Are You Confident of the Diagnosis?
What you should be alert for in the history
The modifier ’plane’ describes a group of xanthomas that range from macules to thin plaques. They are non-inflammatory macules or plaques. This group includes several well-defined subsets, some pathognomonic for specific diseases:
Intertriginous xanthomas appear as slightly yellow, raised dermal plaques, often with a cobblestone surface. They develop in intertriginous areas and are characteristically seen in finger webspaces. Though rare, they are pathognomonic for homozygous familial hypercholesterolemia.
Persons with homozygous familial hypercholesterolemia can exhibit other xanthomas including: tuberous xanthoma, tendon xanthoma, sub-periosteal xanthoma, and other planar xanthomas. In this disease, patients possess two mutant low-density lipoprotein (LDL) receptor alleles and their plasma levels of LDL can be elevated beyond 1,000mg/dl. Consequently, they are substantially at risk of atherosclerotic disease, with many succumbing to coronary disease in childhood.
Palmar crease xanthomas
Known also as xanthoma striata palmaris, these xanthomas are pathognomonic for familial dysbetalipoproteinemia, type III. They appear as yellow-orange macular discoloration of the palmar and finger creases. They can be quite subtle, and are often missed. These xanthomas are best visualized in natural light when the distinctive color change is more apparent. Two thirds of patients with familial dysbetalipoproteinemia, type III will also have tuberous and tuberoeruptive xanthomas, especially involving the elbows.
Patients with this inherited disorder have abnormal apolipoprotein-E isoform, apo-E2. When the apo-E2 isoform is present (in place of E3 or E4) there is impaired uptake of chylomicron and very low density lipoprotein (VLDL) remnants by the liver. The homozygous apo-E2 state occurs more commonly in the population (1/100 persons) than the clinical syndrome of dysbetalipoproteinemia (1/10,000 persons). The clinical phenotype is unmasked once patients develop an additional abnormality characterized by overproduction of VLDL: diabetes mellitus, obesity, or hypothyroidism.
Planar xanthomas of cholestasis
The xanthomas of cholestasis present as beige-orange macules on the hands and feet, but may arise elsewhere on the body. On the hands they can be differentiated from the palmar crease xanthoma by their plaque-type morphology (rather than macules), extension beyond the creases, and evolution to a dusky or gray hue. Occasionally, they may generalize and be difficult to distinguish from diffuse plane xanthoma. Patients can also present with xanthelasma, tuberous xanthoma and other stigmata of biliary obstruction like jaundice and pruritus.
Diffuse plane xanthoma
Also known as generalized plane xanthomatosis, these are rare xanthomas that appear as symmetrically distributed macular yellow-orange or yellow-brown discoloration over the trunk or sides of the neck. They occur in the setting of normal lipids and were originally thought to be idiosyncratic. However it was observed that many of these patients eventually developed dysglobulinemias, paraproteinemia, multiple myeloma, monoclonal gammopathy, cryoglobinemia, leukemia, lymphoma, eosinophilic granulomatosis, or rheumatoid arthritis.
The xanthoma may precede other clinical symptoms of the systemic disease by years; therefore, these patients should be followed closely. When diffuse xanthomas are found in the setting of monoclonal gammopathy, the M protein is usually an immunoglobulin G.
Also called xanthelasma palpebrarum, these planar yellow-to-gray plaques are present on the eyelids and periorbital skin (Figure 1). They are the most common and least specific of all xanthoma. Though they can be present in normolipemic patients, their presence, especially in a younger patient, warrants a history, physical, and measurement of a fasting plasma lipid profile.
Characteristic findings on physical examination
Plane xanthomas appear as well circumscribed (except in the case of diffuse plane xanthoma), non-inflammatory, dermal macules or plaques. The unique subtypes have subtle morphologic features and different distributions on the body that allow them to be better characterized.
Expected results of diagnostic studies
The hallmark histopathologic feature of all xanthomas is the presence of foam cells within the dermis. These cells represent macrophages, which contain lipid. These cells will stain positive for lipid with special stains (Oil-red-O). Planar xanthoma can demonstrate histologic features of the body site they arise within. For example, xanthelasma specimens can contain striated muscle, vellus hairs, and a thin epidermis reflecting their periorbital localization.
The patient with a plane xanthoma should have a fasting lipid profile performed. The specific subtypes will demonstrate unique laboratory abnormalities.
Patients with intertriginous xanthomas and familial homozygous hypercholesterolemia will have characteristically high LDL levels, with elevations at times near 1,000mg/dl.
In xanthoma striate palmaris, which is pathognomonic for dysbetalipoproteinemia, the most common lipid abnormality will be the elevation total cholesterol and triglycerides, which are equally raised. The diagnosis of dysbetalipoproteinemia can be confirmed by the identification of the mutant apolipoprotein-E2 allele.
Patients with the planar xanthomas of cholestasis will have markedly elevated total cholesterol (often to levels more than 500 mg/dl) in addition to other laboratory markers of cholestasis.
Diffuse planar xanthomas generally arise in the setting of normal lipids. However, given their association with systemic illnesses, paraproteinemia, and malignancy a thorough history, physical, and directed laboratory examination are warranted.
The patient presenting with xanthelasma warrants a history and physical examination, and the clinician should consider performing a fasting lipid profile.
In plane xanthoma, the plaque-type morphology and distribution create a differential diagnosis that includes other dermal infiltrates like amylodiosis, sarcoidosis, and histiocytosis.
The location of xanthelasma generates a differential diagnosis that includes appendageal tumors.
Who is at Risk for Developing this Disease?
Each subtype of plane xanthoma has its own association with either an inherited disorder of lipoprotein metabolism or systemic disease.
The intertriginous xanthomas are pathognomonic of homozygous familial hypercholesterolemia. Palmar crease xanthomas are pathognomonic of familial dysbetalipoproteinemia. The planar xanthomas of cholestasis are associated with either primary or secondary obstructions of the biliary system. Diffuse planar xanthomas are associated with a variety of systemic illnesses including paraproteinemia, myeloma, and leukemia and lymphoma. Lastly, xanthelasma are non-specific and may be associated with hyperlipidemia or may occur in a normolipemic patient.
What is the Cause of the Disease?
There is good evidence that the lipid found within xanthomas is the same lipid circulating in high concentrations in the plasma of patients. However, the exact mechanisms that induce xanthoma formation are less clear. It has been demonstrated that using scavenger receptors for LDL macrophages can take-up lipid and become transformed into foam cells.
It has also been shown that extravasated lipid can attract foam cells through modulation of vascular endothelial receptors. Furthermore, oxidized low density lipoprotein has been shown to induce the formation and infiltration of foam cells within the dermis.
For a detailed discussion of LDL metabolism view the tendon xanthoma section.
Palmar crease xanthomas
The steps of cholesterol metabolism relevant to the formation of tuberous xanthomas in dysbetalipoproteinemia involve the metabolism of two remnant particles, the chylomicron and VLDL remnants. In dysbetalipoproteinemia there is an abnormal apolipoprotein-E isoform, apo-E2. When the apo-E2 isoform is present there is impaired uptake of chylomicron and VLDL remnants by the liver.
Planar xanthomas of cholestasis
In the setting of disorders of cholestasis, typified by primary biliary cirrhosis, Alagille syndrome (congenital biliary hypoplasia), and secondary biliary obstruction an abnormal lipoprotein (lipoprotein X) forms and accumulates. Infiltration of lipoprotein X or its components into the dermis or subcutis is probably responsible for the formation of the planar xanthoma.
Diffuse plane xanthoma
The proposed pathomechanism of diffuse plane xanthoma is formation of a complex between the abnormal paraprotein and the lipoprotein. This complex is phagocytized by macrophages, which become the foam cells of a xanthoma. These xanthomas may resolve with treatment of the systemic disease, although in some cases they persist.
Systemic Implications and Complications
Recognition of a plane xanthoma and proper characterization into one of the subtypes mentioned above should prompt the clinician to take an appropriate history and physical examination and perform indicated laboratory testing.
Treatment of the underlying disorder
Ablative laser therapy
Optimal Therapeutic Approach for this Disease
The treatment of plane xanthomas is targeted towards correcting the underlying lipoprotein abnormality or systemic disease. If a patient’s lipid levels are corrected the plane xanthomas may improve, although in some patients they will persist.
Intertrigenous xanthomas (associated with familial hypercholesterolemia)
The treatment approach to familial hypercholesterolemia is detailed in the tendon xanthomas section of this reference.
Palmar crease xanthomas (associated with dysbetalipoproteinemia)
The treatment approach to familial dysbetalipoproteinemia is detailed in the tuberous xanthomas section of this reference.
Planar xanthomas of cholestasis
Planar xanthomas of cholestasis will demonstrate improvement and resolution if the biliary obstruction is reversed.
Diffuse plane xanthomas
Diffuse plane xanthomas may demonstrate improvement once the systemic illness is treated. However, in some patients the xanthomas will persist.
A large proportion of patients with xanthelasma will have no underlying lipid abnormality. For these patients cosmetic resolution of the xanthelasma is their chief concern. Ablative and surgical treatments should consider the size and location of the xanthoma and available modalities include: surgical excision, ablative (carbon dioxide) laser, trichloroacetic (35%) acid, and cryotherapy.
Through recognizing these cutaneous manifestations of hyperlipidemia, biliary obstruction, or systemic illness, patients can be identified and their underlying disease process treated. Since the underlying disease processes are diverse, patients will need regular and specifically targeted follow up and should be managed in conjunction with their primary care physician, cardiologist, and gastroenterologist/hepatologist, as necessary.
Unusual Clinical Scenarios to Consider in Patient Management
In normolipemic patients, it must be remembered that many of these individuals eventually develop dysglobulinemias, paraproteinemia, multiple myeloma, monoclonal gammopathy, cryoglobinemia, leukemia, lymphoma, eosinophilic granulomatosis, or rheumatoid arthritis.
What is the Evidence?
Cruz, PD, East, C, Bergstresser, PR. “Dermal, subcutaneous, and tendon xanthomas: diagnostic markers for specific lipoprotein disorders”. J Am Acad Dermatol. vol. 19. 1988. pp. 95-111. (A review of the dermatologic manifestations of the various types of xanthomas is presented.)
Elder, DE. “Lever’s Histopathology of the Skin”. 2005. (The salient histologic features of plane xanthomas are reviewed.)
Kasper, DL. “Harrison’s Principles of Internal Medicine”. 2005. (This reference provides a complete review of lipoprotein metabolism.)
Goodman, LS. “Goodman and Gilman’s pharmacological basis of therapeutics”. 2011. (The therapeutic principles of the treatment of hyperlipidemia are reviewed, as well as dosing regimens.)
Daoud, MS, Lust, JA, Kyle, RA, Pittelkow, MR. “Monoclonal gammopathies and associated skin disorders”. J Am Acad Dermatol. vol. 40. 1999. pp. 507-35. (A review article about the association between monoclonal gammopathies and their associated dermatologic findings including plane xanthomas.)
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