Managing periocular sarcoids

Periocular sarcoids can be seen in a variety of forms. Six clinical presentations of sarcoid lesions have been described: occult (Figure 1), verrucose (Figure 2), nodular (Figure 3), fibroblastic (Figure 4), mixed (Figure 5) and malignant/malevolent (Figure 6) (Knottenbelt and Kelly, 2000). In reality, the majority of cases have features of more than one form of sarcoid, i.e. are mixed lesions (Figures 7 and 8). Nodular lesions may take several forms: those that are clearly demarcated, which frequently become ulcerated in their later stages (Figure 9); and those that are more invasive and extensive, have less obvious margins and may occur in the upper or lower eyelid (Figures 10 and 11). The treatment options for periocular sarcoids vary with the location and type of sarcoid, and no one treatment is universally appropriate (Table 1). Many treatments are expensive and time consuming, and some have additional potential health and safety implications that are often overlooked or glossed over in equine veterinary practice, but should be considered prior to choosing a treatment modality. ‘Benign neglect’ of a periocular sarcoid lesion is a misnomer, as leaving them is not a benign procedure. In a series of 42 periocular lesions that were not treated when first examined, all 42 lesions required treatment at a later stage, and in 64% of these cases the lesions were too extensive to treat following referral, leading to the euthanasia of the horse (Knottenbelt and Kelly, 2000).

Surgical excision (including laser and cryosurgery)

Sharp surgical excision is commonly accepted to be an inappropriate sole treatment for the vast majority of sarcoids in any location, because of the propensity for this to lead to aggressive recurrence of the lesions (Knottenbelt and Kelly, 2000). In 28 periocular sarcoids treated with surgical excision, 82% had recurrences either at the surgical site or immediately adjacent to it (Knottenbelt and Kelly, 2000).

However, laser surgical excision has been shown to be a successful method of control of sarcoids, with 83% of lesions (across all locations treated) having no recurrence following diode laser surgical excision (Compston et al, 2016). Interestingly, in the same study, lesions on the head and neck were more likely to recur than those in other locations, and verrucose lesions were also more likely to reoccur (Compston et al, 2016). Carbon dioxide laser surgery has also been reported for the treatment of sarcoids, with a success rate of 62% (Carstanjen et al, 1997). If laser surgical excision is performed, owners should be counselled to expect a large, open wound that will have to granulate and heal (Figure 12), and that this wound healing takes a long time because of the nature of the surgery performed. Where lesions have no defined margin, laser surgical excision is very unlikely to be a successful treatment, so careful case selection and a skilled surgeon are imperative to achieve the best possible results.

Cryosurgery has been reported as a treatment modality in 28 cases of periocular sarcoid; 91% had aggressive recurrence of the sarcoid within 12 weeks of treatment, which in many cases led to eventual euthanasia due to uncontrollable disease (Knottenbelt and Kelly, 2000). Cryosurgery cannot therefore be recommended as a suitable treatment option for periocular sarcoids. Interestingly, 66% of sarcoid lesions in other locations had a good response to cryosurgery (Lane, 1977), and it is not clear why there would be such a discrepancy in the response to treatment.

Topical creams

The use of topical creams for the treatment of periocular sarcoids is complicated by the proximity to the globe and the potential for the creams to cause severe collateral damage (Hollis, 2017a). It has been suggested that topical creams for periocular sarcoids are only useful in the treatment of small, superficial lesions (deep margins measuring less than 5 mm) (Malalana, 2016).

The use of a compounded chemotherapy-based cream, AW3, AW4, and more recently AW5 has been commonplace in the UK for the treatment of sarcoids for many years. In periocular lesions its utility in the form of AW3 appears to be somewhat limited, with a success rate of just 35% reported (Knottenbelt and Kelly, 2000). No updated data are available on any improvements as the cream's ingredients have been modified. Interestingly, topical 5-flourouracil cream had a success rate of 67% in the same case series, although its use was restricted to a small number of occult and verrucose lesions (Knottenbelt and Kelly, 2000). This probably reflects careful case selection rather than a benefit of the 5-flouro-uracil cream compared with AW formulations, as the AW formulations contain 5-flourouracil amongst other ingredients.

Imiquimod has been used for the treatment of sarcoids; this topical cream causes a severe local reaction that can make it difficult to continue to treat the area (Figure 13), and requires treatment three times a week for up to 32 weeks in some cases. The main advantage is that this can be completed by the owner, but the degree of the local reaction can make application of the cream to the horse's lesion challenging towards the end of the course of treatment. Overall, the response rate has been reported as 60–72% of selected, superficial, sarcoid lesions in any location (Nogueira et al, 2006; Haspeslagh et al, 2016), and it seems a reasonable option for superficial lesions.

Bloodroot ointment, made from extracts of the bloodroot plant (Sanguinarua canadensis), has also been used. There is some evidence to suggest efficacy of bloodroot ointment for the treatment of sarcoids, in which 58% of lesions in any location resolved in an owner-based survey of its use (Wilford et al, 2014a; 2014b). Horses in that study were treated anywhere from 1 to >42 days, so exact recommendations for its use are not possible based on these data. To the author's knowledge, there are no data available specifically looking at treating sarcoids in the periocular region, but bloodroot ointment may be worthy of consideration for the treatment of small lesions.

Acyclovir has proven a controversial treatment, with one report of a success rate of 68% in small, early sarcoid lesions (Stadler et al, 2011), and another report suggesting that acyclovir was associated with treatment failures in sarcoid cases, despite reporting an overall success rate of 53% (Haspeslagh et al, 2016).

Topical bleomycin has been used in carefully selected cases with periocular sarcoids. When combined with other topical treatments, the combination of bleomycin with either 5-flourouracil or tazarotene was more effective than either treatment alone (Knottenbelt et al, 2018).

Electrochemotherapy

Electrochemotherapy has been reported to have a success rate of 86–94% for the treatment of sarcoids in any location (Haspeslagh et al, 2016; Tozon et al, 2016). The treatment involves general anaesthesia, and larger lesions will require several treatments to achieve the end result, which is a significant disadvantage in many cases; its use specifically for the treatment of periocular sarcoids has not yet been reported. However, the disadvantages of general anaesthesia aside, this is an interesting approach that is worthy of consideration for selected cases.

Photodynamic therapy

Photodynamic therapy involves the application of a photodynamic substance to the sarcoid lesion, followed by the application of a specific wavelength of light. The major limitation is the poor penetration of the majority of photoactive substances, which makes this technique suitable for only the most superficial of lesions. A recent small study in sarcoids in any location used a penetration enhancer, which appeared to improve response rates from 14% without the enhancer to 93% with the enhancer (Golding et al, 2017), although there was only 1 month of follow-up, and no longer term results were reported.

Immunotherapy

Intra-lesional BCG (Bacillus Calmette-Guérin) has been widely accepted as a good option for nodular and some fibroblastic lesions, with a reported success rate of 58–69%, but may be unsuccessful in the treatment of verrucose and occult lesions, and is associated with anaphylactic reactions (Knottenbelt and Kelly, 2000; Haspeslagh et al, 2016). At the present time BCG is unavailable in the UK, therefore it will not be discussed further in this review.

Intra-lesional chemotherapy

Intra-lesional chemotherapy can be successful, but has health and safety implications, and there are few published data on the success of this approach for periocular tumours. One report found only a 33% success rate following cisplatin injection into periocular sarcoids, and stated that accurate injection was extremely difficult (Knottenbelt and Kelly, 2000), raising further health and safety concerns should this approach be taken. In addition, the use of intra-lesional platinum-based chemotherapy drugs was associated with treatment failure in a recent report (Haspeslagh et al, 2016). The success rates reported in lesions treated in other locations vary from 53–96%, with no obvious reason for the huge variation in the success rates seen in two different studies (Théon et al, 2007; Haspeslagh et al, 2016).

The most commonly used forms of chemotherapy for this application with the some published evidence behind them are mitomycin C (McKane, 2014), cisplatin (Théon et al, 2007), and 5-flourouracil (Stewart et al, 2006), although only mitomycin C was described specifically in periocular tumours. Carboplatin and bleomycin may also be used in this manner, although to the author's knowledge there are no published data on their intra-lesional use.

Radiotherapy

Radiotherapy has long been considered the ‘gold standard’ for the treatment of periocular sarcoids (Knottenbelt and Kelly, 2000; Hollis, 2017a; Hollis and Berlato, 2017; Knottenbelt et al, 2018), although its use has been restricted by the high cost and limited availability of the treatment. Low dose brachytherapy has been used for the treatment of periocular sarcoids for over 40 years; however, the availability has become increasingly limited due to the high cost of the sources; practicalities; and the health and safety concerns associated with their use (Hollis and Berlato, 2017). Recently, a technique of high dose rate brachytherapy has been described that eliminates any operator exposure and therefore many of the health and safety concerns, although this technique remains expensive and very limited in availability; currently the Animal Health Trust in Newmarket is the only centre in the UK to offer this treatment option (Hollis and Berlato, 2017). The results of high dose rate brachytherapy can be spectacular, even in cases where multiple other treatment modalities have failed (Figures 14–16) and the technique requires no isolation of the horse, as treatment times are very short and treatments are performed under standing sedation in specially designed stocks (Figure 17).

Strontium plesiotherapy is a form of very superficial radiotherapy that has been briefly described for the treatment of periocular sarcoids (Knottenbelt and Kelly, 2000; Hollis, 2017b) and appears to be effective in carefully selected cases, although the number of reported cases is extremely small. Strontium plesiotherapy has very limited penetration, and is therefore only suitable for use in cases with small, superficial lesions. Although it is relatively cost-effective, does not require any isolation of the horse, and usually requires only standing sedation (Figure 18), within the UK it is only available at the Animal Health Trust in Newmarket, so is not practical for many owners.

Electronic brachytherapy, another form of radiotherapy, has been reported to successfully treat a single sarcoid on the medial stifle region (Bradley et al, 2017), but there are no published data on its efficacy in periocular sarcoid lesions. This technique requires multiple general anaesthetics and may be a sole treatment or combined with other modalities.

Conclusions

Periocular sarcoids present a particular clinical challenge, because of their location, their proximity to sensitive structures, and their apparent propensity to become especially extensive and invasive. Their location frequently makes them difficult or impossible to remove via laser surgical excision. While radiotherapy continues to be the ‘gold standard’ for the treatment of periocular sarcoids, the high cost of treatment and limited availability makes this inaccessible for many owners. Other options may therefore be more suitable for carefully selected cases. In all cases, owners should be encouraged to treat the lesions in their early stages, because they are much easier (and therefore cheaper) to treat when small than when left to grow and invade the eyelids, by which time treatment with any modality is difficult and sometimes impossible.

KEY POINTS

• Periocular sarcoids are difficult to manage, and no one treatment is suitable for all cases.
• Laser excision is growing in availability and is very successful for carefully selected cases.
• Radiotherapy remains the ‘gold standard’ treatment but is expensive and has limited availability.
• Intra-lesional and topical treatments can also be successful in carefully selected cases.
• In all cases, early treatment should be sought — ‘benign neglect’ is not an appropriate course of action.