Published Web Locationhttps://doi.org/10.5070/D30rr0b85w
Necrobiotic xanthogranulomaThe Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York
Amy Rose MD, Maria Robinson MD, Hideko Kamino MD, Jo-Ann Latkowski MD
Dermatology Online Journal 18 (12): 30
Necrobiotic xanthogranuloma (NXG) is a rare, chronic, progressive, non-Langerhans histiocytosis that is strongly associated with hematologic malignant conditions. Only about 100 cases have been reported in the literature since it was first described in 1980. It is important for dermatologists to recognize NXG and initiate a prompt hematologic evaluation. IgG kappa is the most frequently discovered monoclonal gammopathy (65%), followed by IgG lambda (35%), and, much less commonly, IgA. Although no modality has been shown to be consistently effective, therapeutic options include glucocorticoids (topical, intralesional, and/or systemic), alkylating agents (chlorambucil and cyclophosphamide). interferon alpha, antimetabolites, antibiotics, thalidomide, and plasmaphersis.
A 63-year-old woman presented to the New York University Dermatologic Associates for the evaluation of erythematous papules and plaques on the breast that had been present for five years. Fourteen months prior to presentation, the eruption expanded to involve the forehead and the extremities. The patient described mild pruritus on the extremities, but she otherwise denied pain, pruritus, or other symptoms that were associated with the lesions. A course of treatment with topical glucocorticoids resulted in minimal improvement.
Past medical history included Raynaud disease and hypertension. She had no prior history of other skin conditions. A punch biopsy was taken of a papule from the left elbow. Low-dose prednisone was initiated with subsequent improvement of the lesions.
On the breasts, there were diffuse, poikilodermatous changes with patches of matted telangiectases and yellow-orange papules that coalesced into plaques. On the lateral aspects of the forehead and adjacent to the superior orbital rim, there were yellow-brown macules that created a reticulated, lattice-like hyperpigmentation. On the arms and legs were scattered yellow papules. There was no lymphadenopathy or hepatosplenomegaly.
A basic metabolic panel, hepatic panel, complete blood count, urinalysis, serum immunoglobulin levels, angiotensin-converting enzyme, and C-reactive protein were normal. The antinuclear antibody was positive with a titer of 1:40 in a homogenous pattern; erythrocyte sedimentation rate was elevated at 34 mm/hr. A serum level of beta-2-microglobulin was 2.89 mg/mL (normal range < 2.51 mg/mL). Double stranded DNA, anti-Smith, anti-ribonucleoprotein, anti-Ro/SSA, anti-La/SSB, anti- SCL-70, anti-cardiolipin, anti-Jo, and lupus anticoagulant were negative. Serum protein electrophoresis and urine protein electrophoresis were normal.
A bone-marrow specimen shows a monoclonal gammopathy of undetermined significance. A computed tomography scan of the chest, abdomen, and pelvis showed no lymphadenopathy.
There is a multinodular dermal infiltrate that extends to the upper portion of the subcutaneous tissue, which is comprised of mononuclear histiocytes. Aggregates of histiocytes are separated by areas of degenerated collagen within which are neutrophils and nuclear dust. There is also a perivascular and periadnexal infiltrate of lymphocytes and plasma cells. Special stains fail to show microorganisms.
Necrobiotic xanthogranuloma (NXG) is a rare, chronic, progressive, non-Langerhans histiocytosis that is strongly associated with hematologic malignant conditions. First described in 1980 by Kossard and Winkelmann, there have been approximately 100 cases reported . NXG presents most often in the fifth or sixth decade of life, with an equal gender predilection . Approximately 80 to 90 percent of patients have an underlying monoclonal gammopathy . The lesions are indurated, yellow, brown, or orange papules and nodules that slowly progress to large plaques. The most common and characteristic area of involvement is periorbital (>80%); although the lesions are typically asymptomatic, they can occasionally ulcerate.
NXG is progressive, locally destructive, and has the potential to affect multiple organ systems, which include the eye, spleen, muscles, lymph nodes, and central nervous system. Patients with extensive periorbital involvement can present with vision changes, diplopia, proptosis, episcleritis, keratitis, iritis, conjunctivitis, and corneal perforation [2, 4]. The diagnosis of NXG should prompt a thorough evaluation for hematologic and lymphoproliferative malignant conditions, which typically manifest approximately 2.4 years after development of the skin lesions . IgG kappa is the most frequent monoclonal gammopathy (MGUS) (65%), followed by IgG lambda (35%), and, much less commonly, IgA. Our patient had findings consistent with MGUS in a bone-marrow biopsy specimen, which is common in patients with a MGUS in the setting of NXG. When a gammopathy is present, the underlying hematologic condition is MGUS in one-half of the cases and myeloma in the other one-half . Because of reports of giant-cell myocarditis, an echocardiogram also is recommended as part of the evaluation for patients with NXG . NXG patients require long-term follow up inasmuch as the development of hematologic disorders can occur up to 11 years after the onset of skin lesions .
The pathophysiology of NXG has not been fully elucidated. One hypothesis is that the paraproteins function as autoantibodies that provoke fibroblast proliferation and the deposition of dermal macrophages . Others believe that the paraproteins bind to monocyte lipoprotein receptors and induce the formation of xanthomatous cells that are deposited in the skin, which induces a granulomatous, foreign-body response . While plausible, this hypothesis would not account for documented cases of NXG without an associated paraproteinemia. Still others believe that NXG has an infectious etiology, with reports of Borrelia species having been identified in skin biopsy specimens . The histopathologic diagnosis of NXG can be difficult inasmuch as there are no findings that are specific for NXG and many of the features are similar to those in necrobiosis diabeticorum lipoidica . Histopathologic features of NXG include intersecting bands of macrophages and foam cells in the dermis and subcutaneous tissue, extensive necrobiosis, Touton and foreign-body giant cells, and lymphoid follicles . The presence of cholesterol clefts in the areas of necrobiosis can be particularly useful in the differentiation of NXG from other conditions with granulomatous inflammation .
NXG is difficult to treat and the post-surgical recurrence rate is high. Although no modality has been shown to be consistently effective, therapeutic options include glucocorticoids (topical, intralesional, and/or systemic), alkylating agents (chlorambucil and cyclophosphamide), interferon alpha, antimetabolites, antibiotics, thalidomide, and plasmaphersis . One recent report described successful treatment of two patients with NXG using intravenous immunoglobulin (IVIG) . One of the patients with extensive involvement of the face was treated with a total of six rounds 0.5 mg/kg/day of IVIG for four consecutive days spaced at intervals of four to six weeks. After the sixth treatment, there was almost complete clinical resolution of the lesions and biopsy specimens from the areas of previous involvement showed complete resolution of the dermal infiltrates . Case reports of resolution of NXG lesions with four weeks of low-dose prednisone (0.5 mg/kg) also have been reported . It has been suggested that cases of NXG that are not associated with an underlying paraproteinemia may be more difficult to treat. One report described a case of isolated NXG that resolved after 47 treatments with psoralen and ultraviolet A (PUVA) photochemotherapy .
The role of cutaneous surgery for the treatment of NXG is limited to palliative intervention. Surgery is delayed as long as possible because of high recurrence rates (approximately 42%), with post-surgical lesions that are sometimes larger than the original ones . Treatment with CO2 laser may be an effective palliative alternative in patients who have failed medical therapy .
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