Bilateral periorbital yellow-brown plaques

A subtype of adult orbital xanthogranulomatous disease, necrobiotic xanthogranuloma (NXG) is an uncommon chronic granulomatous condition with cutaneous, ocular, and visceral manifestations.1-4 First described by Kossard and Winkelmann5 in 1980, NXG is a relatively new entity; approximately 150 cases have...

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A subtype of adult orbital xanthogranulomatous disease, necrobiotic xanthogranuloma (NXG) is an uncommon chronic granulomatous condition with cutaneous, ocular, and visceral manifestations.^1-4 First described by Kossard and Winkelmann⁵ in 1980, NXG is a relatively new entity; approximately 150 cases have been documented in the medical literature. The name is based on the histologic presence of necrobiosis described in eight patients with similar periorbital xanthomatous nodules and plaques.⁵ Classically, cutaneous NXG presents as yellow-orange-brown papules, indurated nodules, or plaques.^1,3,5-7 Secondary features include telangiectasias, violaceous borders, atrophy, ulceration, and scarring.^1,3,4,8

NXG most commonly develops within the periorbital region, affecting up to 85% of patients; the trunk and extremities are affected in up to 65% of patients.^4,9 Periorbital lesions can be unilateral or bilateral, and can affect upper and/or lower eyelids.³ Approximately 90% of patients have involvement of multiple cutaneous sites.¹⁰ Extracutaneous involvement is observed in up to 18% of patients.¹⁰ Reported extracutaneous sites include the oral cavity,¹¹ orbit,^1,12 mastoid,⁸ parotid gland,¹³ lacrimal gland,¹⁴ brain,¹⁵ facial nerve,⁸ respiratory tract (larynx, trachea, bronchi, and lung),^6,9,16-18 heart,^6,19 pericardium,¹⁸ liver,¹ spleen,⁶ kidney,²⁰ penis,⁸ vulva,²¹ ovary,⁶ skeletal muscle,²² and bone.²³

Although lesions are classically asymptomatic, a minority of patients complain of pruritus, tenderness, and/or dysesthesia.⁶ Ophthalmologic manifestations include episcleritis, uveitis, iritis, keratitis, cellulitis, and proptosis.⁹ Half of all patients with NXG have ocular symptoms, most commonly burning, dry, and painful eyes.⁶ Rarely, patients report diplopia or blurry vision.⁶

The mean age of onset is the fifth decade, with a range from the first to eighth decade, of life.^6,9,10 Originally believed to have an equal sex-related ratio,^6,9 a recent systematic review revealed a predominance in girls and women of 3:2.¹⁰

The presence of NXG is highly associated with the presence of an underlying immunoproliferative disorder; 90% of patients with NXG have a monoclonal gammopathy.^9,10 A monoclonal gammopathy of undetermined significance is present in up to half of all patients, and approximately 17% have multiple myeloma.^9,10 Less commonly associated malignancies include non-Hodgkin lymphoma, Hodgkin lymphoma, and chronic lymphocytic leukemia.^10,24,25 Hematologic disorders are diagnosed, on average, 2.4 years after the onset of NXG.⁸ Routine follow-up is necessary to monitor for the development of possible immunoproliferative disorders.^2,4,8

Given the potential for visceral involvement and an underlying malignancy, diagnostic screening tests may be extensive. It is reasonable to obtain a complete blood cell count, comprehensive metabolic panel, lipid panel, erythrocyte sedimentation rate (ESR), C-reactive protein level, complement levels, and urine/serum protein electrophoresis or immunofixation.⁴ A systematic review of 118 patients with NXG demonstrated an elevated ESR in 75% and leukopenia in 54% of patients.¹ Another review of 141 patients reported a low serum complement component 4 level and the presence of cryoglobulinemia in 77% and 32% of patients, respectively.¹⁰ In those with a monoclonal gammopathy, 95% had immunoglobulin (Ig) G involvement (71% IgGκ and 28% IgGλ); the remaining subjects had either IgA or IgM involvement.^1,10 Interestingly, despite the yellowish hue, patients with NXG typically have low to normal lipid levels.²⁶

Depending on clinical suspicion, additional studies, including a bone marrow biopsy, periorbital imaging, or echocardiogram, may be justified.^4,17,27 Although laboratory findings are supportive for the diagnosis, physical examination and biopsy are paramount. In addition to the characteristic cutaneous lesions (vide supra), further evaluation may reveal abnormal eye findings, hepatomegaly, splenomegaly, and lymphadenopathy.⁶ Histopathology results of the suspected lesions should be obtained for confirmation; Mehregan and Winkelmann⁶ advocate for three biopsies from three different lesions to support the diagnosis.

Several histopathologic findings are characteristic for NXG. Dermal granulomatous inflammation and central necrosis extending into the subcutaneous tissue with sparing of the epidermis is typically seen.^1,6 By definition, there are extensive areas of necrobiosis, or physiologic cell death with collagen degradation, with cholesterol clefts scattered throughout the area.^1,4,10,28 Touton giant cells—multinucleated giant cells with an eosinophilic core and a ring of nuclei extending along the periphery surrounded by a foamy rim of cytoplasm—are typically seen.^1,4,10 They are found in areas of high lipid content throughout the xanthogranulomatous lesion.^1,4,10 Palisading foamy histiocytes and large foreign-body-type multinucleated giant cells may accompany Touton giant cells in the granulomatous milieu.^1,4,10 Lymphocytes, plasma cells, and lymphoid nodules, occasionally with germinal centers, may also be present.^1,4,6,10 Supportive immunohistochemical (IHC) findings include positive CD68 and CD163 staining results of the foamy histiocytes and Touton giant cells, confirming monocyte origin.^7-10 Negative CD1 and PS100 IH staining results confirm NXG to be a type of non-Langerhans cell histiocytosis.

Disorders that resemble NXG must be considered in the differential diagnosis, including the three other adult orbital xanthogranulomatous diseases: adult-onset xanthogranuloma, Erdheim-Chester disease, and adult-onset asthma with periocular xanthogranuloma; hyperlipemic xanthoma and diffuse plane normolipemic xanthoma should also be considered.³ Of these, NXG, hyperlipemic xanthoma, and diffuse plane normolipemic xanthoma are all associated with a monoclonal gammopathy, cholesterol accumulation, and low complement levels with cutaneous and visceral manifestations.^10,29 Other cutaneous conditions should also be considered, including xanthelasma, xanthoma disseminatum, juvenile xanthogranuloma, granuloma annulare, foreign body granuloma, subcutaneous rheumatoid nodules, amyloidosis, and atypical sarcoidosis.^6,9,10,28

Although the etiology of NXG remains elusive, several proposed hypotheses regarding its pathogenesis exist, all based on unknown triggers. Some postulate that the necrobiotic changes result from immune complex-mediated inflammatory necrosis with a subsequent foreign-body giant cell reaction.²⁸ Others suggest lipid accumulation, along with the giant cell inflammatory reaction, are due to an elevation in macrophage colony-stimulating factor and complement reactions.²⁶ Activation of fibroblasts and dermal macrophages by preexisting monoclonal immunoglobulins has also been proposed.³⁰ An IgG monoclonal gammopathy could incite macrophage activation via their Fc receptors, resulting in xanthogranuloma formation.³¹ Alternatively, monoclonal immunoglobulins could induce lipid uptake by binding lipoprotein receptors on macrophages.⁷ Szalat and colleagues²⁹ theorize that heightened cholesterol influx and decreased cholesterol efflux within the macrophage is a fundamental factor.

To date, there is no consensus regarding the most reliable and efficacious treatment regimen for NXG. Various therapeutic modalities have been utilized, with varying success. Given the rarity of the condition, treatment selection relies solely on outcomes reported from individual case series and reports. The review by Spicknall and Mehregan¹ provides a summary of reported treatments and subsequent outcomes. Alkylating medications (chlorambucil, cyclophosphamide, and melphalan), with or without systemic corticosteroids, were the most frequently used agents.¹ Of these, melphalan had the best response rate and is the most frequently used agent.¹ NXG typically does not respond to topical corticosteroids, although intralesional and systemic corticosteroids have provided intermittent success.¹ Favorable outcomes have also been reported with azathioprine, thalidomide, and interferon alfa.¹ Treatment with methotrexate, dapsone, clofazimine, psoralen and ultraviolet A light, plasmapheresis, and radiation therapy have been used to little or no avail.¹ Lesion excision can be curative, although recurrence after surgical intervention is common.^1,24 Laser therapy is variably successful.¹

Histologic examination of biopsies from the patient in our case revealed the characteristic findings consistent with the diagnosis of NXG, occurring in the setting of both a monoclonal gammopathy and underlying chronic lymphocytic leukemia. Because his disease was confined to the periorbital regions, he was referred to the ophthalmology department; he has had partial response to multiple injections of intralesional triamcinolone.

Matthew M. Wallace, BSc, is a medical student and Julia R. Nunley, MD, is a professor of dermatology and program director of dermatology at the Medical College of Virginia Hospitals of Virginia Commonwealth University in Richmond.

References 

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