Dr Firas Al-Niaimi explores the aetiology and treatment options for the dermatological condition presenting on patients’ eyelids
Xanthelasma, also called xanthelasma palpebrarum (XP), are yellowish papules and plaques caused by localised accumulation of lipid deposits commonly seen on the eyelids. The global prevalence is estimated at 4%,1 with an incidence of 1.1% in women and 0.3% in men.2 The age of onset can range from 15 to 73 years, although typical peaks are seen in the fourth and fifth decades. In around half of the cases it can be associated with an underlying hyperlipidaemia and a presentation prior to the age of 40 should prompt screening to rule out underlying inherited disorders of lipoprotein metabolism.3
Whilst the exact pathogenic mechanism is not fully understood, cutaneous xanthelasma represent the deposition of fibroproliferative connective tissue associated with lipid-laden histiocytes, also known as foam cells.4
Primary hyperlipidaemia is caused by genetic defects in the receptors or enzymes involved in lipid metabolism. Inherited disorders of low-density lipoprotein (LDL) cholesterol metabolism are typical examples that are seen in 75% of those with familial hypercholesterolaemia.2 The pathogenesis in this cohort of patients is thought to be secondary to elevated serum lipoprotein levels, which leads to extravasation of the lipoprotein through dermal capillary blood vessels and subsequent macrophage engulfment.1,2 Secondary causes of hyperlipidaemia include certain physiological states and systemic diseases. Examples include pregnancy, obesity, diabetes mellitus, hypothyroidism, nephrotic syndrome and cholestasis.5-8 Certain medications such as oestrogens, tamoxifen, prednisolone, oral retinoids, cyclosporine and protease inhibitors, can also lead to a state of hyperlipidaemia.9-11
The most common cutaneous presentation of secondary hyperlipidaemia is XP.2 They present as soft symmetrical, bilateral, yellow, thin polygonal papules and plaques typically in the periorbital area (Figure 1). Other sites that may be affected include the neck, trunk, shoulders and axillae.2 There is no reported association between xanthelasmas and high-density lipoprotein (HDL) or triglyceride levels.
Christoffersen et al.12 found that independent of well-known cardiovascular risk factors, the presence of XP appears to be a predictor of risk for myocardial infarction, ischaemic heart disease, severe atherosclerosis, and death in the general population. Contrary to common belief, arcus senilis of the cornea is not an independent predictor of risk of the cardiovascular concerns listed above.12
The differential diagnosis of xanthelasma includes chalazion, sebaceous hyperplasia, syringoma, nodular basal cell carcinoma and necrobiotic xanthogranuloma (NXG).13
XP are typically asymptomatic and treatment is often sought for cosmetic purposes. Unfortunately, there is paucity of strong evidence in the literature for the effective treatment of XP. Nevertheless, current treatment options are discussed.
There is limited evidence in the literature for the effective treatment of normolipidaemic (not-elevated lipids) XP. Commonly cited treatments include topical trichloroacetic acid (TCA), laser ablation, and surgical excision. There are also case reports of XP responding to systemic interleukin-1 blockade and cyclosporine-A therapy.10,14 Below are the most common treatment modalities used for normolipidaemic XP, their associated efficacy, particular limitations and side-effects.
Whilst systemic therapy in practice is rarely used in XP, there are nevertheless emerging drugs that have shown to be associated with XP regression. These drugs include probucol and alirocumab.
There are reports of successful treatment using oral probucol in the literature. It is proposed that probucol, an antioxidant, acts by potentially inhibiting atherogenesis through limiting the oxidative modification of low-density lipoprotein cholesterol essential for foam cell formation.15 Harris et al. showed 68% of xanthelasma regressed after probucol therapy in seven cases.16
Alirocumab, a monoclonal antibody which belongs to a novel class of anti-cholesterol therapy through inhibition of PCSK9, is primarily used in the treatment of hypercholesterolemia. Civeira et al.17 reported rapid resolution of XP after treatment with alirocumab in a middle-aged man with severe high levels of LDL cholesterol, due to a familial hypercholesterolemia. The regression of the XP was associated with lowering of LDL cholesterol concentrations.17
Topical therapy is probably the most widely used modality, particularly in clinics or settings that lack energy-based devices.
Trichloroacetic acid (TCA) is a form of destructive therapy, used topically at concentrations of 50-100%. The approach is relatively simple. It is applied in a painting fashion; carefully ensuring the greatest amount of TCA is smeared at the margin of the lesion. The treatment endpoint is white frosting. One study reviewed the efficacy and tolerability of different concentrations of TCA in the treatment of 30 patients with XP.18 TCA concentrations of 35%, 50%, and 70% were trialled. The authors initially degreased the skin using cotton gauze soaked in acetone. Sensitive areas, for example, the inner canthus and nasolabial folds, were protected with petrolatum ointment. The TCA was then applied using a cotton-tipped
applicator until solid frosting without pink background was achieved. This was usually seen within 30 seconds to two minutes. The area was then neutralised and rinsed with cold water, followed by the application of a thin coat of antibiotic ointment and sunscreen.18 TCA 70% was found to be the most effective concentration. It was well-tolerated and associated with significant clinical efficacy. This concentration required the least number of sessions in the treatment of XP. Furthermore, it was noted that TCA 70% was particularly useful in treating papular lesions, whilst TCA 50% was effective for macular (flat) xanthelasma. A study by Haque and Ramesh mirrored these findings.19 They also concluded that TCA 70% was effective in treating flat plaques, however TCA 100% was required for papulonodular lesions.19 In practice, this translates to lesion thickness; the thicker the lesion, the higher the required concentration. Overall, TCA therapy for XP was found to be more effective for smaller lesions, with repeated procedures resulting in pigmentation and scarring.20 In general, post-inflammatory hyper and hypopigmentation with TCA is reported at a frequency of 9-12.5% and 21.5-33.4%, respectively.19,21 Some studies reported that this was dependent on the TCA concentration, whilst others did not corroborate this association.19,21,22 It is also important to note that with any procedure close to the eye, care should be taken given the risk of ocular injury and the thin skin. Existing literature suggests recurrences ranging between 25 to 39%,19-21 with Goal et al. describing a recurrence rate of 34.5% at six-month follow-up in their cohort.23
Liquid nitrogen cryotherapy is a simple and effective treatment option. The risk of intense swelling due to the lax skin tissue in the eyelid is the reason this treatment is generally avoided in XP. One small case series involving four patients did show efficacy in the treatment of XP using very short freeze time.24 They reported clearance of lesions in all cases with only minor swelling associated, and no recurrences during a 10-year period. The proposed mechanism of action of cryotherapy is suggested to be associated with vasoconstriction and microthrombi formation caused by cryo-induced cell death. Potential adverse effects seen with cryotherapy include oedema, vesicular and blister formation depending on intensity of inflammatory response. These correlate with the length of freezing and thus the temperature that the tissue reaches.24
Intralesional Pingyangmycin was described in one study by Wang et al.25 This is a broad-spectrum anti-tumor antibiotic. A total of 12 patients with 21 lesions received two treatment sessions, and in all patients except one the result was satisfactory. One patient experienced local recurrence 12 months after treatment. The authors described no severe associated complications.25
Low-voltage radiofrequency (RF) ablation was used in a study for the treatment of XP.26 Out of the 15 patients who participated in the study, nine achieved an improvement of greater than 75%. The authors concluded that this modality of treatment was effective in the treatment of XP, in particular lesions close to the eye and those that are multiple, especially with indistinct borders.26 A comparative study by Reddy et al. evaluated the efficacy of RF ablation versus TCA in the treatment of XP.27 Although both treatments resulted in similar improvement scores, RF ablation required fewer sessions to achieve more than 75% clearance of lesions. However, at four weeks post treatment, 40% in the RF group and 15% in the TCA group had scarring, and 45% in the RF group and 30% in the TCA group had pigmentation.27 So whilst fewer treatment sessions were required with RF ablation to achieve an excellent result, the treatment was associated with more complications comparatively in this study.
Laser ablation has been used to deliver targeted therapy in the treatment of XP. The mechanism of action, in addition to lesion vaporisation, is proposed to include 1) destruction of perivascular foam cells via thermal energy damage and 2) coagulation of dermal vessels leading to blockage of further lipid leakage into tissue, thus preventing recurrence. The use of a variety of lasers has been described in the literature including carbon dioxide (CO2), argon, erbium and pulsed-dye lasers. The CO2 and Erbium:YAG use longer wavelengths of light absorbed best by cellular water, thus allowing for their use in removal of epidermal lesions.28 Argon and pulsed-dye lasers, on the other hand, use shorter wavelengths of light, preferentially absorbed by haemoglobin, and therefore are primarily used for vascular lesions.28 Argon lasers are no longer used in clinical practice.
The CO2 is considered the gold standard ablative laser. The vaporisation of water within cells results in the ablation of skin lesions layer by layer.28 A number of studies utilising the CO2 laser to treat patients with XP have been reported. The overall outcome was excellent and complete initial resolution was achieved in the majority of cases. Raulin et al. published a large case series of 23 patients receiving high-energy ultra-pulsed CO2 laser therapy.29 The ultrapulsed variation enables vaporisation of a thin layer of tissue whilst the pulses allow time for thermal relaxation of surrounding tissue, limiting excessive heat build-up.30 All lesions were successfully removed, with no scarring associated and a recurrence rate of 13% at 10 months. The authors recommended treatment should be performed in the early stages of XP development in order to prevent recurrence. A prospective randomised study involving 20 patients compared the efficacy and safety of super pulsed (SP) and fractional CO2 laser treatment for XP in bilateral XP lesions, with either a single session of ablative SP CO2 or three to five sessions of ablative fractional CO2 at monthly intervals.31 Lesions treated with SP CO2 laser showed significantly better improvements and patient satisfaction in comparison with fractional CO2 laser, although scarring and recurrence was also higher.31 The CO2 laser has also been compared to other treatment modalities. A comparison study using 30% TCA and CO2 laser for the treatment of XP in 50 patients showed that both these modalities were effective treatments for clinically mild lesions.23 The laser group achieved complete clearance in all patients, in contrast to the TCA group whom achieved a complete clearance rate of 56%. The CO2 laser was the superior treatment option for severe lesions due to its associated coagulative effect that spreads beyond the ablative zone. Unfortunately recurrence was a concern with both treatments, particularly for lesions that extended deep into the dermis. At six months, the recurrence rate with TCA was 34.8%, consistent with existing literature that report rates ranging from 25-39%.19-21 In this study, the recurrence rate with CO2 at six months was 16%.23 The recurrence rates reported in the literature for CO2 are variable from no recurrence after four years 32 to 13% at 10 months.29 The efficacy of CO2 laser therapy has also been compared to higher concentrations of TCA. Mourad et al.18 found CO2 laser ablation to be as effective as TCA 70% in the treatment of XP in 30 patients. Side effects reported include post-inflammatory hyperpigmentation (22.2%) and hypopigmentation (33.3%).18,33
Erbium:yttrium-argon-garnet, also known as the Er:YAG laser, is a purely ablative laser, with a smaller thermal coagulation zone in comparison to CO2 laser. The latter is associated with a potential higher risk of scarring. The Er:YAG also has the added advantage of faster healing time, shorter duration of post-laser erythema, post-inflammatory hypo and hyperpigmentation.34
Mannino et al.35 treated 30 patients with a total of 70 xanthelasma using the Er:YAG laser. All lesions were effectively removed with no associated scarring or dyschromia.35 The follow-up observation period was 12 months with no recurrences reported. Similar effective results (100% lesion removal) were also seen in a study conducted by Borrelli and Kaudewitz who treated 33 xanthelasma lesions with the Er:YAG laser. 36
Another study by Lieb et al.37 found that the wound healing was slower with CO2 compared with Er:YAG laser due to its larger associated thermal necrosis zone. The latter form of laser also had excellent results in the treatment of superficial xanthelasma. Nevertheless, the authors concluded that CO2 laser was better suited for deeper lesions possibly due to its associated haemostatic property.38 The efficacy and complication rates of Er:YAG laser ablation in comparison to 70% TCA in the treatment for XP has also been reviewed. Gungor et al.38 treated different XP lesions in the same patient using these two treatment modalities. They reported that both treatments have similar effectiveness and complications rates.
The benefits using the 1064 nm Q-switched Nd:YAG laser is not clear. Fusade39 reported a case series of 11 patients with a total of 38 xanthelasma lesions. After a single course of treatment they noted an excellent response (greater than 75% clearance) in six patients, a good response (51-75% clearance) in a further two patients and moderate (25-50% clearance) response in the remainder.39 However, it is important to note none of the patients achieved complete clearance.
Furthermore, these promising findings could not be replicated by Kerasi et al.,40 who treated a total of 76 lesions in 37 patients with two sessions of Q-switched Nd:YAG laser (1064 nm and 532 nm wavelengths). In total 57 lesions were treated with the 1064 nm wavelength and 19 with the 532 nm wavelength. The overwhelming majority of patients showed no clearance.40 The early disappointing results accounted for the high dropout rate, therefore the authors advised against using Q-switched Nd:YAG laser treatment for XP due to poor clearance.40 I would advise against the Q-switched laser in XP given the potential ocular risk and poor evidence of efficacy.
Potassium titanyl phosphate (KTP) laser works on the principle of selective photothermolysis and is primarily a vascular laser. One study used KTP laser (532 nm) to treat xanthelasma in 14 patients and reported an efficacy of 85.7% without side effects.41
Karsai et al.42 described the use of 585 nm pulsed-dye laser in 20 patients with XP. A total of 38 lesions were treated. The authors described promising results with majority of the patients achieving greater than 50% clearance rates. Reported side effects included purpura, oedema and post-inflammatory hyperpigmentation. No long-term follow-up was mentioned.
Traditionally, surgical excision has been used and often yields excellent cosmetic outcomes with various surgical techniques advocated.
The classic blepharoplasty may be used to excise the xanthelasma in a serial staged approach.43 Recurrence, however, is common, and reported to be up to 40 and 60% following primary and secondary excision, respectively.43 Lee et al. conducted a four-year retrospective review of patients who received surgery for XP.44 Patients were classified into four grades according to the location and extent of the lesion. In total, 95 cases were reviewed; 70% of which were treated with simple excision in conjunction with blepharoplasty. The remaining 30% were treated with a combination of simple excision and local flaps or skin grafts. These were performed in patients with more advanced grades of the disease. There were no associated complications apart from postoperative scar contracture (4.2%) in patients graded III or IV.44 Recurrence was reported in 3.1% of patients at 12 months and this was found to be irrespective of the grade. The incidence of recurrence, however, is increased with incomplete excisions and has been reported in the past to be up to 40% after primary surgical excision, 60% after secondary excision, and 80% with bilateral upper and lower eyelid involvement.45 Mendelson and Masson advocate that surgical excision should be the mainstay of treatment for XP lesions that involve the deep dermis or infiltrate the underlying muscle. It is therefore apparent from the literature that recurrence following surgery is higher if the lesion excised was a recurrence, there is presence of underlying hyperlipidaemia, and if all four eyelids are involved.45 Other surgical techniques include a combination approach of surgery and chemical peeling. Zarem and Lorincz recommend superficially excising the xanthelasma lesions using light electrodesiccation followed by the application of topical trichloroacetic acid.46
Although XP lesions are considered benign, they can cause significant psychological distress due to their associated cosmetic disfigurement. Their presence can also indicate an underlying plasma lipid disorder in approximately 50% of patients caused by a lipoprotein or apolipoprotein abnormality. Patients should therefore be screened for underlying causes of hyperlipidaemia and may require follow-up for associated morbidities. XP rarely cause functional problems, however treatment is usually sought due to aesthetic reasons. Unfortunately recurrence is often seen with all therapeutic modalities and currently a gold-standard long-term treatment option has yet to be established. I recommend TCA or ablative lasers as a first choice given the current level of evidence.
Upgrade to become a Full Member to read all of this article.