Non-infectious Granulomatous Diseases of the Skin and their Associated Systemic Diseases: An Evidence-based Update to Important Clinical Questions

Elena Balestreire Hawryluk; Leonid Izikson; Joseph C. English III

Disclosures

Am J Clin Dermatol. 2010;11(3):171-181. 

In This Article

4. Is Paraproteinemia in Necrobiotic Xanthogranuloma Always Associated with an Underlying Malignancy?

NXG is a rare condition characterized by progressive periorbital xanthomas, in addition to periorbital edema and potential ophthalmologic complications in approximately 50% of patients.[43] Skin papules or plaques tend to have telangiectasias and ulcerate, followed by scarring.As a type II normocholesterolemic xanthoma, NXG is associated with lymphoproliferative diseases or paraproteinemias. A retrospective study of 26 NXG patients by Ugurlu et al.[44] in 2000 revealed that paraproteinemia was present in approximately 80% of NXG patients.[44] Immunofixation electrophoresis is required for evaluation of paraproteinemia in these patients, as it is much more sensitive for detection of specific monoclonal proteins compared with the screening serum protein electrophoresis. While the pathogenesis of NXG is unclear, it has been proposed that increased circulating immunoglobulins may form immune complexes that become deposited in the periorbital tissues, which may elicit the granulomatous inflammatory response of NXG.[45] Conversely, a recent dermatopathologic analysis of seven NXG biopsies suggested the presence of Borrelia spirochetes in six of seven samples, implicating spirochetes as a potential trigger for NXG.[46]

Of the patients with paraproteinemia, the most frequent type is increased IgG-k monoclonal gammopathy (65%), followed by IgG-λ (35%).[44] IgA paraproteinemia has also been reported,[47] along with a patient with two monoclonal paraproteins.[48] A patient with IgG-k paraproteinemia who developed multiple myeloma during monitoring was described.[49] In general, patients (without NXG) who have a paraproteinemia or monoclonal gammopathy of undetermined significance (MGUS) have a rate of progression to multiple myeloma of approximately 1%per year, or 25%at 20 years after diagnosis.[50] ForNXGpatients, retrospective analyses indicate that 10–25% of patients with an associated MGUS may subsequently develop multiple myeloma.[44,51] Paraproteinemia and/or progression to multiple myeloma are not necessarily prevented by treatment.[52] Other malignancies associated with NXG include mycosis fungoides, lymphoma, and leukemia.[53]

While malignancy is clearly a concern forNXGpatients, it is important to consider systemic involvement of NXG, which has been shown to involve a number of organs including the heart and lung, in addition to the kidney, liver, intestine, spleen, ovary, pharynx, and/or retro-orbital skull.[53,54] It may be prudent to consider evaluation of these patients for systemic involvement with MRI, echocardiography, and chest x-ray.

4.1 Summary and Recommendations

NXG is not always associated with an underlying malignancy; approximately 80% of NXG patients have an MGUS, with a smaller proportion having or developing an associated multiple myeloma. However, all patients with NXG should be screened for the presence of an associated paraproteinemia by immunofixation electrophoresis, in addition to exploring for concurrent systemic disease. In NXG patients with an associated MGUS, evaluation and continued monitoring for a malignant conversion to multiple myeloma is prudent.

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