Patients with cutaneous or tendinous xanthomas often present to their primary care clinician or a variety of specialty providers including dermatology, general surgery, orthopedic surgery, and ophthalmology. It is not uncommon for these patients to present to specialty clinics for the treatment of a visible lesion and then be diagnosed with an associated metabolic condition such as familial hypercholesterolemia. Therefore, providers of various disciplines must be familiar with the presentations of these fairly common lesions and their associations with systemic disease. 

On clinical exam, xanthomas have been generally described as lesions that are eruptive, tuberoeruptive, tuberous, tendinous, or planar.[3] Eruptive xanthomas are acute, inflammatory lesions that appear rapidly in groups of papules and then disappear over several weeks. Tuberoeruptive and tuberous xanthomas are often grouped together in reports, and they are associated with various hyperlipoproteinemia states. They appear as red, inflamed papules that coalesce. The predilection of these lesions to particular anatomic regions such as the elbows or palms can be pathognomonic for specific types of hyperlipoproteinemia.[3]

These lesions are also reported to resolve spontaneously, although this may only occur after several months. Tendinous xanthomas commonly affect the Achilles tendons, elbows, and extensor tendons of the hand.[5] These are very gradually progressive lesions that bear a strong association with familial hypercholesterolemia. The heterozygous form of this disease is associated with a better prognosis than the homozygous form in which patients have high mortality rates at younger ages. Cerebrotendinous xanthomatosis, as previously described, represents a form of this presentation. This condition can present with neurologic findings such as corticospinal tract signs, cognitive decline, and gait difficulty.[10] 

Planar xanthomas can be on the palmar creases and flexure surfaces of fingers, and skin folds and are typically seen with biliary cirrhosis. They can occur in a variety of anatomic regions and can be pathognomonic for different systemic conditions based on their presentation. For example, palmar crease xanthomas can be pathognomonic for familial dysbetalipoproteinemia type III.[3] Xanthoma planum lesions can be spread on large planes of the body. Xanthoma diabeticorum can be seen with severe diabetes and verrucous xanthoma is often seen in association with histiocytes in connective tissues.

On the initial clinical presentation of patients with xanthomas, an evaluation must focus on both locoregional and systemic disease. For the locoregional lesion, a clinical exam is often enough to make a ready diagnosis of xanthoma. Radiographs are typically normal in these patients. Ultrasound study may be performed of tendinous xanthomas, and advanced imaging in the form of magnetic resonance imaging (MRI) may be helpful to rule out differential diagnoses and for surgical planning. Upon diagnosis of xanthoma, a systemic workup must be undertaken simultaneously.

Early recognition of morbid conditions such as familial hypercholesterolemia can avoid delays in management. Therefore, prompt workup by the treating clinician should start with laboratory investigations that include plasma triglycerides, plasma cholesterol, serum LDL, and high-density lipoproteins (HDL). These tests should preferably be performed under fasting conditions and as per other collection and processing standards prescribed by the local laboratory. Specific clinical patterns of presentation such as diffuse plane xanthomas or palmar crease xanthomas should warrant investigation for known pathognomonic conditions that are associated with such findings. As part of the workup for metabolic syndrome, blood glucose and hemoglobin A1c may also be performed as indicated.

The main treatment for xanthomas is for the associated medical conditions that produce these lesions. On occasion, surgical excisional biopsy of these lesions may be performed for symptomatic lesions or to exclude other differential diagnoses. It has been reported that identifying the specific lipid type in a lesion can help with the diagnosis of the broader systemic condition underlying this finding. In symptomatic lesions such as tendinous xanthomas over areas that sustain frequent contact with the external environment (for example, shoe wear in Achilles tendon lesions), complete excision in tandem with medical stabilization of the underlying systemic disease process is preferred in order to minimize the risk of recurrence.[8]

In areas such as the Achilles tendon, where wound healing may be difficult after lesion excision, it is imperative to exercise careful soft tissue management and optimize wound closure techniques (including the potential use of flaps).[11] In medical management, the primary objective is to optimize the lipid profile of the patient. HMG-CoA reductase inhibitors have been quite successful in this regard and have the dual benefit of controlling hyperlipidemia while potentially decreasing the size of xanthomatous lesions.[12] 

Interestingly, reports of spontaneous resolution of smaller xanthomas have been described following liver transplant and plasmapheresis. These findings again emphasize the importance of controlling the systemic disease as the primary objective. Newer treatment options have emerged in the treatment of these metabolic diseases. For example, monoclonal antibodies against the proprotein convertase subtilisin/kexin type 9 gene have been found to be effective agents in familial hypercholesterolemia.[2] Treatment of xanthoma disseminatum with 2-chlorodeoxyadenosine is another promising agent that has recently been described in various reports as being highly effective.[13]

Rare cases of xanthomas produced by unusual sterol deposits have been reported in the literature. These include the aforementioned cerebrotendinous xanthomatosis (accumulation of cholestanol) and beta-sitosterolemia.[14] These patients also have a higher incidence of atherosclerotic burden, so careful management of both local and systemic disease is essential.[3]

The overall clinical outcomes in patients with xanthomas depends on a variety of factors. Most importantly, the underlying systemic disease must be appropriately managed. Some of the underlying systemic diseases in these patients may have early and high mortality rates, such as homozygous familial hypocholesterolemia. Others may be managed with lifestyle modifications and systemic therapies that can provide substantial improvements in survival rates. In terms of local disease, most smaller xanthoma lesions may either decrease in size or even completely resolve with effective systemic management. For those local lesions which are symptomatic due to their size or anatomic location, recurrence after excision can be minimized by careful surgical planning. Partial resection or debulking has been associated with a very high recurrence rate in these lesions.

Adverse events in the management of xanthomas are generally related to systemic therapy. For example, the use of HMG CoA reductase inhibitor therapy has a well-known side effect profile. These side effects range from the more commonly reported statin-associated muscle symptoms (including mild myalgia in up to 10% of users) to rarer but more feared complications such as rhabdomyolysis and necrotizing autoimmune myopathy.[15]

Therefore, systemic therapy for patients presenting with xanthomas should be initiated and managed closely by a provider who is able to recognize and manage any adverse effects of such medications. Surgical complications from the excision of xanthomatous lesions are also well described. As tendinous xanthomas tend to develop in areas that are well known to be at high risk for delayed wound healing, careful surgical planning is essential to avoid wound complications and local recurrence.

Patients may present to a dermatologist or surgeon initially, without knowing that the cause of their lesion is an underlying systemic medical condition. Therefore, patient education is essential upon diagnosis. Adequate counseling must be provided regarding lifestyle modifications, management options, and the need for regular follow-up. Careful management of the lipid and cholesterol profile can provide effective control against the development of new lesions in the same patient. It is demonstrated in various studies that atheromatous deposits are concurrent with xanthoma formation, which could have significant mortality and morbidity associated with it.[16]

An interprofessional team approach is essential upon the diagnosis of xanthomas to ensure optimal outcomes. This involves a comprehensive workup and prompt referral to the appropriate medical and surgical specialists for further management. It is important for treating surgeons to ensure that patients establish care with a medical specialist who can help optimize their lipid profile in the long-term for best outcomes.