Are You Confident of the Diagnosis?
What you should be alert for in the history
Xanthoma disseminatum (XD) is a rare, normolipemic form of histiocytosis. Patients rapidly develop hundreds of red-brown papules that become increasingly yellow with time. The lesions are symmetrically distributed and involve the eyelids, trunk, face, and flexural folds of the proximal extremities. In the folds the papules often coalesce into soft plaques.
The histiocytic infiltrate of XD can involve other extracutaneous organ systems including the central nervous system, ocular structures, and the respiratory and gastrointestinal tracts. A notable association is diabetes insipidus due to CNS involvement. Typically the diabetes insipidus is mild and responsive to vasopressin.
Erdheim-Chester disease is a progressive variant of XD, presenting most commonly with bone pain, due to involvement of the long bones. Extraosseous involvement is common and can affect almost any organ including the lungs, liver, kidney, heart, and CNS.
Characteristic findings on physical examination
The cutaneous findings of XD are hundreds of papules that are red-brown in their initial phase, but become progressively yellow in later stages. The lesions typically have a symmetric distribution with a predilection for the skin folds and flexures.
Expected results of diagnostic studies
Skin biopsy specimens of xanthogranuloma disseminatum will demonstrate a mixture of histiocytes, foam cells, and inflammatory cells. If a later lesion is biopsied a predominance of foam cells may be observed, as well as Touton giant cells.
Immunohistochemical staining will demonstrate S100 negativity, CD1a negativity, and CD68 positivity.
Patients with XD are typically normolipemic to slightly hyperlipidemic, which differentiates it from hyperlipidemic xanthomatous conditions.
XD has been reported in association with multiple myeloma, Waldenström macroglobulinemia, and monoclonal gammopathy.
The differential diagnosis of XD includes the xanthomas and the histiocytoses (including disseminated Langerhans cell histiocytosis, generalized eruptive histiocytoma, and multicentric reticulohistiocytosis).
Who is at Risk for Developing this Disease?
XD is a very rare disorder. Since Montgomery and Osterberg first described it in 1938, only about 100 cases have been reported in the literature. It affects males more frequently than females and fifty percent of cases are diagnosed before the age of 25.
What is the Cause of the Disease?
The etiology and pathogenesis of XD are unknown. Some authors have speculated that the association with paraproteinemia suggests an immunologic basis for this disease.
Systemic Implications and Complications
Three clinical variants of XD have been described: a self-healing form, a persistent form, and a progressive form (exemplified by Erdheim-Chester disease). The persistent form is the most frequently encountered, and prognosis is generally good. In the self-healing form lesions may last from 2-40 years. In the progressive form the prognosis is poor, because of the high risk of visceral involvement.
Identification of a paraproteinemia in association with XD should prompt a referral to the appropriate specialists for evaluation and treatment.
Since XD has been reported in such a few numbers of cases, treatment recommendations stem mainly from these case reports. Therapies that have been tried with variable success include:
Immunosuppressive drugs (azathioprine)
Lipid lowering agents
Localized radiation therapy
Optimal Therapeutic Approach for this Disease
Patients with XD should be managed in accordance with the severity of their disease. Most cases are initially managed with systemic steroids employing doses of at least 1mg/kg of prednisone either as monotherapy or in combination with an immunosuppressive agent (azathioprine can be used at doses of 100 -300mg daily). Though as a rule XD is not associated with hyperlipidemia, if a particular patient presents with an abnormal lipid profile the patient should be treated accordingly (e.g. with a fibrate or statin as deemed appropriate and at doses recommended to treat hyperlipidemia).
Patients who fail these treatments are typically escalated to treatment with cytotoxic chemotherapeutic drugs and radiation therapy. Even with this escalation of treatment, progressive cases of XD typically have a poor prognosis.
Patients diagnosed with XD should be screened for central nervous system, visceral, and musculoskelal involvement, as well as for paraproteinemia.
Unusual Clinical Scenarios to Consider in Patient Management
One clinical scenario that should be considered is the involvement of the mucous membranes. In about one-half of cases xanthomatous lesions may be found on the mouth, pharynx, larynx, conjunctiva, and cornea. If the upper aerodigestive tract is involved, patients can manifest symptoms of stridor, dyspnea, and dysphagia. A few reported cases with laryngeal involvement have required tracheotomy to maintain patency of the airway.
What is the Evidence?
Alexander, AS, Turner, R, Uniate, L, Pearcy, RG. “Xanthoma disseminatum: a case report and literature review”. The British Journal of Radiology. vol. 78. 2005. pp. 153-157. (A case of XD is presented including MRI images of involvement of the CNS. The limited literature on XD is reviewed and some treatment recommendations are provided.)
Zeleger, B, Cerio, R, Orchard, G. “Histologic and immunohistochmical study comparing xanthoma disseminatum and histiocytosis X”. Arch Dermatol. vol. 128. 1992. pp. 1207-12. (The differing immunophenotypic profiles of XD and histiocytosis X (Langerhan's cell histiocytosis) are compared.)
Montgomery, H, Osterberg, A. “Xanthomatous correlation of clinical, histopathalogical, and chemical studies of cutaneous xanthoma”. Arch Dermatol Syphilol. vol. 37. 1938. pp. 373-402. (The first report of XD. It was made by Montgomery and Osterberg.)
Buyukavci, M, Selimoglu, A, Yildirim, U, Ertekin, V, Atasoy, M. “Xanthoma Disseminatum with Hepatic Involvement in a Child”. Pediatric Dermatology. vol. 22. 2005. pp. 550-553. (A rare case of XD in a child is reported.)
Allen, TC, Chevez-Barrios, P, Shetlar, DJ, Cagle, PT. “Pulmonary and Ophthalmic Involvement With Erdheim-Chester Disease”. Arch Pathol Lab Med. vol. 128. 2004. pp. 1428-1431. (A case of the fulminant and progressive variant of XD, Erdheim-Chester disease, is reported and the features of this entity are reviewed.)
Elder, DE. “Lever’s Histopathology of the Skin”. 2005. (The salient histologic features of XD are reviewed.)
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