Necrobiotic xanthogranuloma

Necrobiotic xanthogranuloma (NXG) is characterized by firm yellow plaques and nodules, often occurring in a periorbital distribution. The histopathology is distinct and shows an infiltrate composed of macrophages, foam cells, and other inflammatory cells as focal aggregates or intersecting bands in the dermis and subcutaneous tissue.1 There is extensive necrobiosis and many Touton and foreign body-type giant cells. Lymphoid follicles and cholesterol clefts are common.1 NXG is often accompanied by a monoclonal gammopathy of the immunoglobulin G-kappa (IgG-κ) type, and the treatment outcome is variable. Necrobiotic xanthogranuloma was first distinguished from normolipemic and hyperlipemic plane xanthomas by Kossard and Winkelmann2 in 1980, when they reported eight patients with periorbital xanthomatous plaques and nodules, all with distinctive xanthogranulomatous nodules and necrobiosis on skin biopsy. In their report, six patients who were evaluated for paraproteinemia showed an IgG monoclonal gammopathy, and the majority of patients also showed an elevated erythrocyte sedimentation rate (ESR) and leukopenia. Many patients showed abnormal bone marrow biopsies, including two with multiple myeloma. In the years since Kossard and Winkelmann's series, reports of NXG have been characterized by similar clinical, laboratory, and histopathologic findings. In 1992, Mehregan and Winkelmann3 published a review of the clinical findings in 48 cases of NXG – 16 from the world literature and 32 new cases evaluated at the Mayo Clinic – confirming the clinical, laboratory, and histopathologic features seen in Kossard and Winkelmann's cases. In particular, the majority of patients had an IgG-κ monoclonal gammopathy, and eight patients had multiple myeloma proven by bone marrow biopsy. In addition, the 1992 review found that 50% of patients reported ophthalmic complaints, not surprising given the periorbital location of most lesions, and emphasized the occurrence of systemic involvement in three cases from the world literature and one case from the Mayo Clinic. Chlorambucil was the most commonly used systemic treatment for NXG, often with good results. In 2000, Ugurlu et al.4 reviewed the long-term ocular and systemic involvement in 26 patients with NXG, also seen at the Mayo Clinic, some of whom were presumably included in Mehregan and Winkelmann's 1992 review.3 The most common ocular findings included periocular skin lesions, lesions in the anterior orbit, proptosis, blepharoptosis, and restricted ocular motility. Radiographic studies showed occasional involvement of the extraocular muscles and fat, and enlargement of the lacrimal glands. Again, the most common laboratory findings were elevated ESR and IgG-κ monoclonal gammopathy. In reviewing long-term outcomes, the authors found that the disease was usually slowly progressive and showed a variable response to chemotherapeutic agents. Skin lesions often recurred after surgical removal. Hematologic disorder or frank malignancy occurred before or after the onset of skin lesions. We sought to review systematically the published cases of NXG, with the goal of further characterizing the clinical, laboratory, bone marrow, and systemic findings associated with the disease. Our review was limited to those publications found in PubMed using the query "necrobiotic xanthogranuloma" with the limits "humans, English," and documenting adequate clinical, laboratory, and histopathologic description. In organizing our review, we divided the literature into the 48 cases described in Mehregan and Winkelmann's 1992 summary,3 and an additional 70 cases reported since the 1992 summary had been sent to press (specifically, from 1989 to present). Reports were carefully evaluated to ensure that duplicate cases were not included; in particular, the series published by Ugurlu et al.4 and summarized above was excluded from our review, as was a series published by Winkelmann et al.5 in 1998, as both reports included patients from the same clinic population as Mehregan and Winkelmann's 1992 series.3 Necrobiotic xanthogranuloma is most commonly characterized by firm, yellow or red–orange plaques or nodules (Fig. 1). Many cases report ulceration,6–18 telangiectases,8,9,11,17,19–27 erythematous and/or violaceous borders,6,9,11,14,15,28–31 and atrophy.11,21,22,24,25,27,32,33 Lesions are nearly always asymptomatic, but can be pruritic.6,25,31 Yellow, erythematous periorbital plaque with crusting Lesions of NXG can occur anywhere on the body. The vast majority of patients have periorbital lesions, particularly on the upper and/or lower eyelids, or elsewhere on the face. Most patients also have cutaneous lesions on the trunk or extremities. There are a number of reports of lesions occurring on the trunk or extremities in the absence of facial lesions.6–8,10,14,15,19,20,22–25,27,34–38 Fortson and Schroeter39 reported a case of NXG involving the lips and tongue, and Flann et al.6 reported perianal involvement. Reports have noted the occurrence of NXG within a scar,20 after trauma,7 or in an area of previous radiation.31 The histopathologic features of NXG are distinct. The epidermis may be atrophic10,21 or normal.9,40,41 NXG is always marked by granulomatous inflammation in the dermis that can extend into the subcutaneous tissue (Fig. 2). The granulomas are usually band-like,35 but can also have a stellate42 or nodular43 shape. The granulomas are composed of foamy histiocytes, lymphocytes, foreign body-type multinucleated giant cells, and Touton giant cells alternating with foci of collagen necrobiosis (Fig. 3). Cholesterol clefts are usually visualized within the necrobiotic foci, but can be rare or absent39,44 (Fig. 4). Nodular lymphoid aggregates are often reported in association with the granulomas.7,15,45 There have been two reports of NXG without necrobiosis.34,46 Special stains are not helpful in the diagnosis of NXG, although a recent report used focus-floating microscopy to identify rare spirochetes near the periphery of granulomas in NXG lesions.47 Extensive dermal lymphohistiocytic inflammation extending into the adipose tissue leading to a lobular panniculitis (hematoxylin and eosin ×25) Numerous typical and atypical multinucleated giant cells (hematoxylin and eosin, ×250) Lymphohistiocytic inflammation, multinucleated giant cells, and cholesterol clefts (hematoxylin and eosin, ×200) A comparison of the laboratory results of the 48 patients reported in 1992 with those of the 70 patients reported since 1992 is given in Table 1. The most frequently reported laboratory tests were ESR, white blood counts, lipids, and protein electrophoresis or immunofixation. Consistent with the 1992 data, approximately one-half of the patients had leukopenia and C4 deficiency; however, a greater percentage of patients reported since 1992 had elevated ESRs and cholesterol levels when compared with the earlier data. Serum protein electrophoresis (or immunofixation) was the most commonly reported laboratory test in both series; patients reported since 1992 continued to show a monoclonal gammopathy, usually of the IgG-κ type. Given the high frequency of monoclonal gammopathy in patients with NXG, bone marrow biopsies are often performed to evaluate for multiple myeloma. Bone marrow biopsies were performed for 37 of the 48 patients reported before 1992, with nine showing a plasmacytosis or plasmaproliferative disorder, eight showing multiple myeloma, two showing lymphoproliferative disorders, and 18 being nondiagnostic. Bone marrow biopsies were obtained for 33 of the 70 patients reported since 1992. These included eight with atypical or increased plasma cells17,23,28,30,38,40,48,49 (ranging from 2% atypical plasma cells to 15% plasma cells), two with multiple myeloma,44,50 two with known myeloproliferative or lymphoproliferative disease (chronic lymphocytic leukemia and non-Hodgkin's lymphoma occurring in a single patient,18 Hodgkin's lymphoma7), and 21 with nonspecific14,15,21,41,51 or normal bone marrow biopsies (Table 2). In addition, several patients carried myeloproliferative or lymphoproliferative diagnoses, although a bone marrow biopsy was not reported. These included a patient with non-Hodgkin's lymphoma,52 a patient with chronic lymphocytic leukemia,52 one with Hodgkin's lymphoma,27 two patients with monoclonal gammopathy of undetermined significance,42,52 a patient with lymphoplasmacytic lymphoma,29 one patient with "smoldering myeloma",34 and a patient with multiple myeloma.53 In 1992, Mehregan and Winkelmann3 included four cases of systemic involvement of NXG in their review. There have been 11 additional cases of systemic involvement reported since 1992, and an additional distant site identified in one of Mehregan and Winkelmann's patients3 (Table 3). The most common extracutaneous site is the respiratory tract,3,4,31,38,39,54,55 including epiglottis, larynx, pharynx, bronchus, and lung, reported in eight patients across both groups. The second most common site is the heart,3,31,38,56–58 reported in seven patients across both groups. Other sites include the spleen in one patient,58 and one patient each with involvement of the lacrimal gland,59 bone marrow,21 frontal lobe,43 and skeletal muscle.32 Approximately one-half of patients reported in 1992 had ophthalmic complaints, including burning, itching, or painful eyes. Less common complaints included diplopia and inflammation of numerous locations within the orbit. In cases published since 1992, ophthalmic complaints were not widely reported. The most common findings were diplopia in five patients,16,52,60 scleritis in four patients,16,41,61,62 decreased visual acuity in three patients,16,61,62 keratitis in two patients,16 and conjunctivitis in two patients.37,63 In addition, two patients had cutaneous NXG lesions that obstructed their vision,29,49 and three had radiographically identified masses in and around the globe that were assumed to be lesions of NXG.50,60,64 The largest series of ophthalmologic findings was published by Ugurlu et al.4 in 2000, discussed in the Introduction. This series was not included in the patients noted above because it is probable that Ugurlu et al.4 obtained their patients from the same Mayo Clinic population as the pooled 1992 patient data. Nonetheless, they reported that the most common ocular findings included periocular skin lesions, lesions in the anterior orbit, proptosis, blepharoptosis, and restricted ocular motility; eyelid lesions responded variably to medical treatment and tended to recur after surgical excision. The treatment for NXG is varied and often unsuccessful. The natural course of NXG tends to be chronic, with gradual progression of existing lesions, occurrence of new lesions, and occasional ulceration. In the patients reported by Mehregan and Winkelmann3 in 1992, the response was greatest to chlorambucil; the response to melphalan was more variable. Lesions did not improve with excision or intralesional corticosteroids. One patient improved with radiation therapy and another with plasmapheresis and hydroxychloroquine. In the patients reported since 1992, physical modalities, corticosteroids, alkylating agents, antimetabolites, antimicrobial, and other miscellaneous treatments have been used with inconsistent results. When lesions improve, the length of remission is often not reported. A summary of the treatment response in NXG is given in Table 4. Some of the treatment outcomes listed in Table 4 warrant further characterization. First, despite the observation by Ugurlu et al.4 that periorbital NXG tends to recur after excision, other cases have shown a mostly favorable response to excision,19,22,42,45,49,63 although the duration of remission is not quantified in most reports. Second, although there have been no documented responses to topical corticosteroids,14,18,46 several patients have responded to intralesional16,52 and systemic7,8,12,40,41 corticosteroids, but the lesions may recur.44 Third, alkylating agents are the most commonly reported treatment for NXG, administered alone or in combination with systemic steroids. Interestingly, alkylating agents were administered to NXG patients with and without accompanying plasma cell dyscrasias or frank multiple myeloma. Among the patients treated with cyclophosphamide, four patients improved13,16,42,64 and four did not.6,12,17 Among the patients treated with chlorambucil, six improved6,23,38,43,48,60 and three did not.6,12,42 Melphalan was used more than any other alkylating agent. Ten of 12 patients improved with melphalan,9,14,17,30,31,40,42,50,53 although one patient with multiple myeloma later showed recurrence of skin lesions,44 and the duration of the remaining responses is unknown. Finally, although it is not included in Table 4, chemotherapy for coexisting hematologic malignancies initially controlled two patients, but skin lesions later recurred,16,27 and a third case with non-Hodgkin's lymphoma did not respond to chemotherapy.18 Several reports have shown that the activity of cutaneous lesions does not necessarily follow the quantitative level of the monoclonal gammopathy, as the paraprotein can improve or resolve when treated with alkylating agents but the skin lesions persist,28 or vice versa.31,48 The pathogenesis of NXG is unknown. Bullock et al.65 first suggested that NXG occurs when serum Igs become complexed with lipid, deposit in the skin, and elicit a foreign body giant cell response. Matsuura et al.51 analyzed the function of serum monocytes in a patient with NXG and hypocholesterolemia, and found enhanced phagocytic ability and a large amount of lipid deposition within the monocytes. The authors hypothesized that monocytes become activated, perhaps by macrophage colony-stimulating factor or by C3b, to accumulate lipids, and that these lipid-laden monocytes are deposited in the skin, thereby eliciting a giant cell inflammatory reaction. This could explain why NXG patients are often normolipemic; however, with the exception of Matsuura et al.'s patient, there have been no reports of hypolipidemia in an NXG patient. It has been reported that the material within giant cells in the lesions of two patients with another non-Langerhans cell histiocytosis, multicentric reticulohistiocytosis, also occasionally associated with monoclonal gammopathy, stained for the light chain type of their M protein. Applying this finding to NXG, Langlois et al.53 suggested that the M protein may be the primary abnormality, and skin lesions may arise from secondary proliferation of macrophages bearing receptors for the Fc portion of their M protein. A recent report from German researchers identified rare spirochetal organisms by focus-floating microscopy in six of seven NXG lesions, including two patients with negative Borrelia serologies, suggesting that NXG may have an infectious etiology.47 Our review of 70 cases of NXG reported in the last 15 years confirms and augments what we have learned from the previous NXG literature. NXG usually occurs as firm, yellow or red–orange plaques or nodules on the upper and lower eyelids or elsewhere on the face. Many patients will have an elevated ESR, leukopenia, and an IgG-κ monoclonal gammopathy. In NXG patients without a known myeloproliferative disorder, bone marrow biopsy may reveal atypical or increased plasma cells and, very rarely, multiple myeloma. It is known that there is an age-related increase in monoclonal paraproteins; furthermore, the diagnosis of multiple myeloma is based on more than just a one-time serum paraprotein or bone marrow biopsy.66 Only three NXG patients of the 70 reported since 1992 had multiple myeloma by bone marrow biopsy or history; in the general population, 18% of all patients found to have a paraprotein have multiple myeloma, certainly a much higher percentage than in NXG patients with a paraprotein. The NXG literature inconsistently cites the concentration of the M protein; this may explain the low incidence of multiple myeloma in the NXG population, which has a high incidence of paraproteinemia. The relationship between the skin lesions of NXG and the associated monoclonal gammopathy is unclear; cutaneous lesions may be the result of the deposition of Igs or lipid–Ig complexes in the skin; however, Ig deposition cannot account for the lesions seen in patients without a monoclonal gammopathy. Furthermore, cutaneous NXG lesions often do not resolve when the monoclonal gammopathy responds to alkylating agents, arguing against a pathogenesis of Ig deposition. Perhaps the most significant observation originating from our review is that systemic involvement has been reported with increasing frequency in recent years, with a total of 15 documented cases. The most common extracutaneous site is the respiratory tract, specifically the larynx and lung, and the second most common is cardiac tissue. Visceral involvement may be symptomatic and found on biopsy of diseased tissue, or may be an incidental finding at autopsy. Unfortunately, there has been little progress in our understanding of the pathogenesis of NXG; it follows that universally effective treatments remain elusive. NXG tends to be chronic and slowly progressive; it is most commonly treated with excision, systemic steroids, or alkylating agents, all with varying responses. NXG most commonly occurs on which body site? Perioral skin. Periocular skin. Ears. Legs. Scalp. The histopathologic features of NXG include which of the following? Cholesterol clefts. Lymphoid aggregates. Stellate or band-like granulomas. (a) and (b) only. (a), (b), and (c). The commonly reported laboratory abnormalities among patients with NXG include which of the following? Monoclonal gammopathy. Elevated erythrocyte sedimentation rate. Elevated liver function tests. (a) and (b) only. All of the above. True or false? The monoclonal gammopathy associated with NXG is more likely to be of the IgG-κ type than of the IgG-λ type. True. False. Which of the following malignancies has been reported in patients with NXG? Esophageal cancer. Cutaneous T-cell lymphoma. Squamous cell carcinoma. Multiple myeloma. Anaplastic large-cell lymphoma. Systemic involvement of NXG has been reported in which of the following tissues? Cardiac. Lung. Larynx. Spleen. All of the above. True or false? Controlled trials have shown topical corticosteroids to be an effective treatment for NXG. True. False. True or false? Many patients with periocular NXG lesions also have ophthalmic complaints. True. False. Which of the following statements regarding the course and treatment of NXG is false? Lesions tend to progress gradually. Surgical excision, systemic steroids, and alkylating agents are commonly used. The monoclonal gammopathy always resolves when the skin lesions of NXG improve. Topical corticosteroids have not been reported to be effective. Lesions may ulcerate. Which of the following theories has been proposed as the pathogenesis of NXG? Serum immunoglobulins become complexed with lipid, deposit in the skin, and elicit a foreign body reaction. Infection with Borrelia. Activated monocytes accumulate lipid and deposit in the skin, eliciting a foreign body reaction. All of the above. (b). (e). (d). (a). (d). (e). (b). (a). (c). (d).