A 62-year-old man with well-controlled rosacea, a monoclonal gammopathy of undetermined significance, and chronic lymphocytic leukemia (CLL; stable on no current therapy) was seen in the clinic for a full-body skin check. Results of his examination were unremarkable except for the presence of periorbital, yellow-brown plaques with violaceous borders involving the upper and lower eyelids, bilaterally. There was induration, but no warmth or tenderness, of the periorbital plaques. He first noticed these lesions around the time he was diagnosed with CLL; initially they were more discrete yellow papules that developed into plaques over time. They are completely asymptomatic.
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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.
- Spicknall KE, Mehregan DA. Necrobiotic xanthogranuloma. Int J Dermatol. 2009;48(1):1-10.
- Rose A, Robinson M, Kamino H, Latkowski JA. Necrobiotic xanthogranuloma. Dermatol Online J. 2012;18(12):30.
- Kerstetter J, Wang J. Adult orbital xanthogranulomatous disease: a review with emphasis on etiology, systemic associations, diagnostic tools, and treatment. Dermatol Clin. 2015;33(3):457-463.
- Wanat KA, Kim B, Rosenbach M. Multisystem diseases affecting the skin and eye. Clin Dermatol. 2016;34(2):214-241.
- Kossard S, Winkelmann RK. Necrobiotic xanthogranuloma with paraproteinemia. J Am Acad Dermatol. 1980;3(3):257-270.
- Mehregan DA, Winkelmann RK. Necrobiotic xanthogranuloma. Arch Dermatol. 1992;128(1):94-100.
- Fernández-Herrera J, Pedraz J. Necrobiotic xanthogranuloma. Semin Cutan Med Surg. 2007;26(2):108-113.
- Wood AJ, Wagner MV, Abbott JJ, Gibson LE. Necrobiotic xanthogranuloma: a review of 17 cases with emphasis on clinical and pathologic correlation. Arch Dermatol. 2009;145(3):279-284.
- Ugurlu S, Bartley GB, Gibson LE. Necrobiotic xanthogranuloma: long-term outcome of ocular and systemic involvement. Am J Ophthalmol. 2000;129(5):651-657.
- Szalat R, Arnulf B, Karlin L, et al. Pathogenesis and treatment of xanthomatosis associated with monoclonal gammopathy. Blood. 2011;118(14):3777-3784.
- AlGain M, Szalat R, Vignon-Pennamen MD, et al. A rare case of disseminated skin and mucosal necrobiotic xanthogranuloma and xanthoma. J Eur Acad Dermatol Venereol. 2016 Jan 25. doi: 10.1111/jdv.13577. [Epub ahead of print]
- Mohsenin A, Sinard J, Huang JJ. Necrobiotic xanthogranuloma and chronic lymphocytic leukemia of the conjunctiva masquerading as scleritis and uveitis. Clin Ophthalmol. 2012;6:2045-2047.
- Zainal A, Razif MY, Makhashen M, et al. Necrobiotic xanthogranulomas of the parotid gland. J Laryngol Otol. 2010;124(5):569-571.
- Tucker NA, Discepola MJ, Blanco G, Burnier MN Jr. Necrobiotic xanthogranuloma without dermatologic involvement. Can J Ophthalmol. 1997;32(6):396-399.
- Shah KC, Poonnoose SI, George R, et al. Necrobiotic xanthogranuloma with cutaneous and cerebral manifestations. Case report and review of the literature. J Neurosurg. 2004;100(6):1111-1114.
- Fortson JS, Schroeter AL. Necrobiotic xanthogranuloma with IgA paraproteinemia and extracutaneous involvement. Am J Dermatopathol. 1990;12(6):579-584.
- Winkelmann RK, Litzow MR, Umbert IJ, Lie JT. Giant cell granulomatous pulmonary and myocardial lesions in necrobiotic xanthogranuloma with paraproteinemia. Mayo Clin Proc. 1997;72(11):1028-1033.
- Bara C, Barbarot S, Hamidou M, et al. Systemic necrobiotic xanthogranuloma with initial pericardial and pulmonary involvement [article in French]. Ann Dermatol Venereol. 2003;130(3):341-344.
- Novak PM, Robbins TO, Winkelmann RK. Necrobiotic xanthogranuloma with myocardial lesions and nodular transformation of the liver. Hum Pathol. 1992;23(2):195-196.
- Hunter L, Burry AF. Necrobiotic xanthogranuloma: a systemic disease with paraproteinemia. Pathology. 1985;17(3):533-536.
- DeLuca IJ, Grossman ME. Vulvar necrobiotic xanthogranuloma. J Am Acad Dermatol. 2014;71(6):e247-e248.
- Yasukawa K, Kato N, Hamasaka A, Hata H. Necrobiotic xanthogranuloma: isolated skeletal muscle involvement and unusual changes. J Am Acad Dermatol. 2005;52(4):729-731.
- Burdick AE, Sanchez J, Elgart GW. Necrobiotic xanthogranuloma associated with a benign monoclonal gammopathy. Cutis. 2003;72(1):47-50.
- Vieira V, Del Pozo J, Martinez W, et al. Necrobiotic xanthogranuloma associated with lymphoplasmacytic lymphoma. Palliative treatment with carbon dioxide laser. Eur J Dermatol. 2005;15(3):182-185.
- Balagula Y, Straus DJ, Pulitzer MP, Lacouture ME. Necrobiotic xanthogranuloma associated with immunoglobulin M paraproteinemia in a patient with Waldenström macroglobulinemia. J Clin Oncol. 2011;29(11):e305-e307.
- Matsuura F, Yamashita S, Hirano K, et al. Activation of monocytes in vivo causes intracellular accumulation of lipoprotein-derived lipids and marked hypocholesterolemia—a possible pathogenesis of necrobiotic xanthogranuloma. Atherosclerosis. 1999;142(2):355-365.
- Umbert I, Winkelmann RK. Necrobiotic xanthogranuloma with cardiac involvement. Br J Dermatol. 1995;133(3):438-443.
- Bullock JD, Bartley GB, Campbell RJ, et al. Necrobiotic xanthogranuloma with paraproteinemia. Case report and a pathogenetic theory. Ophthalmology. 1986;93(9):1233-1236.
- Szalat R, Pirault J, Fermand JP, et al. Physiopathology of necrobiotic xanthogranuloma with monoclonal gammopathy. J Intern Med. 2014;276(3):269-284.
- Hallermann C, Tittelbach J, Norgauer J, Ziemer M. Successful treatment of necrobiotic xanthogranuloma with intravenous immunoglobulin. Arch Dermatol. 2010;146(9):957-960.
- Langlois S, Brochot P, Reguiai Z, et al. Necrobiotic xanthogranuloma with multiple myeloma. Case report and pathogenic hypotheses. Joint Bone Spine. 2006;73(1):120-122.