Indian J Otolaryngol Head Neck Surg

(October 2019) 71(Suppl 1):S439–S446; https://doi.org/10.1007/s12070-018-1345-0

ORIGINAL ARTICLE

Xanthelasma Palpebrarum: More than Meets the Eye

Shailesh Khode1 • Soon Heng Terry Tan1 • En-Pei Amanda Tan1 •

Sandeep Uppal1

Received: 19 September 2017 / Accepted: 5 April 2018 / Published online: 7 April 2018
Ó Association of Otolaryngologists of India 2018

Abstract Xanthelasma palpebrarum (XP) is the most Introduction

common form of cutaneous xanthomata, and is important
aesthetically, because of its close relation to the eyes, as Xanthelasma palpebrarum (XP) is the most common form
well as medically for its association with cardiovascular of cutaneous xanthomata [1, 2], so called because of its
disease (CVD). To provide avant-garde review discussing location close to the eye. It is derived from the Greek
the various aspects of XP, including its aetio-pathogenesis words, xanthos which means yellow and elasma which is a
and various treatment modalities. A structured Pubmed and beaten metal plate. It is more commonly seen in middle-
Medline were searched for relevant articles. The finding of aged to elderly adults, with an incidence of 0.3% in males
recent research has strongly espoused the link between XP and 1.1% in females [3]. It is not a disease of modern
and CVD, and mechanisms have been suggested for its times; the painting of Mona Lisa by Leonardo da Vinci
formation. The new technologies have led to a multitude of (1503–1506) represents possibly the first recorded evidence
treatment options for XP. XP is a multi-faceted entity; of XP, as suggested by Dequeker et al. [4].
other than simple treatment of the cosmetic aspect of the Patients often present to their doctor because of cos-
disease, one must be cognizant of its cardiovascular metic concerns and request treatment of these aesthetically
implications. undesirable lesions in a prominent part of their face.
Lesions are typically raised, soft, yellowish, irregularly
Keywords Xanthelasma palpebrarum
Lipid
shaped plaques that are slow growing, and are usually
Cardiovascular disease
Tri-chloroacetic acid
Laser
found over the medial aspect of the eye [1, 2]. They can
Blepharoplasty also be found over the upper and lower eyelids, and cir-
cumferential lesions have been described [5]. The doctor
not only needs to address the aesthetic concerns of the
patient, but also needs to be cognizant of the aetiopatho-
genesis of this condition and its association with
atherosclerotic cardiovascular disease (CVD).
& Shailesh Khode
shaileshkhode@gmail.com Histopathology
Soon Heng Terry Tan
tan.terry.sh@ktph.com.sg Xanthelasma comprises mainly of perivascular and peri-
En-Pei Amanda Tan adnexal foamy histiocytes and occasional Touton giant
tan.amanda.ep@ktph.com.sg cells in the upper and middle dermis [6], giving a macro-
Sandeep Uppal scopic appearance of an unsightly soft, yellowish plaque.
uppal.sandeep@ktph.com.sg The intracellular vacuoles contain esterified cholesterol,
1 and there may be surrounding inflammation and fibrosis.
Department of Otolaryngology – Head and Neck Surgery,
Khoo Teck Puat Hospital, 90 Yishun Central, Yishun 768828, Lymphocytes and mast cells [7] are common components
Singapore of the inflammatory matrix. There appear to be similarities

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in the ultra-structural makeup of xanthomata and evolving More recently carotid intima media thickness measure-
atheromas, for instance between the intimal smooth muscle ments (CIMT) are accepted as a surrogate marker for
cells of arteries and the perithelial cells of dermal capil- generalised atherosclerosis and risk of CVD [20]. Noel [21]
laries, hence suggesting that analogous mechanisms may was one of the first to evaluate CIMT in patients with XP,
be involved [8, 9]. There is variation in terms of the and found an increase in mean CIMT values in patients
extensiveness of involvement, with the upper eyelid and with XP compared to controls. Pandhi et al. [22] found the
medial canthus frequently affected. The fact that the peri- same results in his study involving BMI matched controls,
ocular region is preferentially affected implies that local and went on to conclude that XP may be a risk factor for
factors, such as constant movement and friction, may play atherosclerosis regardless of the patient’s lipid levels.
a role in its pathogenesis, though its mechanism is not well There was, however, no correlation with the duration or
elucidated. extent of the lesion. Another index of arterial stiffness is
cardio-ankle vascular index (CAVI) which is significant
Aetiopathogenesis and Prevalence marker for sub-clinical atherosclerosis. Akyuz A R et al.
investigated the association between CAVI and XP, and
While XP is usually diagnosed by clinical appearance concluded that XP was an independent predictor for
alone, it may be an important marker of underlying disease. abnormal CAVI [23].
It is present in a fair proportion of patients with familial
hyperlipoproteinemia, most frequently the type-IIa Other Associations of Xantholesma
Fredrickson phenotype [10–12]. It is classically associated
with an increased risk of atherosclerotic CVD. Hence it is Besides lipid abnormalities, XP has also been associated
generally recommended that patients with XP should at with allergic contact dermatitis, periorbital hyperpigmen-
least have a basic lipid screen, including low and high- tation, smoking and obesity [24, 25]. XP can also develop
density lipoprotein (LDL and HDL) levels. Reported following surgical procedures such as injection fillers [26],
prevalence of atherosclerotic CVD amongst XP patients and septorhinoplasty [27] (See Table 1). An inflammatory
have been varied, with numbers ranging from 15 to 70% mechanism with resultant vascular permeability and
[11, 13–16]. Conversely other studies have found little or oedema has been proposed [28]. Local trauma has been
no increase in the risk of atherosclerosis [12]. This wide shown to increase capillary leakage of LDLs, and xan-
range may be attributed to limitations and differences in thomas are a result of subsequent inflammatory reactions.
methodology over the years [1, 17]. For instance, hyaluronic acid from injections in the extra-
cellular matrix can bind extravasated LDL, and this LDL-
Association Between Xanthelasmata, glycosaminoglycan complex is taken up more easily by
Hyperlipidemia and Cardiovascular Disease macrophages than native LDL [29]. Furthermore, gly-
cosaminoglycans promote the oxidation of LDLs, which in
Although many patients with XP have raised total choles- turn leads to foam cell formation. Nilotinib, a tyrosine
terol levels, up to half of these may have normal lipid kinase inhibitor used in the treatment of chronic myloid
levels. While it is generally accepted that xanthelasmata in leukemia is also believed to cause both lipid panel abnor-
hyperlipidemic patients are associated with higher LDL malities and cutaneous lesions [30].
and lower HDL levels, both of which are established
atherogenic risk factors, the reasons behind the evolution of Treatment Options
xanthelasma in normolipidemic patients remain more
obscure. Possible implicating factors other than hyper- Until about 30 years ago, XPs were only effectively
lipoproteinemia include increased vascular lipid perme- removed by surgery with cold steel instruments [31].
ability, lipid synthesis and macrophagic uptake [18]. Other Although, meticulous percutaneous resection of the lesions
apolipoproteins have been shown to be associated with XP followed by direct suture has remained one of the more
formation, though not conclusively. For instance, popular techniques, the high risk of recurrence and other
apolipoprotein B (Apo-B), a marker of atherosclerotic complications like ectropion are among the reasons which
CVD, was reported to be elevated in normolipidemic XP have drawn surgeons to seek alternative methods of
patients by Douste-Blazy et al. [19], but not so by Gomez removal. The relative paucity of skin at the lower lid means
et al. [12] Likewise, Douste-Blazy et al. [19] too found that repeated resections of recurrences may not be possible
increased prevalence of apolipoprotein E2 and E3 pheno- if cosmesis is to be preserved [32], hence the search for
types in normolipidemic XP patients, but the results were skin sparing techniques. With the advent of medical tech-
not replicated by Gomez et al. [12]. nology and research, a plethora of options has surfaced
(See Table 2).

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Table 1 Clinico-pathological conditions associated with xanthe- with different concentrations trialed. Cannon et al. [37]
lasma palpebrarum [10–12, 24–30] investigated the efficacy of 95% TCA in a retrospective
Clinico-pathological conditions review of 102 patients, of which 44 and 51 patients were
Familial hyperlipoproteinemia examined clinically and interviewed respectively. They
Macrophage abnormalities found a limited success rate of 61% at a mean follow up of
Allergic contact dermatitis 31.8 months. Hague and Ramesh [38] used varying con-
Periorbital hyperpigmentation centrations (50, 70 and 100%) of TCA on 51 patients, and
Smoking commented that higher concentrations worked better with
Obesity papulo-nodular lesions and flat plaques, while 50% TCA
Injection of intradermal hyaluronic acid fillers was sufficient for macular lesions. However the duration of
Post septorhinoplasty
follow-up was not cited. In a study of 24 patients treated
A new side effect of Nilotinib
with 70% TCA, Nahas et al. [39] found that an average of
1.5 applications was required to treat till resolution and
25% of lesions had recurrence 6 months after treatment.
Nonetheless, patient satisfaction was high, making this an
Surgical Excision attractive, simple and low-cost viable alternative for the
treatment of XPs.
Hoon Young Lee et al. graded XP into four types, on basis
of location and extent of lesion. Grade I lesions involve Low Voltage Radiofrequency
only the upper eyelids; grade II extends to the medial
canthal area; grade III involves medial side of both upper Radiofrequency works by causing vaporization at a cellular
and lower eyelids, and grade IV ones have diffuse level in tissues. It initiates fibrosis followed by volume
involvement of the medial and lateral side of both upper reduction during healing. This novel technique has been
and lower eyelids. Hoon treated grade I and II lesions by attempted by Dincer et al., on 15 patients. A dual-fre-
simple excision while grade III and IV ones were managed quency radiofrequency machine was used at low power
by excision in combination with skin grafting, local flaps, settings. Electrodes were applied superficially onto the
blepharoplasty and medial epicanthoplasty [33]. Similarly, lesions under local anaesthesia, following which creams
Kose R treated large XP defects with full thickness skin were applied to reduce the risk of infection and hasten re-
grafts harvested from the lateral aspect of the upper eyelid. epithelialization. Pateints were followed up for 5 months,
Good patient satisfaction was achieved by performing and success was graded according to a subjective 5 point
blepharoplasty of the upper eyelid simultaneously with the scale (0 = no result, 0–25% Mild, 26–50% = moderate,
excision of XPs [34]. Authors suggested that for lesions 51–75% = good, and 76–100% = excellent). Preliminary
involving the deep dermis and/or muscle, cold steel dis- results were promising, with 14 patients having at least a
section may be the most suitable treatment option (Fig. 1). ‘good’ (second best) result. Of the 15 patients who were
treated this way, 5 required a second session to achieve a
Di- and Tri-Chloroacetic Acids (DCA and TCA) satisfactory result. Main complications were pain, and
hyper- or hypopigmentation. This technique is potentially a
These chemicals have been described in the treatment of quick, inexpensive and relatively safe therapeutic modality.
XP. They are chlorinated acetic acids, and are used in The authors recommended that it may be useful in cases
different concentrations as tissue cauterants [35]. They where there are multiple lesions; lesions have indistinct
work by dissolving lipids and coagulating proteins. A thin borders or are situated close to the eyes [40].
layer is applied over the lesion with a wooden applicator
stick, with care taken to avoid the surrounding healthy skin. Cryotherapy
Blanching will subsequently be observed, and antibiotic
creams are then applied. Side effects associated with this Cryotherapy works by one or more of the following ways:
form of treatment include hypo- and hyperpigmentation, ice crystal formation, thermal shock, enzyme inhibition,
scarring and accidental application to the conjunctiva or cellular dehydration and electrolyte disruption [41–43].
cornea. Haygood et al. [36] treated 25 patients with 100% Dewan et al. [44] looked at 100 patients with a total of 237
Bichloracetic acid (BCA), with 85% of them achieving lesions, and performed closed probe cryosurgery with
initial complete clearance. The other 28% of the lesions nitrous oxide as the cryogen, without local anaesthesia.
required repeated application after an average period of Freezing time was 15 s, and the number of freeze–thaw
64 months, but these recurrences generally responded well cycles ranged from 1 to 21 depending on the size and
to retreatment. TCA has increased in popularity recently, number of lesions. Follow up was set at 6 months, which

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Table 2 Different modalities of treatment for XPs

Modality of treatment Principle No. of session Advantage Side effects

Surgical excision [33, 34] Meticulous percutaneous One or Simple Recurrence,

resection of the lesions revision Best for lesion involving deep Ectropion
followed by direct suture surgery dermis and muscle Scar contracture
with or without flap
Combined with blepharoplasty Revision surgery
TCA peeling (concentration Dissolving lipids and 1–12 Simple Hypo- and Hyper-pigmentation
35–100%) [35–39] coagulating proteins Low-cost Scarring
Out-patient clinic procedure Accidental application to the
conjunctiva or cornea—
atrophy,
Koebner-like phenomenon
Low/Mid Voltage Thermal energy induces Single Quick, Hypo- and Hyper-pigmentation
Radiofrequency [40] vaporization at the cellular Inexpensive Pain
level in tissues
Relatively safe
Cryo-surgery (nitrous oxide) Ice crystal formation, Cellular 1–21 Cycle Easy for application Recurrence,
[44, 45] dehydration and electrolyte Low risk of adverse effects Hypopigmentation
disruption, Thermal shock,
Healing is slow
Enzyme inhibition or Effect
on proteins Extensive lesions are difficult
to treat
CO2 laser (ultra pulse) Absorbed by the extracellular 1–5 Sessions Less downtime, Hyperpigmentation, scaring,
(10,600 nm) [47–50] fluid of tissue cells, leading High patient satisfaction recurrence
to non-specific vaporisation
Erbium:YAG laser Absorption by water- Single Suitable for early lesion Mild erythema.
(2940 nm) [51–55] containing tissues Hypo- and Hyper-pigmentation
Nd:YAG laser (1064 nm) Q-switched—cellular Single Large lesions Erythema
[56–59] fragmentation via shock
waves
KPT laser (532 nm) [60, 61] Continuous wave Single Safe Hypopigmentation,
Recurrences
Diode laser (1450 nm) Preferentially targets water Single Satisfactory result Transient focal
[66, 67] hyperpigmentation
Pulsed dye laser (585 nm) Vascular specific, targeting 5 Sessions High patient satisfaction Blisters, crusting and ectropion
[31, 62] small vessels
Intra-lesional A broad-spectrum antitumor 1 Session Cheap, effective, and safe No complications
Pingyangmycin [73] antibiotic

showed that 68% of the cases had complete resolution of multitude of surgical techniques, give rise to an interesting
the lesions and 6% had incomplete resolution, with a tiny range of treatment options [46].
central area of hypopigmentation. The other 26% had
either persistence or recurrence of the lesion. Labanderia Ablative Lasers
et al. treated four cases of XPs with gentle liquid nitrogen
spray cryotherapy. This treatment modality was advocated Carbon dioxide (CO2) lasers are one of most widely uti-
because of its easy applicability and minimal adverse lised lasers in the medical arena. Its 10,600 nm wavelength
effects [45]. means that it is selectively absorbed by the extracellular
fluid of tissue cells, leading to non-specific vaporisation,
Laser Therapy regardless of pigmentation. It is an ablative laser, hence the
need for some form of anaesthesia during the procedure. It
Laser vaporisation is the latest technique in the treatment results in an open wound, therefore the need for wound
of XP. Within this category, the different lasers with their care and dressing post-operatively. Its ablative effect,
varying wavelengths and properties, coupled with a especially in the continuous mode, may result in collateral
tissue damage leading to unpredictable scarring and

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less invasive compared to the conventional CO2 laser,

making it possible to ablate thin layers of skin to a depth of
a few nanometers, hence allowing for precise manipulation
with less damage to surrounding healthy tissues. Post-
treatment complications are also minimised because of the
non-invasive nature of this laser, with erythema disap-
pearing after 2 weeks for most patients. Borelli and
Kaudewitz [51] treated 33 lesions in 15 patients and noted
no recurrence in a follow-up period of 7–12 months. They
concluded that this laser was a minimally invasive method
suitable for treating early lesions before they become aes-
thetically problematic. In addition, he commented on the
merits of the CO2 laser, for instance, better hemostasis and
allowed for removal of deeper lesions which were also
documented by Mannino et al. [52], Kaufman and Hibst
[53], and Drnovsek-Olup and Vedlin [54] in 70 XPs, 9XPs
and 32 XPs respectively. Levy and Trelles [55] described
an inverted resurfacing technique with the erbium:YAG
laser, whereby the eyelid skin is everted, exposing the
lesional tissue and orbicularis oculi. The lesion is then
precisely vaporised with the laser until normal tissue
architecture is seen, following which the skin flaps are
replaced and closed.
Fig. 1 a, b (Pre-operative) and c, d (post operative) clinical
photographs of a patient presenting with xanthelasma palpebrarum Non-ablative Lasers
involving the left upper lid

asymmetrical skin retractions. With current technology, it Non-ablative lasers are gaining favour in recent years due
has become possible to deliver high energy beams in to their non-invasive properties, safety profile, and possi-
extremely short impulses, beyond the skin thermal relax- bility of using them in office based procedures. The
ation time. This ultrapulsed CO2 laser allows for more 1064 nm Q-switched Nd:YAG laser has been in use since
precise ablation of skin layers and less injury to the sur- the 1990s for the treatment of tattoo and pigmented lesions.
rounding tissues. Raulin et al. [47] treated 23 patients (52 The mechanism of action is cellular fragmentation via
lesions) with the ultrapulsed CO2 laser with good effect, shock waves generated from sudden energy transfer, con-
removing all lesions with a single treatment. Pigmentary finement and release in a photoacoustic phenomenon [56].
changes were transient, seen in 17% of cases, without Fusade [57] treated 38 lesions in 11 patients with this laser,
visible scarring. Three patients developed a recurrence, and obtained good to excellent results (defined as 50% or
which the authors postulated may be due to an inadequate more clearing) in 26 lesions. On the contrary, Karsai et al.
depth of treatment. Pathania et al. and Saif MYS et al. [58] could not replicate Fusade’s results, getting instead a
[48, 49] achieved similarly good results. A randomized high dropout rate (due largely to apparent inefficacy) and
control trial was conducted by Esmat et al. to compare the low success rate (70–75% of treated lesions showed no
efficacy and safety of super pulsed (SP) and fractional CO2 clearance). However, later, Leonardo Marini treated 20
laser in 20 adult patients with bilaterally symmetrical XPs. periocular XPs in twelve patients, all achieving at least
Randomly assigned XP lesions were treated with one ses- good outcomes, defined as more than 50% clearance [59].
sion of super pulsed CO2 laser or 3–5 sessions of fractional Another non-ablative laser is the KTP (Potassium Tita-
CO2 laser. After removal, XP lesion on both sides showed nyl Phosphate) laser. It has a wavelength of 532 nm and
remarkable improvement in size, colour and thickness of was first time introduced by Berger C and Kopera D in the
lesions. The lesions treated with SP CO2 laser showed treatment of XP. They treated 33 lesions in 14 patients.
significant improvement in colour and thickness of lesions. After one to three sessions 86% patients showed convinc-
Nevertheless, better patient satisfaction and shorter time- ing reduction of XPs without side effects. Moreover, 70%
out was observed with fractional CO2 laser [50]. of patients tolerated procedure without any anaesthesia
The erbium:YAG laser is another form of ablative laser [60]. Recently a retrospective study was conducted by
that has been tried. It has a wavelength of 2940 nm, with Greijimans et al. to evaluate the safety and efficacy of
preferential absorption by water-containing tissues. It is continuous wave KTP laser treatment for XPs. Overall,

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97% (29/30) patient had excellent aesthetic results. How- Discussion

ever, recurrences were frequent (43%; 13/30) which war-
ranted regular maintenance therapy [61]. Few studies have been published in literature comparing
The pulsed dye laser (PDL) was first described by different modalities of treatment for XPs. Mourad B and
Schönermark and Raulin [62], and had been used to some colleagues assessed the clinical efficacy and tolerability of
success by Karsai et al. [31]. In his prospective clinical trial different concentration of topical TCA (35, 50, and 70%)
of 38 cases (in 20 patients), a 585 nm wavelength laser was against CO2 laser in 30 XPs. Both 70% TCA peeling and
utilised. The laser is vascular specific, targeting small CO2 laser ablation demonstrated more significant clinical
vessels to which the offending histiocytes are adherent to, efficacy and patient satisfaction with minimum number of
thereby simultaneously causing the destruction of these treatment sessions than 35 and 50% TCA peeling [70].
cells. The 20 patients underwent five sessions with the Similarly, a prospective study comparing ultra-pulsed CO2
laser, after which pre- and post-operative photographs were laser and 30% TCU was conducted by Goel K et al. It
compared and assessed by independent examiners. Two- suggested that both TCA and lasers are good for clinically
thirds of lesions showed clearance of more than 50%, while small lesions but the laser works more effectively in severe
one-quarter had clearance of more than 75%. Patient sat- lesions [71]. Another comparative study was conducted by
isfaction was high, and there were no major side effects Mona Abdelkader et al., this time comparing argon laser
like blisters, crusting and ectropion. Karsai et al. [31] against the erbium: YAG laser. Thus concluded that former
suggested that a combination of ablative and non-ablative was good for small lesions while the later was better for
laser therapy holds promise in the removal of tuberous larger nodular lesion [72]. On the other hand, Gungor S and
lesions. co-workers documented no significant difference in the
Other kinds of lasers that have been utilised in recent post treatment improvement scores as well as complication
years include the 1450 nm diode laser. It preferentially scores for both Erbium:YAG laser ablation and 70% TCA
targets water, causing photothermal destruction of seba- application [73].
ceous lobules and hair follicles, up to 500 lm in depth Overall, some authors have suggested that surgical
[63]. It has been used for the number of years, safely and excision of deep dermal and/or muscle XPs may be the
efficaciously, for a number of skin lesions including acne most suitable modality of treatment in experienced hands.
[63, 64], sebaceous hyperplasia [65] and scarring [66]. Its Higher concentrated TCA in papulo-nodular XP lesions
exact mechanism in the treatment of xanthelasma is not and 50% TCA in macular lesions showed promising
well elucidated, but it is believed that the foamy histiocytes results. XPs near the lid margin or close to the canthus can
are targeted by the 1450 nm wavelength energy emission. be managed safely with low voltage radiofrequency. Lat-
Park et al. [67] used it to good effect in 16 patients, with terly, non-ablative lasers are well accepted more by
75% achieving moderate to marked clearance (defined as patients as well as physicians because of their minimal side
more than 40%) after one to four sessions. Transient focal effects, desirable outcomes and may be performed as out-
hyperpigmentation was the most common post-operative patient clinic procedures.
side effect, occurring in five patients.

Other Treatment Modalities Conclusion

Non-surgical treatment of XP has limited applicability. A There is a myriad of options available for the treatment of
decade ago, Shields et al. published an observational case XP, but thus far, a preferred modality has not emerged, as
report on the disappearance of XP following oral simvas- no one method has been shown to be irrefutably superior to
tatin. They postulated that oral statins combined with a fat the rest. Furthermore, only a limited number of comparison
restricted diet might result in resolution of XP, and studies have been done, and they are relatively small with
reduction in cardiac risk, especially in young patients [68]. short follow-up durations [38, 68–71]. More research and
A novel technique was introduced by Wang et al., making development, as well as well-designed large prospective
use of Pingyangmycin which is a broad spectrum antitumor trials, will be needed to further our knowledge in this area
antibiotic. Twenty-one lesions in 12 patients were treated of medicine. However, other than just treating the aesthetic
by intralesional infiltration of this antibiotic. All patient aspect of this condition, one must be aware of its cardio-
except one achieved satisfactory result after 2 sessions vascular implications, thus allowing for holistic manage-
without any complications like infection, atrophy, ulcera- ment of the patient.
tion or scarring [69].

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Conflict of interest The authors declare that they have no conflict of risk patient for primary prevention: non-invasive tests of
interest. atherosclerotic burden—Writing Group III. Circulation
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