Xanthelasma

Key Points at a Glance

Key Points at a Glance

• Xanthelasma palpebrarum is a type of xanthoma formed by clusters of lipid-containing foam cells in the dermis.
• It commonly appears as a well-defined, yellowish, flat elevation at the inner canthus of the upper eyelid, often bilaterally symmetrical.
• About 50% of cases are associated with dyslipidemia (especially high LDL cholesterol), but it can also occur with normal lipid levels.
• It has been reported as an independent risk marker for cardiovascular disease; blood tests (lipid profile) are recommended upon detection.
• Treatment primarily includes surgical excision, laser ablation, or trichloroacetic acid application based on cosmetic preference. Recurrence rate is high, ranging from 26% to 60%.
• When associated with hyperlipidemia, statins may reduce the lesion, and management of the underlying condition is important for preventing recurrence.
• If associated with pseudoxanthoma elasticum (PXE), attention should be paid to progression to angioid streaks and neovascular maculopathy.

1. What is Xanthelasma Palpebrarum?

Xanthelasma palpebrarum is a type of xanthoma that commonly occurs after middle age. It is formed by clusters of lipid-containing histiocytes (foam cells) in the dermis, producing a well-defined, yellowish, flat elevation at the inner canthus of the upper eyelid. It often appears bilaterally symmetrical.

Epidemiology

• The prevalence in the general adult population is reported to be approximately 0.56% to 1.5%¹⁾
• Slightly more common in women (male-to-female ratio ≈ 1:1.3)¹⁾
• Commonly occurs after middle age
• Among benign eyelid tumors, the frequency by pathological diagnosis is about 5% (3/64 eyes)
• Often associated with hyperlipidemia (especially high LDL cholesterol)
• About 50% of cases have dyslipidemia²⁾
• There is also “normolipidemic xanthoma” that occurs even with normal lipid levels²⁾
• Familial hypercholesterolemia has a high rate of xanthelasma palpebrarum³⁾

Q Does having xanthelasma mean high cholesterol?

A

About 50% of cases have dyslipidemia, but the remaining 50% have normal blood lipids. Even with normal lipids, it can occur due to local lipid metabolism abnormalities, so “xanthoma = always hyperlipidemia” is not true. However, to assess cardiovascular risk, blood tests (total cholesterol, LDL, HDL, triglycerides) are recommended upon detection.

2. Main symptoms and clinical findings

Clinical image of xanthelasma palpebrarum: yellow flat elevation on the inner canthus of the upper and lower eyelids

Klaus D. Peter, Wikimedia Commons, 2005. Figure 1. Source ID: commons.wikimedia.org/wiki/File:Xanthelasma.jpg. License: CC BY 3.0.

Bilateral symmetrical yellow flat elevations with clear borders at the inner canthus of the upper and lower eyelids (xanthelasma palpebrarum). Corresponds to the yellow flat elevation at the inner canthus of the upper eyelid discussed in section “2. Main symptoms and clinical findings”.

Subjective symptoms

• The main complaint is cosmetic issues due to yellow flat elevations
• Painless and usually does not affect visual function
• Gradually enlarges, but rapid enlargement is rare

Clinical findings

• Commonly occurs as a well-demarcated yellow flat elevation at the inner canthus of the upper eyelid
• The surface is smooth, soft, and elastic.
• Often appears bilaterally symmetrically.
• May also appear on the lower eyelids¹⁾.
• Lesion size varies from a few mm to several cm.

Ocular symptoms associated with pseudoxanthoma elasticum (PXE)

Pseudoxanthoma elasticum is a genetic disorder in which degeneration and fragmentation of elastic fibers occur in the skin, with both autosomal dominant and recessive inheritance patterns. The following ocular symptoms may appear.

• Xanthelasma develops on both eyelids.
• Rupture of Bruch’s membrane leads to angioid streaks around the optic disc.
• The coexistence of PXE and angioid streaks is called Grönblad-Strandberg syndrome.
• A peau d’orange appearance of the fundus is observed as an abnormal coloration.
• If the lesion extends to the macula, it may lead to neovascular maculopathy.

Q Can eyelid xanthelasma cause vision loss?

A

Ordinary eyelid xanthelasma is only a cosmetic issue and does not affect visual function. However, this is different when associated with pseudoxanthoma elasticum (PXE). In PXE, Bruch’s membrane of the retina ruptures, leading to choroidal neovascularization from angioid streaks, which can progress to neovascular maculopathy and cause vision loss. If you have small yellow papules on the neck or armpits, suspect PXE and undergo a thorough ophthalmic examination.

3. Causes and Risk Factors

Multiple factors are involved in the development of eyelid xanthelasma.

• High LDL cholesterol: The greatest risk factor. Oxidized LDL is taken up by dermal macrophages, forming foam cells²⁾
• Familial hypercholesterolemia: Mutations in LDLR, APOB, or PCSK9 genes are associated with a high rate of xanthelasma³⁾
• Normolipidemic xanthelasma: Can occur even with normal blood lipid levels due to local increased lipoprotein lipase activity²⁾
• Diabetes mellitus: Increases risk through abnormal lipid metabolism¹⁾
• Hypothyroidism: Can be a risk factor via elevated LDL¹⁾
• Cardiovascular risk: Xanthelasma is considered an independent risk marker for atherosclerotic diseases (ischemic heart disease, cerebral infarction)⁴⁾
• Pseudoxanthoma elasticum (PXE): A genetic disorder caused by ABCC6 gene mutations, leading to systemic calcification and fragmentation of elastic fibers

When to see a doctor

If you notice a yellow, flat bump on the inner corner of your eyelid, please see an ophthalmologist or dermatologist. Early consultation is especially recommended in the following cases: if you have small yellow bumps on your neck or armpits (possible PXE), if you have a family history of high cholesterol or early cardiovascular disease, or if you experience decreased vision or visual field abnormalities.

4. Diagnosis and examination methods

Key points for diagnosis

Clinically, typical cases can be diagnosed by visual inspection alone. The following findings should be confirmed.

• Bilateral, yellow, flat bumps on the nasal side of the upper eyelids (inner canthus) in middle-aged or older individuals
• Well-defined borders, smooth surface, painless
• Bilateral symmetry

For atypical cases or when diagnosis is uncertain, definitive diagnosis is made by excisional biopsy. Histopathology shows clusters of foam cells (lipid-laden macrophages) in the dermis.

Systemic evaluation

The following are performed as screening for hyperlipidemia:

• Serum total cholesterol
• LDL cholesterol (Friedewald method or direct method)
• HDL cholesterol
• Triglycerides (fasting blood sample)

If PXE is suspected, the following are added:

• Skin biopsy (confirms calcification and fragmentation of elastic fibers)
• ABCC6 genetic testing⁵⁾
• Fundus examination (presence of angioid streaks and peau d’orange)
• Fluorescein angiography (evaluation of choroidal neovascularization)

Differential diagnosis

Differential disease	Key differentiating points
Chalazion	Inflammatory, ill-defined, tender
Sebaceous adenoma	White to yellow gyrate elevation at eyelid margin
Pseudoxanthoma elasticum (PXE)	Yellow papules on skin (neck, axillae), with angioid streaks
Lipoma	Soft subcutaneous mass, faint yellow hue
Orbital fat hernia	Soft, fluctuant, size changes with intraocular pressure

5. Standard Treatment

Xanthelasma palpebrarum is benign; observation is acceptable if there are no cosmetic concerns. If treatment is desired, choose from the following methods.

Treatment of underlying disease

If hyperlipidemia is present, lipid management with statins (e.g., atorvastatin 10–20 mg/day) may reduce xanthelasma. Addressing the root cause is also important for preventing recurrence.

Comparison of treatment methods

Treatment	Indications	Recurrence rate	Notes
Surgical excision	Large size, cosmetic priority	26–40%	Definitive but causes scarring
Trichloroacetic acid (TCA) topical application	Minimally invasive desired	30–60%	Chemical cauterization at 50–100% concentration 7)
CO2 laser vaporization	Cosmetic priority, small size	10–30%	Minimal scarring, precise vaporization possible 7)
Er:YAG laser vaporization	Precise vaporization	10–30%	Suitable for superficial and small lesions8)
Radiofrequency (RF) treatment	Small lesions	Not established	Minimally invasive6)

Details of each treatment

Surgical excision: Basic procedure when cosmetic improvement is desired. A fusiform excision with safety margins is performed; if the defect is large, a flap or skin graft may be required. Postoperative recurrence rates are reported to be 26–40%⁶⁾.

Trichloroacetic acid (TCA) topical application: A minimally invasive treatment in which 50–100% TCA is applied directly to the lesion to chemically coagulate and necrotize it. No anesthesia is required, and it can be performed as an outpatient procedure. Multiple sessions are often needed, and recurrence rates are high at 30–60%. There is a risk of hyperpigmentation and scarring⁷⁾.

CO2 laser vaporization: A method that vaporizes the lesion with a laser. It has the advantage of minimal scarring after wound healing. Recurrence rates tend to be lower compared to TCA⁷⁾.

Er:YAG laser: Enables precise vaporization and is suitable for superficial and small lesions. Reports indicate that recurrence rates and complications are comparable to surgical excision⁸⁾.

Q Does xanthelasma palpebrarum recur after treatment?

A

Recurrence rates vary by treatment method but are generally high at 26–60%, and recurrence is especially likely if hyperlipidemia is untreated. Even after surgical excision, recurrence can occur, so concurrent lipid management with statins etc. is important for prevention. If recurrence is repeated, more invasive treatment (larger excision, skin graft) may be necessary.

6. Pathophysiology and Detailed Pathogenesis

Mechanism of Foam Cell Formation

The essence of xanthelasma palpebrarum is the dermal accumulation of lipid-laden macrophages (foam cells).

LDL and oxidized LDL from the blood deposit in the dermis and are taken up by tissue-resident macrophages. Oxidized LDL is massively internalized by macrophages via scavenger receptors (SR-A, CD36), transforming them into lipid-rich foam cells ²⁾. Local enhancement of lipoprotein lipase activity is also thought to contribute to lipid accumulation ²⁾. The aggregated foam cells form yellowish, flat elevations in the dermis.

Histopathologically, there is a layer of coarse collagen fibers beneath the epidermis, with clusters of lipid-laden macrophages (foam cells). Multinucleated giant cells may occasionally be present.

Pathophysiology of Pseudoxanthoma Elasticum (PXE)

PXE is an autosomal genetic disorder caused by mutations in the ABCC6 gene (chromosome 16p13.1) ⁵⁾. Loss of function of the ABCC6 protein (MRP6) impairs secretion of inorganic pyrophosphate (a calcification inhibitor) into elastic fibers. This leads to progressive calcification, degeneration, and fragmentation of elastic fibers systemically, primarily affecting the skin, blood vessels, and Bruch’s membrane of the eye.

In the fundus, the following sequence occurs:

1. Elastic fibers of Bruch’s membrane (the supporting membrane of the fundus) calcify and break.
2. Radial gray-brown streaks (angioid streaks) appear around the optic disc.
3. Choroidal neovascularization (CNV) develops at the sites of Bruch’s membrane rupture.
4. When CNV involves the macula, it causes exudative changes, hemorrhage, and vision loss (neovascular maculopathy).
5. In advanced cases, vitrectomy may be indicated.

The coexistence of PXE and angioid streaks is called Grönblad-Strandberg syndrome. The abnormal fundus color is referred to as “peau d’orange” and is a characteristic fundus finding of PXE.

Association with Cardiovascular Risk

Xanthelasma palpebrarum is not merely a cosmetic issue; it has been suggested as an independent risk marker for atherosclerotic disease. In a large Danish cohort study (Copenhagen City Heart Study), individuals with xanthelasma showed significantly higher risks of ischemic heart disease, cerebral infarction, peripheral artery disease, and mortality ⁴⁾. This association remained independent even after adjusting for lipid levels.

7. Latest Research and Future Perspectives (Investigational Reports)

For Patients: Please Read Carefully

The following content is currently under investigation or in clinical trials and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Effect of PCSK9 Inhibitors on Refractory Xanthomas

PCSK9 inhibitors (evolocumab, alirocumab) are potent lipid-lowering drugs that reduce LDL cholesterol by 50–70%. In RCTs targeting familial hypercholesterolemia, evolocumab showed a reduction effect even on statin-resistant xanthomas ⁹⁾. The biological mechanism and clinical significance of xanthoma regression continue to be studied.

Anti-VEGF Therapy for Angioid Streaks

Intravitreal injections of anti-VEGF drugs (ranibizumab, aflibercept, bevacizumab) have been reported effective for choroidal neovascularization arising from angioid streaks associated with PXE. In long-term observation of bevacizumab (mean 38 months), vision maintenance or improvement was achieved in many cases ¹⁰⁾. However, evidence for anti-VEGF therapy in angioid streaks is limited compared to AMD, and standardization of indications and treatment intervals has not been established.

Improvements in Surgical Excision Techniques

Combining blepharoplasty techniques for large xanthelasma (vertical diameter >10 mm) has been reported to reduce recurrence rates while maintaining cosmetic satisfaction ¹¹⁾.

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8. References

1. Bergman R. The pathogenesis and clinical significance of xanthelasma palpebrarum. J Am Acad Dermatol. 1994;30(2 Pt 1):236-242.

2. Nair PA, Singhal R. Xanthelasma palpebrarum — a pathogenic and clinical update. Indian Dermatol Online J. 2018;9(5):295-300.

3. Civeira F. Guidelines for the diagnosis and management of heterozygous familial hypercholesterolemia. Atherosclerosis. 2004;173(1):55-68.

4. Christoffersen M, Frikke-Schmidt R, Schnohr P, et al. Xanthelasmata, arcus corneae, and ischaemic vascular disease and death in general population. BMJ. 2011;343:d5497.

5. Le Saux O, Urban Z, Tschuch C, et al. Mutations in a gene encoding an ABC transporter cause pseudoxanthoma elasticum. Nat Genet. 2000;25(2):223-227.

6. Laftah Z, Al-Niaimi F. Xanthelasma: an update on treatment modalities. J Cutan Aesthet Surg. 2018;11(1):1-6.

7. Mourad B, Elgarhy LH, Ellakkawy HA, et al. Assessment of efficacy and tolerability of different concentrations of trichloroacetic acid vs. carbon dioxide laser in treatment of xanthelasma palpebrarum. J Cosmet Dermatol. 2015;14(3):209-215.

8. Güngör S, Canat D, Gökdemir G. Erbium:YAG laser ablation versus surgery for xanthelasma palpebrarum. J Dermatolog Treat. 2014;25(2):130-132.

9. Raal FJ, Stein EA, Dufour R, et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia. Lancet. 2015;385(9965):341-350.

10. Finger RP, Charbel Issa P, Schmitz-Valckenberg S, et al. Long-term effectiveness of intravitreal bevacizumab for choroidal neovascularization secondary to angioid streaks. Retina. 2011;31(7):1380-1386.

11. Lee HY, Jin US, Minn KW, et al. Outcomes of surgical excision with blepharoplasty technique for large xanthelasma. Ann Plast Surg. 2013;71(4):380-383.