and a few small pedunculated fibroblastic lesions (Knottenbelt & Walker 1994, Knottenbelt 2019). It is considered extremely dangerous, especially where there is a root structure. Still, it may be effective if the lesion has no roots. It is important to realize that the tumor will die slowly over some weeks and will eventually fall off leaving an open wound. This may in some cases be much larger than expected due to elastic recoil in the skin. Although simple, there is a strong recommendation against the use of this technique. There is a very high rate of recurrence following this method, usually with more aggressive sarcoids (Knottenbelt & Walker 1994).

Cryosurgery (freezing)

Cryosurgery, using liquid nitrogen spray at -196oC, can be used either on its own or in conjunction with other methods, such as surgical excision of the bulk of the lesion (Taylor & Haldorson 2013). Each lesion must be frozen quickly and thawed slowly at least three times (cryosurgical cycle) (Hewes & Sullins 2009). It can be used for most sarcoid types (Taylor & Haldorson 2013). There are several drawbacks of the technique. It is very time consuming and tedious if many lesions are to be treated. The recurrence rate is a quite high. In order to be effective, cryosurgery needs to be aggressive, and it may cause extensive damage to surrounding structures and consequent extensive scarring (Taylor & Haldorson 2013).

Bacillus Calmette Guerin (BCG) Injection

These agents are thought to stimulate a local cell-mediated immune response when injected intratumorally and thus induce cytotoxic T cell and natural killer cell activity against tumor cells (Davies 1982, Misdorp et al. 1985). This method works reasonably well for nodular and fibroblastic lesions around the eyes but is much less effective elsewhere (Knottenbelt & Kelly 2000). It is recommended that intratumoural injections be repeated every 2-4 weeks until regression occurs; an average of 12 ml per treatment and 3.2 treatments were required to achieve regression of periorbital sarcoids (Lavach et al. 1985, Taylor & Haldorson 2013). It should not be used on sarcoids on the limbs, as it usually leads to the deterioration of the lesions. The method has significant risks and so careful supportive medication is required at the time of each injection. The risks relate to the chance that the horse will react adversely to the protein in the injection (Knottenbelt & Kelly 2000).

Chemotherapy

Injection of cytotoxic drugs, such as cisplatin or 5-fluorouracil, into the center of lesions is a useful method of treatment for most types. Two approaches are available for controlled-release administration: percutaneous injection of a viscous fluid and implantation of biodegradable beads (Taylor & Haldorson 2013). Cisplatin in arachid oil is proven effective as it leads to complete regression in 78% of the sarcoid cases, with no systemic side-effects encountered (Spoormakers et al. 2002). Still, although treatment is easy to perform, the ALARA (As Low As Reasonably Achievable) principle should be followed when using cytostatics (Spoormakers et al. 2002). The combined use of injecting a chemotherapeutic drug (cisplatin) into the sarcoid followed by the application of high-voltage electric pulses is called electrochemotherapy (ECT). ECT is a new anticancer therapy that utilizes electrical field pulses to induce increased cell membrane permeability to antitumor hydrophilic drugs, such as cisplatin (Tamzali et al. 2012). This increases the drug concentration into the cells of the sarcoid by 100 times thereby increasing its effect (Tamzali et al. 2012). Due to the electric shock the procedure is completed under a brief (usually 15 minute) general anesthetic (Tamzali et al. 2012). Intratumoural injections of 5-fluorouracil have also been used for the treatment of equine sarcoids. This treatment modality should be used in relatively smaller tumors as sarcoids smaller than 13.5 cm3 are significantly more likely to resolve with treatment than larger sarcoids (Stewart et al. 2006). In general, the success rate of intratumoral 5-fluorouracil climbs up to 61.5% (Stewart et al. 2006).

5-Fluorouracil cream can be effective for the milder forms of occult or verrucose sarcoid. It is particularly useful as a pre-treatment modality before another method, such as surgery, cryosurgery or AW4-LUDES is used.

AW4-LUDES (Liverpool cream) are compounded topical chemotherapy creams that contain 5% fluorouracil, heavy metals and thiouracil. They are caustic agents that are dispensed at varying concentrations and cause inflammation and necrosis of sarcoid tissue without harming normal skin. There are variations in the power, duration, and interval between treatments. Usually, application of the cream daily or every other day is recommended for 3-5 treatments with necrosis of the sarcoid expected 5-10 weeks after the final treatment (Newton 2000).

Imiquimod cream is available for topical human use, and it can be used in some areas of the body and on superficial sarcoids only. It requires very specialized management with prolonged applications that may last up to 32 weeks. According to a recent study (Nogueira et al. 2006), application of imiquimod 5% cream three times a week until complete resolution of the tumor or 32 weeks led to marked improvement (80%) or complete resolution of tumors (60%). Advantages of imiquimod therapy include convenient application by owners without special equipment and facilities, a noninvasive treatment protocol and a satisfactory cosmetic outcome. It may be the first therapy choice for tumors in certain locations, such as the limbs, perineal and periorbital areas where other treatments may be inappropriate. Common adverse effects include exudation, erythema, erosions, depigmentation and alopecia; these are usually limited to the tumor and adjacent areas (Nogueira et al. 2006).

Radiotherapy

Radiotherapy is considered the gold standard treatment, and high dose rate brachytherapy (HDRB) may represent a safer and more effective method of delivering radiotherapy in the standing sedated horse (Bradley et al. 2017, Hollis & Berlato 2018). Usually, radiation is limited to localized lesions at difficult sites such as around the eyes and over joints. There are several ways in which radiation can be applied. The common method is the use of interstitial brachytherapy (Bradley et al. 2017). In this method radiation sources are implanted into the tumor and left to deliver the calculated dose of radiation before either being removed or fading sufficiently to be insignificant (Taylor & Haldorson 2013). Most current radiation systems use sealed radiation sources in the form of pellets or wires of a radioactive material (usually radio-222, gold-198 or, more often, iridium-192) to deliver gamma radiation. However, iridium-192 implants and other radioisotopes are expensive and not widely available but may be the best option for recurrent aggressive lesions (Taylor & Haldorson 2013). Radiation gives by far the best results (both in cure rates and cosmetic effects) but it is very expensive and very restricted (Hollis & Berlato 2018).

Plant extracts

European mistletoe, Viscum album austriacus aqueous extracts (VAE) are used in the treatment of human cancer. The antitumoral properties of the VAE are mainly attributed to mistletoe lectins, which are glycoproteins, and viscotoxins, a class of polypeptides. VAE proved effective for treatment of equine sarcoids. It can be recommended particularly when excision is not indicated as the primary therapy, tumors near the eye, and in cases with multiple sarcoids, where complete surgical removal or local medical treatment is impractical (Christen-Clottu et al. 2010, Felenda & Stintzing 2018).

A “herbal paste” for topical use known as XXTERRA is reported to be effective in some cases. It is an extract of Blood Root (Sanguineria canadensis)along with zinc salts. Apparently, XXTERRΑ affects sarcoids by altering the tumor antigens in vivo. This stimulates the immune system to recognize them as foreign and mount a response quite similar to the host vs. graft rejection. The tumor bed becomes lined with sensitized white blood cells and becomes inflamed causing it to slough off.

Recently, therapeutic vaccines composed of chimeric virus-like particles have resulted in tumor regression in approximately half of treated equids (Ashrafi et al. 2008, Mattil‐Fritz et al. 2008, Taylor & Haldorson 2013). Further research is needed in this field and attempts to circumvent virus-mediated immunosuppression are ongoing (Ashrafi et al. 2008, Mattil‐Fritz et al. 2008).

Conclusions

In clinical practice, it is usually easy to identify sarcoids, therefore biopsy should be avoided, as sarcoids tend to become more aggressive afterwards. Still, it is always tricky to decide which is the best therapeutic approach. The best treatment plan is to start treatment early, before the tumor increases substantially in size. If means of radiation are available, this would be the treatment of choice. In not, and the size of the mass is relatively small, surgical excision with wide margins is the most practical solution and the patient should be monitored closely for the following months. If a relapse occurs, then, a topical cream should be applied while the size of the mass is still small. Although imiquimod is good, according to our experience, XXTERRA gives better results.

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Published

2021-07-29

How to Cite

Diakakis, N. and Tyrnenopoulou, P. (2021) “Equine Sarcoids. A therapeutic challenge”, Hellenic Journal of Companion Animal Medicine, 10(1), pp. 40–49. Available at: https://hjcam.hcavs.gr/index.php/hjcam/article/view/111 (Accessed: 3December2021).

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