Xanthomas

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Xanthomas

Lucile E. White, Marcelo G. Horenstein and Christopher R. Shea

Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports

(Courtesy of Arlene Ruiz de Luzuriaga, MD, MPH)

Xanthomas are flat, yellow plaques or nodules consisting of abnormal lipid deposits. Clinically, xanthomas can be classified as eruptive, tuberoeruptive, tuberous, tendinous, verruciform, or plane. Plane xanthomas are the most common and include xanthelasma palpebrarum, xanthoma striatum palmare, and intertriginous xanthomas. Verruciform xanthomas typically affect genital skin, and may be a consequence of lymphedema. Necrobiotic xanthogranulomas are scarring, commonly ulcerated nodules with a predilection for the periorbital areas, and associated with paraproteinemia.

Management strategy

Xanthomas may be idiopathic or a sign of underlying hyperlipidemia. Diagnosing and treating the underlying disease is necessary not only to decrease the size of the xanthomas, but also to reduce the risk of atherosclerosis associated with lipoprotein disorders. Treatment of the hyperlipidemia initially consists of diet and lipid-lowering agents such as statins, fibrates, bile acid-binding resins, probucol, or nicotinic acid. The lipid-lowering effects of these agents have been well documented, but few studies document the efficacy of these drugs at resolving xanthomas, limiting an evidence-based evaluation of what would appear to be a rational management approach. Anecdotally, eruptive xanthomas typically appear to resolve within weeks of initiating systemic treatment, and tuberous xanthomas after some months, but tendinous xanthomas may take years to resolve or even persist indefinitely. Surgery or locally destructive modalities can be used for idiopathic or unresponsive xanthomas.

Specific investigations

Serum lipid panel of cholesterol, triglycerides, VLDL, LDL, and HDL

Gas–liquid and high-performance liquid chromatography to diagnose sitosterolemia

Capillary gas chromatography of urine to diagnose cerebrotendinous xanthomatosis

Serum protein electrophoresis, immunoelectrophoresis, or immunofixation to detect M proteins

Excluding an underlying condition is essential in the management of most clinical forms of xanthomas. Eruptive xanthomas typically occur in the setting of hypertriglyceridemia. Hypertriglyceridemia can be the result of lipoprotein lipase deficiency, familial hyperlipoproteinemia, or secondary causes such as diabetes mellitus, alcohol ingestion, or exogenous estrogens. Tuberoeruptive and tuberous xanthomas represent parts of a spectrum and are seen most commonly in the setting of familial dysbetalipoproteinemia. Tuberous xanthomas may also be a presentation of homozygous familial hypercholesterolemia, cerebrotendinous xanthomatosis (associated with neuropsychiatric symptoms), or sitosterolemia. Patients with sitosterolemia and cerebrotendinous xanthomatosis may have normal serum lipid panels; therefore diagnosis may require liquid chromatography for plant sterols or urinary gas chromatography. Tendinous xanthomas may also occur with cerebrotendinous xanthomatosis, sitosterolemia or, more commonly, heterozygous familial hypercholesterolemia. Certain xanthomas are diagnostic for an inherited hyperlipidemia: xanthoma striatum palmare for familial dysbetalipoproteinemia, and intertriginous xanthomas for homozygous familial hypercholesterolemia. Even in the presence of these classic presentations, a serum lipid panel is still indicated to confirm the diagnosis.

Regarding xanthelasma palpebrarum, a type of plane xanthoma, levels of total cholesterol are elevated in only about half of patients; however, patients with xanthelasma may have elevated apolipoprotein B and decreased apolipoprotein A1 levels, as well as subclinical increases in carotid intima-media thickness. Moreover, xanthelasma is a risk factor for myocardial infarction, ischemic heart disease, severe atherosclerosis, and death in the general population, independently of plasma cholesterol and triglyceride concentrations. Less commonly, plane xanthomas can signal a monoclonal gammopathy. In this situation, the differential diagnosis of necrobiotic xanthogranuloma with paraproteinemia, a condition usually associated with lymphoproliferative disorders, should be considered.

Extreme xanthomatosis in patients with both familial hypercholesterolemia and cerebrotendinous xanthomatosis.

Huijgen R, Stork AD, Defesche JC, Peter J, Alonso R, Cuevas A, et al. Clin Genet 2012; 81: 24–8.

Xanthelasma palpebrarum: a marker of premature atherosclerosis (risk of atherosclerosis in xanthelasma).

Pandhi D, Gupta P, Singal A, Tondon A, Sharma S, Madhu SV. Postgrad Med J 2012; 88: 198–204.

Xanthelasmata, arcus corneae, and ischaemic vascular disease and death in general population: prospective cohort study.

Christoffersen M, Frikke-Schmidt R, Schnohr P, Jensen GB, Nordestgaard BG, Tybjærg-Hansen A. Br Med J 2011; 15: 343:d5497.

Sitosterolaemia and xanthomatosis in a child.

Cheng WF, Yuen YP, Chow CB, et al. Hong Kong Med J 2003; 9: 206–9.

Pathogenesis and treatment of xanthomatosis associated with monoclonal gammopathy.

Szalat R, Arnulf B, Karlin L, Rybojad M, Asli B, Malphettes M, et al. Blood 2011; 118: 3777–384.

Verruciform xanthoma: localized lymphedema (elephantiasis) is an essential pathogenic factor.

Lu S, Rohwedder A, Murphy M, Carlson JA. J Cutan Pathol 2012; 39: 391–4.

First-line therapies

Low-fat diet and systemic lipid-lowering therapy: statins, bile acid-binding resins, fibrates, and/or nicotinic acid

Opposite effects on serum cholesteryl ester transfer protein levels between long-term treatments with pravastatin and probucol in patients with primary hypercholesterolemia.

Inazu A, Koizumi J, Kajinami K, Kiyohar T, Chichibu K, Mabuchi H. Atherosclerosis 1999; 145: 405–13.

This prospective study examined whether pravastatin or probucol was better at regressing tendon xanthomas and xanthelasma in patients with primary hypercholesterolemia. In both the pravastatin and probucol groups, xanthelasma regressed in two of four patients. Achilles tendon xanthoma regressed in four of five patients treated with pravastatin and two of five patients on probucol.

A comparative study of the therapeutic effect of probucol and pravastatin on xanthelasma.

Fujita M, Shirai K. J Dermatol 1996; 23: 598–602.

Fifty-four patients were treated with probucol or pravastatin. Xanthelasmas regressed in 13 of 36 patients treated with probucol and one of 18 patients treated with pravastatin. Total cholesterol levels decreased in both treatment groups, while HDL cholesterol decreased only in those treated with probucol.

Effects of probucol on xanthomata regression in familial hypercholesterolemia.

Yamamoto A, Matsuzawa Y, Yokoyama S, Funahashi T, Yamamura T, Kishino B. Am J Cardiol 1986; 57: H29–35.

This study examined 51 patients with familial hypercholesterolemia, including eight homozygotes. Patients were treated with combinations of probucol, cholestyramine, clofibrate, and compactin. The sizes of Achilles tendon xanthomas were decreased in all patients who received probucol. Probucol possibly reduces the size of HDL particles, increasing reverse cholesterol transport.

Second-line therapies

Surgery	B
CO₂ laser	B
Erbium : YAG laser	C
Pulsed dye laser	B
Argon laser	B
Q-switched Nd : YAG laser	D
KTP laser	D
1450-nm-diode laser	C
Low-voltage radiofrequency	C

Treatment of xanthelasma by excision with secondary intention healing.

Eedy DJ. Clin Exp Dermatol 1996; 21: 273–5.

Xanthelasmas were removed in 28 patients by scissor excision. After 18 months, two patients, one with hypercholesterolemia and one with primary biliary cirrhosis, had recurrence. One patient developed scarring. No ectropion developed.

Xanthelasma palpebrarum.

Parkes ML, Waller TS. Laryngoscope 1984; 94: 1238–40.

This review of several different methods of excision suggests that routine blepharoplasty with staged excisions achieves the best results.

Upper and lower eyelid reconstruction for severe disfiguring necrobiotic xanthogranuloma.

Schaudig U, Al-Samir K. Orbit 2004; 23: 65–76.

Severe cicatricial eyelid deformation caused by necrobiotic xanthogranuloma can be treated successfully by excision and free skin grafting.

New operative technique for treatment of xanthelasma palpebrarum: laser-inverted resurfacing. Preliminary report.

Levy JL, Trelles MA. Ann Plast Surg 2003; 50: 339–43.

The authors propose use of pulsed Er : YAG vaporization of the lipomatous tissue off the inner surface of the eyelid after incision and eversion of the incised tissue to expose the xanthelasma. In two patients treated by this technique no recurrence was seen in up to 1 year of follow-up.

Treatment of xanthelasma palpebrarum by 1064-nm Q-switched Nd : YAG laser: a study of 11 cases.

Fusade T. Br J Dermatol 2008; 158: 84–7.

The results after even a single treatment were reported to be good or excellent in eight of 11 patients (in 26 of 38 lesions), and healing was rapid.

Is Q-switched neodymium-doped yttrium aluminium garnet laser an effective approach to treat xanthelasma palpebrarum? Results from a clinical study of 76 cases.

Karsai S, Schmitt L, Raulin C. Dermatol Surg 2009; 35: 1962–9.

In contrast to the reference cited above, in this study of 37 patients (76 lesions) treated with 6 J/cm² at 1064 nm or 2 J/cm² at 532 nm, with 4 mm spot size and two to three passes, only two-thirds of the patients completed the treatment course; disappointing early results were the main reason for dropping out. Most lesions ultimately failed to respond.

Treatment of xanthelasma palpebrarum with argon laser photocoagulation.

Basar E, Oguz H, Oxdemir H, Ozkan S, Uslu H. Int Ophthalmol 2004; 25: 9–11.

Twenty-four patients with 40 xanthelasmas were treated with an argon laser at settings of 500 µm, 0.1–0.2 s, and 900 mW. Complete removal of all lesions occurred with one to four sessions at intervals of 2 or 3 weeks. Six lesions recurred over 8 to 12 months and required re-treatment. Erythema persisted for 1 month in eight lesions. Hyperpigmentation occurred in one patient and persisted for 3 months, while hypopigmentation occurred in two lesions. No bleeding, infections, or ectropion occurred.

Histopathological study of xanthelasma palpebrarum after pulsed dye laser.

Soliman M. J Eur Acad Dermatol Venereol 2004; 18(suppl): 19–33.

Twenty-six patients were treated with fluences ranging from 6.5–8 J/cm², a spot size of 5 mm, and a pulse width of 450 ms. All patients experienced very good to excellent clinical improvement with one to three treatments at 3- or 4-week intervals.

KTP laser coagulation for xanthelasma palpebrarum.

Berger C, Kopera D. J Dtsch Dermatol Ges 2005; 3: 775–9.

The authors employed the potassium titanyl phosphate (KTP) laser (532 nm) to treat 14 patients with xanthelasma palpebrarum on 33 eyelids. Over 70% of patients tolerated laser irradiation without analgesia; 85.7% showed reduction of lesions after one to three treatment sessions, without reported side effects.

Xanthelasma palpebrarum treatment with a 1,450-nm-diode laser.

Park EJ, Youn SH, Cho EB, Lee GS, Hann SK, Kim KH, et al. Dermatol Surg 2011; 37: 791–6.

Sixteen patients received one to four treatments using a 1450 nm-diode laser at 12 J/cm², 6 mm spot size, and 20–30 ms. Twelve patients (75%) experienced moderate to marked improvement. The treatment was well tolerated, with focal mild transient hyperpigmentation noted in five patients.

Effectiveness of low-voltage radiofrequency in the treatment of xanthelasma palpebrarum: a pilot study of 15 cases.

Dincer D, Koc E, Erbil AH, Kose O. Dermatol Surg 2010; 36: 1973–8.

Fifteen patients were treated by superficial application of electrodes from a dual-frequency 4.0 MHz radiofrequency machine. All subjects completed the study; excellent results were achieved in nine patients and good results in five patients.

Third-line therapies

Di- or trichloracetic acid	C
Cryotherapy	E
Bleomycin	B
Intralesional triamcinolone acetonide	D
Chlorambucil	E
Prednisolone	E
Intravenous immunoglobulin	E

Treatment of xanthelasma palpebrarum with bichloracetic acid.

Haygood LJ, Bennett JD, Brodell RT. Dermatol Surg 1998; 24: 1027–31.

Ten of 13 patients (with 25 lesions) had complete clearing with bichloracetic acid application. Five lesions recurred and required a second treatment to achieve complete resolution. No complications were reported.

Evaluation of three different strengths of trichloroacetic acid in xanthelasma palpebrarum.

Haque MU, Ramesh V. J Dermatolog Treat 2006; 17: 48–50.

Three strengths of TCA were tested on 51 patients. For papulonodular lesions, on average approximately two applications were required with 100% or 70% TCA, versus approximately four applications with 50% TCA. For flat plaques an average of approximately 1.50 applications of 100% or 70% TCA sufficed, versus approximately three applications with 50% TCA. Macular lesions responded to a single application of all strengths of TCA studied.

Koebner phenomenon in xanthelasma after treatment with trichloroacetic acid.

Akhyani M, Daneshpazhooh M, Jafari AK, Naraghi ZS, Farahani F, Toosi S. Dermatol Online J 2006; 12: 12.

Despite initial improvement, a 47-year-old female patient noticed extension of biopsy-proven xanthelasma lesions at the site of TCA treatment. Physicians should be aware of the possibility of an isomorphic (Koebner) response when treating xanthelasma palpebrarum with TCA.

Cryotherapy may be effective for eyelid xanthoma.

Hawk JL. Clin Exp Dermatol 2000; 25: 351.

One patient was treated with liquid nitrogen applied for 0.5–1 s. Treatment was carefully limited to only the yellow areas. Previous treatment with TCA had been unsuccessful.

Therapeutic effect and pathology changing of eyelid xanthelasma by bleomycin A5.

Meng RH, Meng Y, Yang L, Sun L, Sun WR, Liu HM. Zhonghua Yan Ke Za Zhi 2005; 41: 231–3.

Twenty-five randomly selected outpatients received intralesional injections of 0.2 mL of 0.4% bleomycin solution every 10 days. In another five cases, one eye received bleomycin injection once and the contralateral eye was left untreated as a negative control. The 25 bleomycin-treated xanthelasmas were reported to disappear completely, without adverse sequelae.

Local corticosteroid treatment of eyelid and orbital xanthogranuloma.

Elner VM, Mintz R, Demirci H, Hassan AS. Trans Am Ophthalmol Soc 2005; 103: 69–73.

Six patients received two intralesional injections of triamcinolone acetonide (40 mg/mL) for eyelid and orbital necrobiotic xanthogranuloma (four patients) or adult-onset xanthogranuloma (two patients). Local control was obtained in all six cases, with a reduction of symptoms and signs of the disease in five cases; no complications were noted.

Necrobiotic xanthogranuloma treated with chlorambucil.

Torabian SZ, Fazel N, Knuttle R. Dermatol Online J 2006; 12: 11.

A 56-year-old man with a 5-year history of multiple necrobiotic xanthogranulomas involving the periorbital area, extremities, and trunk was treated with chlorambucil at 2 mg/day, later increased to 4 mg/day, which resulted in complete resolution of the lesions.

Necrobiotic xanthogranuloma of extremities in an elderly patient successfully treated with low-dose prednisolone.

Kawakami Y, Yamamoto T. Dermatol Online J 2011; 17: 13.

A 93-year-old woman with an IgG λ paraproteinemia and ulcerated, tender necrobiotic xanthogranulomas involving the left lower leg experienced resolution 4 weeks after starting treatment with oral prednisolone, 20 mg daily (0.5 mg/kg).

Successful treatment of necrobiotic xanthogranuloma with intravenous immunoglobulin.

Hallermann C, Tittelbach J, Norgauer J, Ziemer M. Arch Dermatol 2010; 146: 957–60.

Two patients with necrobiotic xanthogranuloma and monoclonal gammopathy responded well to intravenous immunoglobulin, 0.5 g/kg/day, administered for 4 consecutive days at 4-week intervals.

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