Xanthomas 

Updated: Dec 15, 2017
Author: Kara Melissa T Torres, MD, DPDS; Chief Editor: Dirk M Elston, MD 

Overview

Background

Xanthomas are lesions characterized by accumulations of lipid-laden macrophages. Xanthomas can develop in the setting of altered systemic lipid metabolism or as a result of local cell dysfunction.

Pathophysiology

Lipids are insoluble in water; therefore, they are transported as complexes of lipoproteins and specific apoproteins. These proteins also serve as ligands to specific receptors, they facilitate transmembrane transport, and they regulate enzymatic activity. Lipoproteins may be classified according to their density, as follows: chylomicrons, very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL).

The metabolic pathways of lipoproteins can be divided into exogenous and endogenous pathways. The exogenous lipoprotein pathway refers to the metabolism of intestinal lipoproteins, the triglyceride-rich chylomicrons, primarily formed in response to dietary fat. The endogenous lipoprotein pathway refers to lipoproteins and apoproteins that are synthesized in tissues other than the intestines, predominantly in the liver. The liver secretes the triglyceride-rich VLDL that contains apoproteins B-100, C-II, and E into the circulation.

In the peripheral tissues, particularly adipose and muscle tissue, VLDL is cleaved by lipoprotein lipase (LPL), extracting most of the triglycerides and forming an IDL that contains apoproteins B-100 and E. IDL can be taken up by the liver through the LDL receptor, or it can be converted to the cholesterol-rich LDL that contains apoprotein B-100. LDL is removed from the circulation primarily by the liver through the LDL receptor. HDL particles that contain apoproteins A-I and A-II interact with other lipoproteins, particularly VLDL and LDL, through lipolysis and the action of lecithin cholesterol acyltransferase (LCAT) enzyme. The main role of HDL is to accept cholesterol and to transport it back to the liver (reverse cholesterol transport).

Lipoprotein (a) (Lp[a]) consists of an LDL-like particle with apoprotein B and a side chain of a highly glycosylated protein. Lp(a) has a role not only in atherogenesis but also in thrombogenesis because of its homology with plasminogen.

Alterations in lipoproteins result either from genetic mutations that yield defective apolipoproteins (primary hyperlipoproteinemia) or from some other underlying systemic disorder, such as diabetes mellitus, hypothyroidism, or nephrotic syndrome (secondary hyperlipoproteinemia). The biochemical and genetic basis for the inherited disorders of lipid and lipoprotein metabolism differ considerably.

Traditionally, hyperlipidemias have been classified according to 6 phenotypes described by Fredrickson. These phenotypes are based on the electrophoretic patterns of lipoprotein level elevations that occur in patients with hyperlipoproteinemia. In recent years, the understanding of the genetic and biochemical basis of these disorders has revealed a large and diverse group of diseases, many of which have similar clinical expressions, exposing the limitations of the Fredrickson classification system. Despite the system's shortcomings, Fredrickson phenotypes are a useful tool for the discussion of these disorders. The understanding of the pathophysiology of these defects provides a basis for diagnosis and treatment.

Familial lipoprotein lipase deficiency is an example of a primary disorder in which a deficiency of lipoprotein lipase in tissue leads to a type I pattern of hyperlipidemia, with a massive accumulation of chylomicrons in the plasma. This effect results in a severe elevation of plasma triglyceride levels. Plasma cholesterol levels are not usually elevated. Patients with type I may present in early childhood, often with acute pancreatitis. Eruptive xanthomas are the most characteristic skin manifestation of this disorder.

Cholesterol is bound to apolipoprotein B-100 as LDL in interstitial fluid. Cells may acquire cholesterol via an LDL receptor on the cell membrane. Familial LDL receptor deficiency and familial defective apoprotein B-100 are examples of primary defects that can lead to the accumulation of LDL, which corresponds to a type IIa pattern of hyperlipidemia. Plasma cholesterol levels are severely elevated, but plasma triglyceride levels are typically normal. Patients with type IIa have severe atherosclerosis.

The type IIb pattern is characterized by the accumulation of both LDL and VLDL, with variable elevations of both triglyceride levels and cholesterol levels in the plasma. Patients with familial combined hyperlipoproteinemia have such a pattern of hyperlipidemia, but a specific genetic defect has not been established.

Patients with type IIa and IIb may present as adults with tendinous and tuberous xanthomas and xanthelasmas.

Type III hyperlipidemia is characterized by the accumulation of IDL (beta-VLDL), which is manifested by increases in both triglyceride levels and cholesterol levels in the plasma. A genetic basis for the primary disorder, familial dysbetalipoproteinemia, has been well established. Various mutations of apoprotein E impair its ability to bind to the IDL receptor. Patients with type III present as adults with premature atherosclerosis and, particularly, plane (palmar) xanthomas.[1]

Familial hypertriglyceridemia is an example of a primary defect resulting in type IV hyperlipidemia. Accumulation of VLDL causes severe elevations of plasma triglyceride levels. Plasma cholesterol levels are typically normal. A definitive molecular defect has not been established. Patients with type IV may present with eruptive xanthomas.

Genetic defects of the apolipoprotein C-II gene result in the accumulation of chylomicrons and VLDL, which is the type V pattern of hyperlipidemia. Patients with this type have severe elevations of triglyceride levels in the plasma. These patients, like those with lipoprotein lipase deficiency, may present in early childhood with acute pancreatitis and eruptive xanthomas.[2]

Decreased synthesis of HDL due to decreased formation of apoprotein A-I and apoprotein C-III leads to decreased reversed cholesterol transport, resulting in increased LDL levels, premature coronary artery disease, and plane xanthomas.

Hyperlipidemia is also related to a variety of secondary causes. Secondary hypercholesterolemia can be found in pregnancy, hypothyroidism, cholestasis, and acute intermittent porphyria. Secondary hypertriglyceridemia can be associated with oral contraceptive use, diabetes mellitus, alcoholism, pancreatitis, gout, sepsis due to gram-negative bacterial organisms, and type I glycogen storage disease. Combined hypercholesterolemia and hypertriglyceridemia can be found in nephrotic syndrome, chronic renal failure, and steroid immunosuppressive therapy.[3, 4]

Normolipemic xanthoma may occur as xanthoma disseminatum, diffuse plane normolipemic xanthomatosis, and verruciform xanthoma.

Xanthoma disseminatum is a non–Langerhans cell of class II histiocytic disorder.[5] The etiology is unknown. Familial inheritance is uncertain.[6]

Diffuse plane xanthomatosis is a rare, noninherited disorder related to diseases of the reticuloendothelial system.[7] The pathogenesis remains unclear.

Verruciform xanthoma is considered a reaction pattern to chronic inflammation or trauma or a result of impaired lymphatic function.[8, 9, 10]

Epidemiology

Frequency

Xanthomas are a common manifestation of lipid metabolism disorders. Xanthelasmas comprise 6% of eyelid tumors.[11] Diffuse normolipemic forms occur less frequently.

Sex

Equal prevalence of xanthoma is reported in males and females. Xanthoma disseminatum occurs in a male-to-female ratio of 2.4:1.[12]

Age

Xanthomas may occur in persons of any age. Xanthelasmas usually occur in people older than 50 years. Xanthoma disseminatum occurs before age 25 years in two thirds of cases.[12]

Prognosis

Cutaneous xanthomas are mostly cosmetic disorders; their presence might suggest an underlying disorder of lipid metabolism.

Recurrences postsurgical treatment of xanthomas are common.

Significant mortality and morbidity arise in patients with involvement of functional anatomic sites in xanthoma disseminatum.[13] Otherwise, the course of the disease is benign and resolves spontaneously.[14]

Morbidity and mortality are related to atherosclerosis (eg, coronary artery disease) and pancreatitis.

Patient Education

For patient education resources, visit the Cholesterol Center. Also, see the patient education articles High Cholesterol, Cholesterol FAQs, and Atorvastatin (Lipitor).

 

Presentation

History

A family history of xanthomas, history of myocardial infarction, aortic regurgitation, atherosclerosis, and even pancreatitis may be encountered in patients with cutaneous xanthomas.[15, 16, 17, 18] Normolipemic forms of tuberous xanthomas and drug-induced tuberous and tendinous xanthomas are uncommon but may occur.[19, 20, 21] Large solitary planar xanthomas may rarely be associated with chronic myelomonocytic leukemia, non–Langerhans cell disease, mastocytoma, and ultraviolet irradiation exposure.[22, 23, 24, 25] Rarely, xanthomas may be associated with the POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein skin changes) syndrome, systemic sarcoidosis, and nonsyndromic paucity of interlobular bile ducts.[26, 27, 28] Cutaneous manifestations may also precede a diagnosis of hyperlipidemia, which may be primary or secondary. If diagnosed in children with pruritus as a symptom, clinicians should investigate the possibility of cholestasis of the liver.[29]

Patients with xanthoma disseminatum may present with symptoms of dysphagia, dyspnea, and obstructive blindness, depending on the involved site.[30, 31, 32] There may be rare gastrointestinal, central nervous system, musculoskeletal, and intracranial involvement.[33, 34, 35, 36] Exceptional cases are those forms that are multisystemic yet asymptomatic and those associated with the Koebner phenomenon.[37, 38] The disease may be persistent and progressive, or it may be self-limited with spontaneous resolution.[39, 14] Diffuse plane xanthomatosis is most commonly associated with lymphoproliferative disorders, monoclonal gammopathies, and hematological malignancies.[40, 41] Xanthoma disseminatum without any underlying abnormality is rare but may occur.[42] It may be infrequently linked with mycosis fungoides, Budd-Chiari syndrome, Hand-Schüller-Christian disease, or rheumatoid arthritis.[43, 44, 45, 46]

Verruciform xanthoma may be associated with lichen planus, Paget disease, epidermal nevus, discoid lupus erythematosus (DLE), pemphigus vulgaris, recessive dystrophic epidermolysis bullosa (RDEB), chronic graft versus host disease (GVHD), actinic keratosis, squamous cell carcinoma, CHILD (congenital hemidysplasia with ichthyosiform nevus and limb defects (CHILD) syndrome, post psoralen with ultraviolet A (PUVA) phototherapy, post radiation therapy, and post hematopoietic stem cell transplantation (HSCT).[9, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57] Rarely, they may occur without an underlying disease or syndrome.[58]

Physical Examination

Cutaneous xanthomas associated with hyperlipidemia can be clinically subdivided into xanthelasma palpebrarum, tuberous xanthoma, tendinous xanthoma, eruptive xanthoma, planar xanthoma, and generalized plane xanthoma. A combination of the different types may occur.[59] A rare “cauliflower xanthoma” type may also be seen.[60] Cutaneous xanthomas may also raise the suggestion of the presence of cerebrotendinous xanthomatosis.[61]

Xanthelasma palpebrarum is the most common type of xanthoma. The lesions are asymptomatic and symmetric soft, velvety, yellow, flat, polygonal papules. They occur most commonly in the upper eyelids near the inner canthus. Giant xanthelasma palpebrarum may demonstrate extensive involvement of all four eyelids.[62] See the image below.

Xanthelasma. Courtesy of Duke University Medical C Xanthelasma. Courtesy of Duke University Medical Center.

Tuberous xanthomas are firm, painless, red-yellow nodules. The lesions can coalesce to form multilobated tumors and can be extensive.[63] Tuberous xanthomas usually develop in pressure areas, such as the extensor surfaces of the knees, the elbows, and the buttocks. They may rarely occur on the cheeks and nasal bridge.[64] See the image below.

Tuberous xanthomas. Courtesy of Duke University Me Tuberous xanthomas. Courtesy of Duke University Medical Center.

Tendinous xanthomas appear as slowly enlarging subcutaneous nodules related to the tendons or the ligaments. Atypical gout-tophi–like lesions over the great toe may occur.[65] The most common locations are the extensor tendons of the hands, the feet, and the Achilles tendons. The lesions are often related to trauma.

Eruptive xanthomas most commonly arise over the buttocks, the shoulders, and the extensor surfaces of the extremities. Rarely, the oral mucosa or the face may be affected. The lesions typically erupt as crops of small, red-yellow papules on an erythematous base. Pruritus is common, and the lesions may be tender. See the image below.

Eruptive xanthomas. Courtesy of Duke University Me Eruptive xanthomas. Courtesy of Duke University Medical Center.

Plane xanthomas are mostly macules; rarely, they form elevated lesions. They can occur in any site. Involvement of the palmar creases is characteristic of type III dysbetalipoproteinemia. Generalized plane xanthomas can cover large areas of the face. The neck, thorax, and flexures can also be involved.

Xanthoma disseminatum and verruciform xanthoma are particular forms of xanthomas that occur in normolipemic patients.[66, 67]

Xanthoma disseminatum presents in adults most commonly as red-yellow papules and nodules with a predilection for the flexures. They may unusually have extensive eyelid involvement.[32] It may rarely present as large plaques with indurated borders and as plaques with surrounding papules.[68] The mucosa is involved 40-60% of the time.[30]

Patients with diffuse plane xanthomatosis have yellow, symmetric, plaque-lesions over periorbital areas, neck, upper trunk, buttocks, and flexures. Unusual forms may present with oral lesions.[45, 69]

Verruciform xanthoma predominantly occurs in the oral cavity of adults as a solitary and asymptomatic papillomatous yellow lesion. They may also occur in the forearm, digits of hand and foot, anogenital area, and esophagus.[58, 70, 71, 72, 73, 74]

 

DDx

Differential Diagnoses

 

Workup

Laboratory Studies

Primary hyperlipidemia is primarily a diagnosis of exclusion. Appropriate blood, urine, and radiographic workups are required to rule out a secondary cause of hyperlipidemia. Lipoprotein profiles are primarily used to assess cardiac risk and to aid in the diagnosis of lipid metabolism disorders.

Plasma levels of triglyceride, cholesterol, and HDL-cholesterol are measured following a 12-hour fast before venipuncture. Cholesterol and triglyceride levels are usually measured by enzymatic methods. HDL-cholesterol levels can be measured after the apoprotein B–containing lipoproteins (chylomicrons, VLDL, IDL, LDL, Lp[a]) are removed by polyanion-divalent cation precipitation. LDL and VLDL can then be calculated as follows:

  • LDL = Total Cholesterol Level – (Triglyceride Levels/5 + HDL Level)

  • VLDL = Triglyceride Levels/5*

*If triglycerides are greater than 700, the denominator is 10.

Chylomicrons, because of their high lipid-protein ratio, are less dense and form a creamy layer when plasma is left standing for several hours. Ultracentrifugation fractions can be electrophoretically examined for the presence of beta-VLDL and Lp(a). Quantification of apolipoproteins, particularly B and A-I, can be achieved by immunologic methods.

Lipoprotein patterns can be determined as follows:

  • I - Elevated triglyceride levels with increased chylomicron levels

  • IIa - Elevated cholesterol level because of increased LDL level

  • IIb - Elevated cholesterol and triglyceride levels because of increased LDL and VLDL levels

  • III - Elevated cholesterol and triglyceride levels, with the presence of beta-VLDL

  • IV - Elevated triglyceride levels because of increased VLDL level

  • V - Elevated triglyceride levels because of increased VLDL level and the presence of chylomicrons

The risk for cardiovascular disease can be determined on the basis of the total cholesterol, LDL-cholesterol, and HDL-cholesterol values in adults and children.

Imaging Studies

Ultrasonography and magnetic resonance imaging (MRI) may enhance the diagnosis of Achilles tendon xanthomas.[75, 76]

Positron-emission tomography/computed tomography may be used to detect disease extent and assess treatment response in cases of xanthoma disseminatum.[77]

Histologic Findings

Changes in the skin and the tendons are characterized by the presence of vacuolated macrophages (foamy macrophages). These macrophages are filled with lipid droplets, which are dissolved and removed from the tissue during histologic processing. Lipid stains are of no use in routinely processed tissue. In contrast, frozen sections can be stained with lipid stains. Foamy histiocytes usually have 1 nucleus, but multinucleated histiocytes (Touton giant cells) are often identified.

See the image below.

Microscopic image of a xanthelasma. The lesion is Microscopic image of a xanthelasma. The lesion is composed of lipid-laden macrophages located in the superficial dermis. Courtesy of Duke University Medical Center.

Eruptive xanthomas may contain infiltrates of lymphocytes and typically contain extracellular lipid. Rarely, eruptive neutrophilic xanthomas with prominent leukocytoclasis may occur.[78] Xanthelasma shows superficially located foamy cells and the characteristic appearance of eyelid skin. Tendinous and tuberous xanthomas may contain prominent fibrosis and occasional cholesterol clefts. Verruciform xanthoma is histologically characterized by hyperkeratosis or parakeratosis with acanthosis, lipid-laden histiocytes within the dermal papillae, and often with a polymorphonuclear infiltrate. Red wedge-shaped areas of epidermal necrosis are characteristically present.[79] Epidermolytic acanthoma is rare but may occur.[80]

 

Treatment

Medical Care

Xanthomas not always associated with underlying hyperlipidemia, but when they are, diagnosing and treating underlying lipid disorders is necessary to decrease the size of the xanthomas and to prevent the risks of atherosclerosis. In patients with severe hypertriglyceridemia, a major goal is to prevent pancreatitis.

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 mention the efficacy of these drugs for resolving xanthomas. Eruptive xanthomas usually resolve within weeks of initiating systemic treatment, and tuberous xanthomas usually resolve after months. Tendinous xanthomas take years to resolve or may persist indefinitely.

Pravastatin, probucol, and a regimen of low-fat, low-cholesterol diet and colestipol may help in reducing the size of lesions in tendinous xanthomas and xanthelasmas with hypercholesterolemia.[81, 82, 83, 84, 85] Xanthelasma palpebrarum may respond to systemic interleukin 1 blockade and plane xanthomas to cyclosporine A therapy.[86, 87]

Familial hypercholesterolemia may be treated with combinations of probucol, cholestyramine, clofibrate, and compactin.[83] New hypolipidemic agents for familial hypercholesterolemia include PCSK-9 inhibitors, lomitapide, and mipomersen.[88]

There are no treatment guidelines for xanthoma disseminatum and verruciform xanthomas, but surgical treatment may be appropriate for lesions that are disfiguring or impair function. Xanthoma disseminatum has been described to respond to 2-chlorodeoxyadenosine, simvastatin, or to combination of lipid-lowering agents.[89, 90, 91] Partial resolution in verruciform xanthomas has been described with use of chloroxylenol surgical scrub.[92]

Oral probucol is an alternative treatment to surgical excision for diffuse plane xanthomatosis.[93]

Surgical Care

The definitive management for all types of xanthomas is surgical.

Xanthelasmas may be treated with topical trichloroacetic acid 50-100%, topical bichloracetic acid, excision, skin flap with blepharoplasty, 1450-nm diode laser, ultrapulsed carbon dioxide laser, argon laser, 1064-nm Q-switched Nd:YAG laser, low-voltage radiofrequency, and fractional carbon dioxide laser.[94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105] However, lesions may recur. Factors that predict recurrence are systemic hyperlipidemia, involvement of all four eyelids, and previous history of recurrent xanthelasma.[106] Er:YAG laser treatment may be recurrence-free for up to 12 months.[107] Transient erythema, infections, scarring, and postinflammatory hyperpigmentation may occur with all surgical treatment alternatives.

Nonablative 1,450-nm diode laser treatment may achieve satisfactory results for patients with xanthoma disseminatum.[108] Wide excision with skin grafting and carbon dioxide laser ablation may be performed for verruciform xanthomas.[47, 72] Lesions may still recur.

Complications

Complications from surgical management may occur.