Clinical Challenge: Progressive Yellow Skin Changes

Normolipemic plane xanthoma (NPX) is characterized by xanthomatous lesions individuals with normal lipid levels. NPX may be idiopathic, or may be the first manifestation of an underlying hematologic or lymphoproliferative disorder. Generally, xanthomas are characterized by lipid-laden macrophages, and are...

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Normolipemic plane xanthoma (NPX) is characterized by xanthomatous lesions individuals with normal lipid levels. NPX may be idiopathic, or may be the first manifestation of an underlying hematologic or lymphoproliferative disorder. Generally, xanthomas are characterized by lipid-laden macrophages, and are often the cutaneous manifestation of a dyslipidemia.

Plane xanthomas are yellow-orange, flat or slightly elevated lesions with barely palpable, non-inflammatory borders. They can present as macules, papules, patches or plaques. They are categorized into those associated with hyperlipidemia or those associated with normal lipid levels (normolipemic).

In normolipidemic individuals, lesions are classically distributed periorbitally, on the lateral neck, upper trunk and in the flexural folds. They may be circumscribed or diffuse. Onset is usually in adulthood. Xanthelasma palpebrarum or xanthelasma is the most common type of plane xanthoma, occurring over the upper and lower eyelids and around the inner canthus. They are associated with hyperlipidemia in about 50% of cases, typically in younger patients.

Histologically, all xanthomas are characterized by foam cells, which are macrophages that contain lipids within their cytoplasm. Plane xanthomas often contain smaller aggregates of foam cells confined to the superficial dermis. There is minimal inflammation and surrounding fibrosis. The superficial positioning and lack of inflammation make plane xanthomas unique amongst other types of xanthomas.

Plane xanthomas in the normolipemic patient may be idiopathic or associated with an underlying hematologic or lymphoproliferative disorder. Specifically, normolipemic plane xanthomas have been observed in patients with monoclonal gammopathies (including MGUS and multiple myeloma), cryoglobulinemia, Castleman disease, non-Hodgkin’s lymphoma and chronic myelomonocytic leukemia.

It is hypothesized that monoclonal immunoglobulins bind circulating plasma LDL. This complex (Ig + LDL) then deposits in the skin, where it is easily phagocytosed by macrophages, forming the characteristic foam cells of xanthomas.

The presence of xanthomas in a patient with normal lipid levels should prompt the physician to search for paraproteins with serum protein electrophoresis and immunofixation, as the presence of xanthomas may precede the onset of clinically significant hematological disease.

All major forms of xanthomas (including eruptive, tuberous, tendinous and plane) are associated with disorders of lipid metabolism (also called hyper- or dyslipoproteinemias). The classification of disorders of lipid metabolism is largely based on Lees and Frederickson’s system first described in 1965.

There are five clinically significant causes of hyperlipidemia associated with xanthomatous lesions. Type I, also called familial hyperchylomicronemia, is characterized by slow chylomicron clearance, reduced LDL and HDL levels and hypertriglyceridemia. There is no increased risk for coronary artery disease.

Type II, called familial hypercholesterolemia is characterized by hypercholesterolemia (LDL or beta lipoproteins) and atherosclerosis of the peripheral and coronary arteries.

Type III, familial dysbetalipoproteinenemia, is characterized by elevated chylomicrons, hypercholesterolemia, hypertriglyceridemia and atherosclerosis of the peripheral and coronary arteries.

Type IV, endogeonous familial hypertriglyceridemia, displays increased VLDL (pre-beta lipoproteins) and hypertriglyceridemia. It is often associated with type 2 noninsulin-dependent diabetes, obesity and alcoholism.

Type V shows decreased LDL and HDL and increased triglycerides and is associated with diabetes mellitus. Secondary causes of hyperlipidemia include causes of cholestasis, such as biliary atresia and primary biliary cirrhosis, as well as diabetes mellitus, hypothyroidism, nephritic syndrome and type I glycogen storage disease.

In addition to planar, the various xanthomatous lesions include eruptive, tuberous and tendinous. Eruptive xanthomas are yellow, 1 mm to 5 mm papules with an erythematous halo. These lesions are often found on the extensor surfaces, buttocks and hands. They may be pruritic, appear in crops and display the Koebner phenomenon.  Lesions are often seen in cases of triglycerides in excess of 3,000-4,000 mg/dl, including types I, IV and V hyperlipidemias. They are usually quick to regress with aggressive lipid-lowering therapy.

Tuberous xanthomas are often seen in cases of hypercholesterolemia, namely types II and III hyperlipidemia. They present with pink-yellow papules and nodules, which may be larger than 3 cm. They are often found on the elbows and knees and may be very slow to regress.

Tendinous xanthomas are firm nodules that develop over tendons, commonly the Achilles tendon and the extensor tendons of the hands, elbows and knees. They are associated with hypercholesteremia – types II and III hyperlipidemia and hypothyroidism.

Plane xanthomas, when associated with hyperlipidemia, may appear in cases of cholestasis, such as biliary atresia and primary biliary cirrhosis. Additionally, intertrigous plane xanthomas of the antecubital fossae and webs of the fingers are virtually diagnostic of type II hyperlipdemia. Similarly, plane xanthomas of the palmar crease are virtually diagnostic of type III hyperlipidemia.

The treatment of xanthomas associated with hyperlipidemia is primarily aimed at lowering lipid levels. In the case of normolipemic xanthomas, treatment is often via surgical excision or ablation with laser surgery, trichloroacetic acid (TCA) and cryosurgery.

Christopher B. Rizk, BA, and Andrew S. Fischer, BA, are medical students at Baylor College of Medicine. 

Adam Rees, MD, is a graduate of the University of California Los Angeles School of Medicine and a resident in the Department of Dermatology at Baylor College of Medicine also in Houston.

References

1. Bolognia J, Jorizzo JL and Rapini RP. “Chapter 92: Xanthomas.” Dermatology. St. Louis, Mo.: Mosby/Elsevier, 2012. pp 1547-1555. 
2. Habif TP. “Chapter 26: Cutaneous Manifestations of Internal Disease.” Clinical Dermatology: A Color Guide to Diagnosis and Therapy. Philadelphia: Mosby/Elsevier, 2010. pp 980-982. 
3. Wolff K, Johnson RA, Suurmond D and Fitzpatrick TB. “Section 15: Endocrine, Metabolic and Nutritional Diseases.” Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology. New York: McGraw-Hill, 2013. pp 90-395.
4. Less RS, Frederickson DS. “The differentiation of exogenous and endogenous hyperlipemia by paper electrophoresis.” J Clin Invest. 1965;44: 1968-77.