Xanthomas

Back

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.

Cerebrotendinous xanthomatosis is a rare serious autosomal recessive disorder of bile acid synthesis associated with neurocutaneous manifestations. Patients may present with bilateral cataracts and chronic diarrhea during childhood. Later manifestations include cognitive decline and motor disorders. Plasma cholestanol is a helpful diagnostic marker. The prognosis may be improved through therapy with cholic or chenodeoxycholic acid.[15, 16]

Patient Education

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

History

A family history of xanthomas, history of myocardial infarction, aortic regurgitation, atherosclerosis, and even pancreatitis may be encountered in patients with cutaneous xanthomas.[17, 18, 19, 20] Normolipemic forms of tuberous xanthomas and drug-induced tuberous and tendinous xanthomas are uncommon but may occur.[21, 22, 23] Large solitary planar xanthomas may rarely be associated with chronic myelomonocytic leukemia, non–Langerhans cell disease, mastocytoma, and ultraviolet irradiation exposure.[24, 25, 26, 27] 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.[28, 29, 30] 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.[31]

Patients with xanthoma disseminatum may present with symptoms of dysphagia, dyspnea, and obstructive blindness, depending on the involved site.[32, 33, 34] There may be rare gastrointestinal, central nervous system, musculoskeletal, and intracranial involvement.[35, 36, 37, 38] Exceptional cases are those forms that are multisystemic yet asymptomatic and those associated with the Koebner phenomenon.[39, 40] The disease may be persistent and progressive, or it may be self-limited with spontaneous resolution.[41, 14] Diffuse plane xanthomatosis is most commonly associated with lymphoproliferative disorders, monoclonal gammopathies, and hematological malignancies.[42, 43] Xanthoma disseminatum without any underlying abnormality is rare but may occur.[44] It may be infrequently linked with mycosis fungoides, Budd-Chiari syndrome, Hand-Schüller-Christian disease, or rheumatoid arthritis.[45, 46, 47, 48]

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, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59] Rarely, they may occur without an underlying disease or syndrome.[60]

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.[61] A rare “cauliflower xanthoma” type may also be seen.[62] Cutaneous xanthomas may also raise the suggestion of the presence of cerebrotendinous xanthomatosis.[63]

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.[64] See the image below.



View Image

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.[65] 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.[66] See the image below.



View Image

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.[67] 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.



View Image

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.[68, 69]

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.[34] It may rarely present as large plaques with indurated borders and as plaques with surrounding papules.[70] The mucosa is involved 40-60% of the time.[32]

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.[47, 71]

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.[60, 72, 73, 74, 75, 76]

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:

*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:

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.[77, 78]

Positron-emission tomography/computed tomography may be used to detect disease extent and assess treatment response in cases of xanthoma disseminatum.[79]

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.



View Image

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

Eruptive xanthomas may contain infiltrates of lymphocytes and typically contain extracellular lipid. Rarely, eruptive neutrophilic xanthomas with prominent leukocytoclasis may occur.[80] 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.[81] Epidermolytic acanthoma is rare but may occur.[82]

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.[83, 84, 85, 86, 87] Xanthelasma palpebrarum may respond to systemic interleukin 1 blockade and plane xanthomas to cyclosporine A therapy.[88, 89]

Familial hypercholesterolemia may be treated with combinations of probucol, cholestyramine, clofibrate, and compactin.[85] New hypolipidemic agents for familial hypercholesterolemia include PCSK-9 inhibitors, lomitapide, and mipomersen.[90]

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.[91, 92, 93] Partial resolution in verruciform xanthomas has been described with use of chloroxylenol surgical scrub.[94]

Oral probucol is an alternative treatment to surgical excision for diffuse plane xanthomatosis.[95]

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.[96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107] However, lesions may recur. Factors that predict recurrence are systemic hyperlipidemia, involvement of all four eyelids, and previous history of recurrent xanthelasma.[108] Er:YAG laser treatment may be recurrence-free for up to 12 months.[109] 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.[110] Wide excision with skin grafting and carbon dioxide laser ablation may be performed for verruciform xanthomas.[49, 74] Lesions may still recur.

Complications

Complications from surgical management may occur.

What are xanthomas?What is the pathophysiology of xanthomas?What is the prevalence of xanthomas?What are the sexual predilections of xanthomas?Which age groups have the highest prevalence of xanthomas?What is the prognosis of xanthomas?Which clinical history findings are characteristic of xanthomas?Which physical findings are characteristic of xanthomas?What are the differential diagnoses for Xanthomas?What is the role of lab tests in the evaluation of xanthomas?What is the role of imaging studies in the evaluation of xanthomas?Which histologic findings are characteristic of xanthomas?How are xanthomas treated?What is the role of surgery in the treatment of xanthomas?

Author

Kara Melissa T Torres, MD, DPDS, Visiting Research Fellow, Ackerman Academy of Dermatopathology

Disclosure: Nothing to disclose.

Coauthor(s)

Dirk M Elston, MD, Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Disclosure: Nothing to disclose.

Specialty Editors

Michael J Wells, MD, FAAD, Dermatologic/Mohs Surgeon, The Surgery Center at Plano Dermatology

Disclosure: Nothing to disclose.

Edward F Chan, MD, Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania School of Medicine

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Ponciano D Cruz, Jr, MD, Professor and Vice-Chair, Paul R Bergstresser Chair, Department of Dermatology, University of Texas Southwestern Medical Center

Disclosure: Received consulting fee from RCTS for independent contractor; Received honoraria from Mary Kay Cosmetics for consulting; Received grant/research funds from Galderma for principal investigator.

Acknowledgements

Kevaghn P Fair, DO Consultant Pathologist and Founder, Dominion Pathology Laboratories

Kevaghn P Fair, DO is a member of the following medical societies: American Society for Clinical Pathology, American Society of Dermatopathology, and College of American Pathologists

Disclosure: Nothing to disclose.

References

  1. Sharma D, Thirkannad S. Palmar Xanthoma-An Indicator of a More Sinister Problem. Hand (N Y). 2009 Sep 22. [View Abstract]
  2. Duzayak S, Sayiner ZA, Erkılıç S, Inaloz HS. Acute pancreatitis with eruptive xanthoma. BMJ Case Rep. 2017 Oct 9. 2017:[View Abstract]
  3. Baila-Rueda L, Mateo-Gallego R, Lamiquiz-Moneo I, Cenarro A, Civeira F. Severe hypercholesterolemia and phytosterolemia with extensive xanthomas in primary biliary cirrhosis: Role of biliary excretion on sterol homeostasis. J Clin Lipidol. 2014 Sep-Oct. 8(5):520-4. [View Abstract]
  4. Taylor B, Cheema A, Soslowsky L. Tendon Pathology in Hypercholesterolemia and Familial Hypercholesterolemia. Curr Rheumatol Rep. 2017 Nov 4. 19 (12):76. [View Abstract]
  5. Rupec RA, Schaller M. Xanthoma disseminatum. Int J Dermatol. 2002 Dec. 41(12):911-3. [View Abstract]
  6. Natanzi N, Peng D, Ahdoot E, Ghatan S, Reinstandler A, Ram R. Xanthoma disseminatum in a pair of blind, deaf male twins. ISRN Dermatol. 2011. 2011:342909. [View Abstract]
  7. Bragg J. Diffuse plane xanthomata. Dermatol Online J. 2005 Dec 30. 11(4):4. [View Abstract]
  8. Cumberland L, Dana A, Resh B, Fitzpatrick J, Goldenberg G. Verruciform xanthoma in the setting of cutaneous trauma and chronic inflammation: report of a patient and a brief review of the literature. J Cutan Pathol. 2010 Aug. 37(8):895-900. [View Abstract]
  9. Fite C, Plantier F, Dupin N, Avril MF, Moyal-Barracco M. Vulvar verruciform xanthoma: ten cases associated with lichen sclerosus, lichen planus, or other conditions. Arch Dermatol. 2011 Sep. 147(9):1087-92. [View Abstract]
  10. Lu S, Rohwedder A, Murphy M, Carlson JA. Verruciform xanthoma: localized lymphedema (elephantiasis) is an essential pathogenic factor. J Cutan Pathol. 2012 Mar. 39(3):391-4. [View Abstract]
  11. Deprez M, Uffer S. Clinicopathological features of eyelid skin tumors. A retrospective study of 5504 cases and review of literature. Am J Dermatopathol. 2009 May. 31(3):256-62. [View Abstract]
  12. Altman J, Winkelmann RK. Xanthoma disseminatum. Arch Dermatol. 1962. 86:582-96.
  13. Davies CW, Marren P, Juniper MC, Gray W, Wojnorowska F, Benson MK. Xanthoma disseminatum with respiratory tract involvement and fatal outcome. Thorax. 2000 Feb. 55(2):170-2. [View Abstract]
  14. Park HY, Cho DH, Kang HC, Yun SJ. A case of xanthoma disseminatum with spontaneous resolution over 10 years: review of the literature on long-term follow-up. Dermatology. 2011. 222(3):236-43. [View Abstract]
  15. Fiorucci S, Distrutti E. Chenodeoxycholic Acid: An Update on Its Therapeutic Applications. Handb Exp Pharmacol. 2019 Jul 3. [View Abstract]
  16. Mandia D, Chaussenot A, Besson G, Lamari F, Castelnovo G, Curot J, et al. Cholic acid as a treatment for cerebrotendinous xanthomatosis in adults. J Neurol. 2019 Aug. 266 (8):2043-2050. [View Abstract]
  17. Kim YR, Han KH. Familial hypercholesterolemia and the atherosclerotic disease. Korean Circ J. 2013 Jun. 43(6):363-7. [View Abstract]
  18. Al Montasir A, Sadik MH. Acute myocardial infarction in a 28 year man with familial hypercholesterolemia. Indian J Med Sci. 2012 Mar-Apr. 66(3-4):78-81. [View Abstract]
  19. Ghosh SK, Majumder B, Dutta A. Tuberous xanthoma as a presenting feature of familial homozygous hypercholesterolemia with aortic regurgitation. J Pediatr. 2015 Jan. 166(1):198. [View Abstract]
  20. Jetha MM, Fiorillo L. Xanthomata and diabetes in an adolescent with familial dysbetalipoproteinemia 9 yr after valproate-induced pancreatitis. Pediatr Diabetes. 2012 Aug. 13(5):444-7. [View Abstract]
  21. Singh AP, Sikarwar S, Jatav OP, Saify K. Normolipemic tuberous xanthomas. Indian J Dermatol. 2009. 54(2):176-9. [View Abstract]
  22. Sinnott BP, Mazzone T. Tuberous xanthomas associated with olanzapine therapy and hypertriglyceridemia in the setting of a rare apolipoprotein E mutation. Endocr Pract. 2006 Mar-Apr. 12(2):183-7. [View Abstract]
  23. Brown CA, Lesher JL Jr, Peterson CM. Tuberous and tendinous xanthomata secondary to ritonavir-associated hyperlipidemia. J Am Acad Dermatol. 2005 May. 52(5 Suppl 1):S86-9. [View Abstract]
  24. Guidry J, Thompson W, Sonabend M. Chronic myelomonocytic leukemia can present with diffuse planar xanthoma. Dermatol Online J. 2014 Jul 15. 20(7):[View Abstract]
  25. Emberger M, Zelger BW, Laimer M, Burgdorf W. Plaque-like papular xanthoma, an unusual, localized variant of non-Langerhans cell disease. Eur J Dermatol. 2013 Apr 1. 23(2):278-9. [View Abstract]
  26. Matsumoto M, Ikeda M, Takeya M, Kodama H. Plane xanthoma associated with multiple mastocytoma. Pediatr Dermatol. 2007 Sep-Oct. 24(5):E66-9. [View Abstract]
  27. Fujimoto N, Mieno H, Hosokawa R, Fujimoto E, Tajima S. Ultraviolet irradiation may generate plane xanthomas on mycosis fungoides. Br J Dermatol. 2013 Jan. 168(1):218-20. [View Abstract]
  28. Kutlubay Z, Engin B, Uzuncakmak TK, Demirkesen C, Altiti MM, Karter Y, et al. POEMS syndrome (polyneuropathy organomegaly endocrinopathy M-protein skin changes) with xanthoma - a case report. J Eur Acad Dermatol Venereol. 2014 Oct 8. [View Abstract]
  29. Maejima H, Katsuoka K. Sarcoidosis coexisting with eruptive xanthoma. Eur J Dermatol. 2011 Mar-Apr. 21(2):298-9. [View Abstract]
  30. Fett N, Teng JM. Xanthoma striatum palmare associated with nonsyndromic paucity of the interlobular bile ducts. Cutis. 2014 May. 93(5):E6-8. [View Abstract]
  31. Pearson HJ, Mosser JL, Jacks SK. The triad of pruritus, xanthomas, and cholestasis: Two cases and a brief review of the literature. Pediatr Dermatol. 2017 Nov. 34 (6):e305-e308. [View Abstract]
  32. Giller RH, Folberg R, Keech RV, Piette WW, Sato Y. Xanthoma disseminatum. An unusual histiocytosis syndrome. Am J Pediatr Hematol Oncol. 1988 Fall. 10(3):252-7. [View Abstract]
  33. Szyfter W, Wierzbicka M, Bem G. [Rare case of xanthoma disseminatum with severe dyspnoea]. Otolaryngol Pol. 2006. 60(1):67-70. [View Abstract]
  34. Kim JY, Jung HD, Choe YS, Lee WJ, Lee SJ, Kim do W, et al. A Case of Xanthoma Disseminatum Accentuating over the Eyelids. Ann Dermatol. 2010 Aug. 22(3):353-7. [View Abstract]
  35. Büyükavci M, Selimoglu A, Yildirim U, Ertekin V, Atasoy M. Xanthoma disseminatum with hepatic involvement in a child. Pediatr Dermatol. 2005 Nov-Dec. 22(6):550-3. [View Abstract]
  36. Zak IT, Altinok D, Neilsen SS, Kish KK. Xanthoma disseminatum of the central nervous system and cranium. AJNR Am J Neuroradiol. 2006 Apr. 27(4):919-21. [View Abstract]
  37. Gupta P, Khandpur S, Vedi K, Singh MK, Walia R. Xanthoma disseminatum associated with inflammatory arthritis and synovitis--a rare association. Pediatr Dermatol. 2015 Jan-Feb. 32(1):e1-4. [View Abstract]
  38. Oka M, Oniki S, Komatsu M, Ikeda T, Matsuo M, Miyamoto Y, et al. Xanthoma disseminatum with intracranial involvement: case report and literature review. Int J Dermatol. 2010 Feb. 49(2):193-9. [View Abstract]
  39. Zinoun M, Hali F, Marnissi F, Lazaar S, Benchikhi H. [Xanthoma disseminatum with asymptomatic multisystem involvement.]. Ann Dermatol Venereol. 2015 Jan 24. [View Abstract]
  40. Ghorpade A. Xanthoma disseminatum with koebnerized pearly penile lesions in an Indian man. Int J Dermatol. 2009 Sep. 48(9):996-8. [View Abstract]
  41. Attia AM, Bakry OA, Mohamed EE. Xanthoma disseminatum: a progressive case with multisystem involvement. J Postgrad Med. 2014 Jan-Mar. 60(1):69-71. [View Abstract]
  42. Spanou Z, Borradori L. Diffuse plane xanthomas, a cutaneous marker for monoclonal gammopathies and lymphoproliferative diseases. Eur J Haematol. 2011 Jan. 86(1):91. [View Abstract]
  43. Bürgesser MV, Calafat P, Diller A. [Diffuse plane xanthomatosis associated with haematologic disorder and solid tumor. Findings of an autopsy]. Rev Fac Cien Med Univ Nac Cordoba. 2011. 68(2):65-9. [View Abstract]
  44. Silva DM, Chacha JJ, Wiziack Nde C, Takita LC, Hayashi FK. [Diffuse plane idiopathic normolipemic xanthoma with hypersplenism]. An Bras Dermatol. 2010 Jan-Feb. 85(1):73-6. [View Abstract]
  45. García-Arpa M, Rodríguez-Vázquez M, Vera E, Romero G, González-García J, Cortina P. [Normolipemic plane xanthomas and mycosis fungoides]. Actas Dermosifiliogr. 2005 Jun. 96(5):307-10. [View Abstract]
  46. Koçak M, Keles H, Yakaryilmaz F, Bozdogan O, Güliter S. Diffuse plane xanthomatosis in a patient with Budd-Chiari syndrome and monoclonal gammopathy. Indian J Dermatol. 2009. 54(4):369-71. [View Abstract]
  47. Lu YT, Chen TJ, Chung WH, Kuo TT, Hong HS. Cutaneous normolipemic plane xanthoma with supraglottic involvement in a patient with hand-Schüller-Christian Disease: a case report. Am J Clin Dermatol. 2009. 10(3):189-92. [View Abstract]
  48. Campanati A, Goteri G, Simonetti O, Marconi B, Brandozzi G, Ganzetti G, et al. Normolipemic plane xanthomatosis with acute development preceding the clinical onset of rheumatoid arthritis. J Cutan Pathol. 2009 Oct. 36 Suppl 1:13-5. [View Abstract]
  49. Ko JY, Shin H, Lee CW. A verruciform xanthoma-like phenomenon in a linear epidermal naevus in the absence of a syndromic association. Br J Dermatol. 2008 Aug. 159(2):493-6. [View Abstract]
  50. Poulopoulos AK, Epivatianos A, Zaraboukas T, Antoniades D. Verruciform xanthoma coexisting with oral discoid lupus erythematosus. Br J Oral Maxillofac Surg. 2007 Mar. 45(2):159-60. [View Abstract]
  51. Gehrig RD, Baughman RA, Collins JF. Verruciform xanthoma in a young male patient with a past history of pemphigus vulgaris. Oral Surg Oral Med Oral Pathol. 1983 Jan. 55(1):58-61. [View Abstract]
  52. Orpin SD, Scott IC, Rajaratnam R, Colloby PS, Heagerty A. A rare case of recessive dystrophic epidermolysis bullosa and verruciform xanthoma. Clin Exp Dermatol. 2009 Jan. 34(1):49-51. [View Abstract]
  53. Shahrabi Farahani S, Treister NS, Khan Z, Woo SB. Oral verruciform xanthoma associated with chronic graft-versus-host disease: a report of five cases and a review of the literature. Head Neck Pathol. 2011 Jun. 5(2):193-8. [View Abstract]
  54. Jensen JL, Liao SY, Jeffes EW 3rd. Verruciform xanthoma of the ear with coexisting epidermal dysplasia. Am J Dermatopathol. 1992 Oct. 14(5):426-30. [View Abstract]
  55. Mannes KD, Dekle CL, Requena L, Sangueza OP. Verruciform xanthoma associated with squamous cell carcinoma. Am J Dermatopathol. 1999 Feb. 21(1):66-9. [View Abstract]
  56. Xu XL, Huang LM, Wang Q, Sun JF. Multiple verruciform xanthomas in the setting of congenital hemidysplasia with ichthyosiform erythroderma and limb defects syndrome. Pediatr Dermatol. 2015 Jan-Feb. 32(1):135-7. [View Abstract]
  57. Yamamoto T, Katayama I, Nishioka K. Verruciform xanthoma in a psoriatic patient under PUVA therapy. Dermatology. 1995. 191(3):254-6. [View Abstract]
  58. Salamanca J, Alemany I, Sosa G, Pinedo F, Hernando S, Martín-Acosta P. Esophageal verruciform xanthoma following radiotherapy. Gastroenterol Hepatol. 2012 May. 35(5):317-20. [View Abstract]
  59. Helm KF, Höpfl RM, Kreider JW, Lookingbill DP. Verruciform xanthoma in an immunocompromised patient: a case report and immunohistochemical study. J Cutan Pathol. 1993 Feb. 20(1):84-6. [View Abstract]
  60. Blankenship DW, Zech L, Mirzabeigi M, Venna S. Verruciform xanthoma of the upper-extremity in the absence of chronic skin disease or syndrome: a case report and review of the literature. J Cutan Pathol. 2013 Aug. 40(8):745-52. [View Abstract]
  61. Pai VV, Shukla P, Bhobe M. Combined planar and eruptive xanthoma in a patient with type lla hyperlipoproteinemia. Indian J Dermatol Venereol Leprol. 2014 Sep-Oct. 80(5):467-70. [View Abstract]
  62. Aliasgarzadeh A, Ghorbanian M, Naghavi-Behzad M. Familial dysbetalipoproteinaemia presenting with cauliflower xanthoma. Niger Med J. 2013 Jul. 54(4):268-70. [View Abstract]
  63. Kalidas K, Behrouz R. Inherited metabolic disorders and cerebral infarction. Expert Rev Neurother. 2008 Nov. 8(11):1731-41. [View Abstract]
  64. Corradino B, Di Lorenzo S, Triolo A, Moschella F. Laser treatment of giant xanthelasma palpebrarum. Lasers Med Sci. 2014 Sep 25. [View Abstract]
  65. Moorthy N, Ananthakrishna R, Bhat P, Nanjappa MC. Xanthoma tuberosum in homozygous familial hypercholesterolemia. Ann Pediatr Cardiol. 2014 May. 7(2):118-9. [View Abstract]
  66. Fujiwara S, Oka M, Kunisada M, Honjo K, Nishigori C. Severe xanthomatosis with prominent tuberous xanthomas on the cheeks and the nasal dorsum in a patient with type IIa hyperlipoproteinemia. Eur J Dermatol. 2013 Jul-Aug. 23(4):517-8. [View Abstract]
  67. Agarwal S, Akhtar MN. Great toe gouty tophus-like lesion revealing extensive tendon xanthomatosis in a asymptomatic hyperuricemic patient. J Postgrad Med. 2013 Jul-Sep. 59(3):238-9. [View Abstract]
  68. Caputo R, Monti M, Berti E, Gasparini G. Normolipemic eruptive cutaneous xanthomatosis. Arch Dermatol. 1986 Nov. 122(11):1294-7. [View Abstract]
  69. Ansarin H, Berenji Ardestani H, Tabaie SM, Shayanfar N. Xanthoma disseminatum with tumor-like lesion on face. Case Rep Dermatol Med. 2014. 2014:621798. [View Abstract]
  70. Hisanaga Y, Akaike Y, Kuroda K. Xanthoma disseminatum with large plaques confined to the back, pulmonary involvement and multiple intestinal xanthomas. Dermatology. 2004. 208(2):164-6. [View Abstract]
  71. Errichetti E, Piccirillo A, Tataranni M, Ricciuti F, Liao KL, Cheng ZL, et al. A case of diffuse plane normolipemic xanthomatosis presenting with oral lesions. G Ital Dermatol Venereol. 2014 Apr. 149(2):278-80. [View Abstract]
  72. Mountcastle EA, Lupton GP. Verruciform xanthomas of the digits. J Am Acad Dermatol. 1989 Feb. 20(2 Pt 2):313-7. [View Abstract]
  73. Kanitakis J, Euvrard S, Butnaru AC, Claudy A. Verruciform xanthoma of the scrotum in a renal transplant patient. Br J Dermatol. 2004 Jan. 150(1):161-3. [View Abstract]
  74. Reich O, Regauer S. Recurrent verruciform xanthoma of the vulva. Int J Gynecol Pathol. 2004 Jan. 23(1):75-7. [View Abstract]
  75. Griffel B, Cordoba M. Verruciform xanthoma in the anal region. Am J Proctol Gastroenterol Colon Rectal Surg. 1980 Apr. 31(4):24-5. [View Abstract]
  76. Becheanu G, Dumbrava M, Arbanas T, Diculescu M, Hoyeau-Idrissi N, Fléjou JF. Esophageal xanthoma--report of two new cases and review of the literature. J Gastrointestin Liver Dis. 2011 Dec. 20(4):431-3. [View Abstract]
  77. Fernandes EÁ, Santos EH, Tucunduva TC, Ferrari AJ, Fernandes AD. [Achilles tendon xanthoma imaging on ultrasound and magnetic resonance imaging.]. Rev Bras Reumatol. 2014 Nov 1. [View Abstract]
  78. Griffith JF, Hu M, Yeung DKW, Guo P, Lam SL, Xiao F, et al. Achilles Tendon Xanthomas: Fat-Water Separation at Baseline and after Treatment. Radiology. 2017 Dec. 285 (3):876-884. [View Abstract]
  79. Jin S, Chae SY, Chang SE, Suh C, Lee SW, Ryu JS. A case of xanthoma disseminatum: evaluation and monitoring by 18F-fluorodeoxyglucose positron emission tomography/computed tomography. Br J Dermatol. 2014 May. 170(5):1177-81. [View Abstract]
  80. Aldabagh B, Bergfeld W. Eruptive neutrophilic xanthomas. Dermatol Online J. 2010 Apr 15. 16(4):6. [View Abstract]
  81. Shafer WG. Verruciform xanthoma. Oral Surg Oral Med Oral Pathol. 1971 Jun. 31(6):784-9. [View Abstract]
  82. Fukuda H, Saito R. Verruciform xanthoma in close association with isolated epidermolytic acanthoma: a case report and review of the Japanese dermatological literature. J Dermatol. 2005 Jun. 32(6):464-8. [View Abstract]
  83. Inazu A, Koizumi J, Kajinami K, Kiyohar T, Chichibu K, Mabuchi H. Opposite effects on serum cholesteryl ester transfer protein levels between long-term treatments with pravastatin and probucol in patients with primary hypercholesterolemia and xanthoma. Atherosclerosis. 1999 Aug. 145(2):405-13. [View Abstract]
  84. Fujita M, Shirai K. A comparative study of the therapeutic effect of probucol and pravastatin on xanthelasma. J Dermatol. 1996 Sep. 23(9):598-602. [View Abstract]
  85. Yamamoto A, Matsuzawa Y, Yokoyama S, Funahashi T, Yamamura T, Kishino B. Effects of probucol on xanthomata regression in familial hypercholesterolemia. Am J Cardiol. 1986 Jun 27. 57(16):29H-35H. [View Abstract]
  86. Kuo PT, Hayase K, Kostis JB, Moreyra AE. Use of combined diet and colestipol in long-term (7--7 1/2 years) treatment of patients with type II hyperlipoproteinemia. Circulation. 1979 Feb. 59(2):199-211. [View Abstract]
  87. Bea AM, Perez-Calahorra S, Marco-Benedi V, Lamiquiz-Moneo I, Jarauta E, Mateo-Gallego R, et al. Effect of intensive LDL cholesterol lowering with PCSK9 monoclonal antibodies on tendon xanthoma regression in familial hypercholesterolemia. Atherosclerosis. 2017 Aug. 263:92-96. [View Abstract]
  88. Szturz P, Adam Z, Rehák Z, Koukalová R. Xanthelasma palpebrarum responding to interleukin-1 blockade. Intern Med J. 2014 Jun. 44(6):617-8. [View Abstract]
  89. Nakajima K, Ikeda M, Nakajima H, Kodama H. Regression of secondary plane xanthomas using cyclosporine A. Int J Dermatol. 2006 Sep. 45(9):1136-8. [View Abstract]
  90. Ceska R, Vrablík M, Altschmiedová T, Prusíková M, Urbanová Z, Šobra J. [Familial hypercholesterolemia - past and present. My experiences and findings in our group of patients with familial hypercholesterolemia]. Vnitr Lek. 2014 Nov. 60(11):963-9. [View Abstract]
  91. Khezri F, Gibson LE, Tefferi A. Xanthoma disseminatum: effective therapy with 2-chlorodeoxyadenosine in a case series. Arch Dermatol. 2011 Apr. 147(4):459-64. [View Abstract]
  92. Lee EH, Kang TW, Kim SC. Successful treatment of xanthoma disseminatum with simvastatin. J Dermatol. 2011 Oct. 38(10):1015-7. [View Abstract]
  93. Kim WJ, Ko HC, Kim BS, Kim MB. Successful treatment of xanthoma disseminatum with combined lipid lowering agents. Ann Dermatol. 2012 Aug. 24(3):380-2. [View Abstract]
  94. Connolly SB, Lewis EJ, Lindholm JS, Zelickson BD, Zachary CB, Tope WD. Management of cutaneous verruciform xanthoma. J Am Acad Dermatol. 2000 Feb. 42(2 Pt 2):343-7. [View Abstract]
  95. Miyagawa F, Fukumoto T, Kobayashi N, Asada H. Successful treatment of diffuse normolipemic plane xanthoma with probucol. Case Rep Dermatol. 2013 May. 5(2):148-51. [View Abstract]
  96. Haque MU, Ramesh V. Evaluation of three different strengths of trichloroacetic acid in xanthelasma palpebrarum. J Dermatolog Treat. 2006. 17(1):48-50. [View Abstract]
  97. Haygood LJ, Bennett JD, Brodell RT. Treatment of xanthelasma palpebrarum with bichloracetic acid. Dermatol Surg. 1998 Sep. 24(9):1027-31. [View Abstract]
  98. Lee HY, Jin US, Minn KW, Park YO. Outcomes of surgical management of xanthelasma palpebrarum. Arch Plast Surg. 2013 Jul. 40(4):380-6. [View Abstract]
  99. Yang Y, Sun J, Xiong L, Li Q. Treatment of xanthelasma palpebrarum by upper eyelid skin flap incorporating blepharoplasty. Aesthetic Plast Surg. 2013 Oct. 37(5):882-6. [View Abstract]
  100. Park EJ, Youn SH, Cho EB, Lee GS, Hann SK, Kim KH, et al. Xanthelasma palpebrarum treatment with a 1,450-nm-diode laser. Dermatol Surg. 2011 Jun. 37(6):791-6. [View Abstract]
  101. Raulin C, Schoenermark MP, Werner S, Greve B. Xanthelasma palpebrarum: treatment with the ultrapulsed CO2 laser. Lasers Surg Med. 1999. 24(2):122-7. [View Abstract]
  102. Basar E, Oguz H, Ozdemir H, Ozkan S, Uslu H. Treatment of xanthelasma palpebrarum with argon laser photocoagulation. Argon laser and xanthelasma palpebrarum. Int Ophthalmol. 2004 Jan. 25(1):9-11. [View Abstract]
  103. Zhao Y, Wen CM, Zhou NN, Feng Q, Tu P. 1064-nm Q-switched Nd:YAG laser is an effective and safe approach to treat xanthelasma palpebrarum in Asian population. J Eur Acad Dermatol Venereol. 2014 Jun 9. [View Abstract]
  104. Sonthalia S, Arora R, Sarkar R. Successful cosmetic ablation of xanthelasma palpebrarum with low-voltage radiofrequency: back to the basics!. Dermatol Surg. 2014 Dec. 40(12):1443-4. [View Abstract]
  105. Esmat SM, Elramly AZ, Abdel Halim DM, Gawdat HI, Taha HI. Fractional CO2 laser is an effective therapeutic modality for xanthelasma palpebrarum: a randomized clinical trial. Dermatol Surg. 2014 Dec. 40(12):1349-55. [View Abstract]
  106. Heng JK, Chua SH, Goh CL, Cheng S, Tan V, Tan WP. Treatment of xanthelasma palpebrarum with a 1064-nm, Q-switched Nd:YAG laser. J Am Acad Dermatol. 2017 Oct. 77 (4):728-734. [View Abstract]
  107. Nguyen AH, Vaudreuil AM, Huerter CJ. Systematic review of laser therapy in xanthelasma palpebrarum. Int J Dermatol. 2017 Mar. 56 (3):e47-e55. [View Abstract]
  108. Mendelson BC, Masson JK. Xanthelasma: follow-up on results after surgical excision. Plast Reconstr Surg. 1976 Nov. 58(5):535-8. [View Abstract]
  109. Borelli C, Kaudewitz P. Xanthelasma palpebrarum: treatment with the erbium:YAG laser. Lasers Surg Med. 2001. 29(3):260-4. [View Abstract]
  110. Hsu MC, Lee CH, Chen GS, Wu CY. Nonablative 1,450-nm diode laser treatment for xanthoma disseminatum. Dermatol Surg. 2014 Dec. 40(12):1423-5. [View Abstract]

Xanthelasma. Courtesy of Duke University Medical Center.

Tuberous xanthomas. Courtesy of Duke University Medical Center.

Eruptive xanthomas. Courtesy of Duke University Medical Center.

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

Xanthelasma. Courtesy of Duke University Medical Center.

Eruptive xanthomas. Courtesy of Duke University Medical Center.

Tuberous xanthomas. Courtesy of Duke University Medical Center.

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