Necrobiotic xanthogranuloma

INTRODUCTION — Necrobiotic xanthogranuloma (NXG) is a form of non-Langerhans histiocytosis characterized by the development of red-brown, violaceous, or yellowish cutaneous papules and nodules that evolve to form infiltrated plaques. The periorbital skin is the most common site for NXG. Extracutaneous involvement of ocular, respiratory, cardiac, or other tissues may also occur in patients with NXG.

Most patients with NXG have an associated monoclonal gammopathy. Other hematologic disorders, including hematologic malignancies, also may occur in association with NXG.

The treatment of NXG is challenging and data on therapeutic options are limited, making the best approach to treatment unclear. Alkylating agents, such as chlorambucil, are commonly used treatments.

The clinical manifestations, diagnosis, and management of NXG will be reviewed here. Examples of other cutaneous disorders associated with internal malignancy are reviewed separately. (See "Cutaneous manifestations of internal malignancy".)

HISTORY — In 1980, Kossard and Winkelmann described eight patients with multiple violaceous, atrophic plaques and nodules on the face (particularly periorbital area), skin flexures, and trunk with associated paraproteinemia [1,2]. They named this condition necrobiotic xanthogranuloma based on the distinctive histologic finding of xanthogranulomas with zones of necrobiosis. (See 'Histopathology' below.)

EPIDEMIOLOGY — The incidence and prevalence of NXG are unknown. NXG typically occurs in adults. A cross-sectional study and systematic review that included 235 patients with NXG found an average age at presentation of 62 years [3]. In addition, although some individual reports have suggested an equal sex distribution in NXG, 63 percent of the 235 patients were female.

PATHOGENESIS — The pathogenesis of NXG is unclear. The association between NXG and paraproteinemias and the xanthomatous features of the disorder have contributed to several theories:

●NXG may represent a foreign-body giant cell reaction to the cutaneous and extracutaneous deposition of serum immunoglobulins complexed with lipids [4].

●NXG may result from an accelerated complement reaction leading to activation of monocytes and accumulation of lipoprotein-derived lipids in monocytes [5].

●NXG may be a result of impaired macrophage lipid homeostasis and an associated systemic inflammatory response. Patients with NXG may have a reduced capacity of high-density lipoprotein (HDL) to promote cholesterol efflux from macrophages leading to cholesterol accumulation [6]. High plasma levels of proinflammatory cytokines, including interleukin-15, have been observed [6].

CLINICAL MANIFESTATIONS — NXG may have both cutaneous and extracutaneous features.

Cutaneous — The typical cutaneous features of NXG are yellow-orange, reddish-brown, or violaceous indurated papules and nodules that gradually enlarge to form infiltrative plaques (picture 1A-B). The central aspect of larger plaques may become atrophic with prominent telangiectasia. The plaques are usually asymptomatic but are occasionally pruritic [7]. Scarring and ulceration occur in 40 to 50 percent of patients (picture 2) [8].

In most cases, more than one site is involved, including the trunk, face, arms, thighs, and lower legs [9,10]. The periorbital region is the most frequent site of involvement, occurring in approximately 60 to 80 percent of patients [3,9,10]. Periocular NXG often has a yellowish hue. In comparison to xanthelasmas, cholesterol-filled plaques that commonly occur on the eyelids, periocular NXG plaques are larger, more indurated, and more erythematous. Periorbital NXG may extend into the orbit, manifesting as soft tissue densities or diffuse orbital inflammation on computed tomography [3,9]. (See 'Ocular involvement' below.)

Other reported presentations of NXG include ulcerated plaques on the extremities and trunk [11-13] or a solitary subcutaneous nodule or plaque [14-17]. NXG has also been reported to occur on the genitalia [18] and within pre-existing scars [19-22].

Extracutaneous — Extracutaneous involvement of NXG can occur in the eye (most common site) and other locations. In rare cases, extracutaneous NXG occurs in the absence of skin disease [23].

Ocular involvement — Ocular involvement in NXG can mimic uveitis and scleritis, with conjunctival biopsy demonstrating necrobiotic xanthogranulomas [23,24]. Approximately one-half of the 48 patients with NXG in a retrospective study had ophthalmic complaints, including pain, burning, itching, blurred vision, diplopia, acute transient vision loss, and dry eyes [9]. Patients can also develop proptosis and limited extraocular mobility from orbital involvement [19].

Other sites — Involvement of internal organs or structures can occur in NXG. An analysis of 235 patients with NXG identified in a cross-sectional study and systematic review revealed patients with gastrointestinal tract, liver, heart, lung, lymphoreticular, parotid, brain, or muscle involvement [3]. The development of NXG at these sites was relatively infrequent, with involvement of each site occurring in fewer than 3 percent of patients.

ASSOCIATED DISORDERS — NXG occurs in association with monoclonal gammopathy in most, but not all, cases [9,15,25]. The overall proportion of patients with a monoclonal gammopathy is approximately 80 percent [3,7,9]. A review of 235 patients with NXG found that the most frequent monoclonal immunoglobulin isotype was immunoglobulin G (IgG; present in approximately 70 percent of patients), with IgG-kappa more common than IgG-lambda [3]. Immunoglobulin A (IgA) and immunoglobulin M (IgM) monoclonal gammopathies were much less common, occurring in only 1 and 2 percent of patients, respectively. Polyclonal gammopathies were detected in 3 percent of patients. Multiple myeloma was the most common associated malignancy, occurring in 14 percent of patients.

Other hematologic disorders that have been reported in association with NXG include B cell lymphoma, chronic lymphocytic leukemia [23], Waldenström macroglobulinemia [26], non-Hodgkin's lymphoma [27], lymphoplasmacytic lymphoma [28], and extramedullary plasmacytoma [29]. Hematologic disorders may precede or follow the development of cutaneous manifestations of NXG with intervals of up to several years or more between the two diagnoses [8]. A retrospective study of 17 patients seen at a tertiary care medical center found a mean time from the development of NXG to the development of a hematologic disorder of 2.4 years [8].

Other abnormalities have been reported in patients with NXG. Leukopenia may occur in one-third to one-half of patients [7,10]. In addition, a C4 deficiency, elevated cholesterol and triglycerides [7,10,30], cryoglobulinemia [9-11,31], and a C1-esterase inhibitor deficiency have been reported in patients with NXG [11,30]. The significance of the detection of Borrelia spirochetes with focus-floating microscopy in the skin biopsies of six patients with NXG is unclear [32].

HISTOPATHOLOGY — Characteristic histologic findings of NXG include (picture 3A-C):

●Palisading histiocytic xanthogranulomas and bands of necrobiosis in the middle dermis extending into the panniculus [9,33]

●Touton-giant cells and characteristic bizarre-appearing, large foreign-body giant cells within xanthogranulomas

Cholesterol clefts, lymphoid nodules (occasionally containing a germinal center), and plasma cells can also be seen. The plasma cells may be located perivascularly at the periphery of the lymphoid nodules or between dermal collagen fibers [33].

DIAGNOSIS — The diagnosis of NXG is made based upon consideration of the clinical and histologic findings.

Diagnostic criteria for NXG have been proposed but have not been validated [3]. The proposed diagnostic criteria require the presence of two major criteria and at least one minor criterion [3]:

●Major criteria:

•Cutaneous papules, plaques, and/or nodules, most often yellow or orange in color.

•Histopathologic features demonstrating palisading granulomas with lymphoplasmacytic infiltrate and zones of necrobiosis. Characteristic features that are variably present include cholesterol clefts and/or giant cells (Touton or foreign-body).

●Minor criteria:

•Paraproteinemia, most often IgG-kappa, plasma cell dyscrasia, and/or other associated lymphoproliferative disorders

•Periorbital distribution of cutaneous lesions

Clinical assessment — A full physical examination, including inspection of the skin, lymph nodes, and eyes, should be performed when NXG is suspected. Cutaneous findings that strongly suggest NXG are yellowish plaques with associated erythema in a periorbital location, particularly if central atrophy and telangiectasias are also present.

A complete review of systems should be obtained to evaluate for symptoms of extracutaneous involvement or underlying disease. In particular, the review of systems should include questions regarding ocular symptoms, unexplained weight loss, and lymphadenopathy.

Biopsy — A skin biopsy from an involved area is recommended to confirm NXG and is usually diagnostic. A punch biopsy at least 4 mm in diameter is typically adequate. The biopsy should demonstrate palisading histiocytic xanthogranulomas, bands of necrobiosis in the dermis that extend into the subcutaneous fat, Touton-giant cells, and bizarre-appearing foreign-body giant cells (picture 3A-C). (See 'Histopathology' above.)

FURTHER EVALUATION — Patients diagnosed with NXG should be evaluated for an associated underlying disorder and systemic involvement. Initial laboratory tests to obtain in all patients include:

●Complete blood count

●Complete metabolic panel

●Serum and urine electrophoresis and immunofixation

●Serum free light chain analysis

●Computed tomography (CT) of the chest, abdomen, and pelvis

Further testing should be based upon suspicion for specific underlying disorders based upon the review of systems and laboratory results. A bone marrow biopsy may be warranted if there is concern for myeloma or leukemia. (See "Diagnosis of monoclonal gammopathy of undetermined significance", section on 'Diagnosis' and "Clinical course and management of monoclonal gammopathy of undetermined significance" and "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis".)

Patients with periorbital NXG or ocular symptoms should be referred for ophthalmologic evaluation. CT or magnetic resonance imaging of the orbit may be needed to evaluate for ocular involvement if the patient has ocular complaints. Imaging of the body may be necessary if the physical examination, review of systems, or laboratory findings suggest systemic involvement.

DIFFERENTIAL DIAGNOSIS — The clinical features of NXG can overlap with a variety of disorders. Plane xanthomas and necrobiosis lipoidica are often in the differential diagnosis:

●Plane xanthomas – Plane xanthomas are cutaneous collections of lipid-laden macrophages that may occur independently or in association with hyperlipidemia, cholestasis, or monoclonal gammopathy. Plane xanthomas most commonly appear as yellow-orange, noninflamed plaques on sites such as the neck, trunk, flexural skin areas, or periorbital skin (picture 4). Xanthelasmas are plane xanthomas that occur on the eyelids (picture 5). The plaques of NXG tend to be larger and more erythematous, violaceous, indurated, or ulcerated than the homogenous yellowish plaques of plane xanthomas. (See "Cutaneous xanthomas".)

●Necrobiosis lipoidica – Necrobiosis lipoidica is a rare chronic granulomatous disease of the skin that often occurs in association with diabetes mellitus. Affected patients develop red-brown or violaceous papules or nodules that progress to form yellow-brown, atrophic, telangiectatic plaques that may ulcerate (picture 6). The anterior lower legs are the most common sites of involvement. Necrobiosis lipoidica may occur on the face and periorbitally [34], although this occurs much less frequently than in NXG. Biopsies of necrobiosis lipoidica reveal a palisaded and interstitial granulomatous dermatitis with necrobiosis of collagen. In NXG, the necrobiosis and granulomatous infiltrate are much more extensive, and characteristic bizarre foreign-body giant cells and Touton-giant cells are present [9]. Furthermore, the lymphoid follicles often seen in NXG are not a common finding in necrobiosis lipoidica and cholesterol clefts are much more common in NXG [8,9]. (See "Necrobiosis lipoidica", section on 'Histopathology' and "Necrobiosis lipoidica".)

Other disorders that may present with clinical features that overlap with NXG are sarcoidosis, juvenile xanthogranulomas, granuloma annulare, xanthoma disseminatum, and panniculitides.

TREATMENT — Treatment of NXG is generally indicated given the chronic and progressive course and the potential for disfigurement, scarring, and ulceration. Successful treatment typically manifests as reductions in plaque size or prominence and healing of ulcerations. Complete resolution of cutaneous manifestations is rare.

Approach to treatment — The treatment of NXG is challenging and the best approach to treatment is unclear. Randomized controlled trials are lacking and data on treatment efficacy are limited to retrospective studies, small case series, and case reports. In addition, responses to the various treatments are inconsistent.

Given the lack of data on the comparative efficacy of treatments, the selection of an initial treatment can be influenced by patient-specific factors such as associated underlying diseases and disease severity, as well as concern for the risks and contraindications of particular treatments. In patients with NXG associated with an underlying malignancy, treatment should be directed at the underlying malignancy. For other patients, alkylating chemotherapeutic agents, such as chlorambucil and melphalan, administered with or without systemic glucocorticoids, are most frequently cited in the literature as beneficial in the treatment of NXG and are considered appropriate first-line agents for this disease. For patients who cannot tolerate or fail to respond to an alkylating agent, limited data suggest that pulsed dexamethasone and intravenous immune globulin (IVIG) are reasonable second-line therapies.

First-line therapy — The alkylating agents chlorambucil and melphalan may be used as first-line therapy for NXG in patients without an underlying malignancy. First-line therapy for patients with an associated malignancy is treatment of the malignancy.

Alkylating agents — Retrospective studies and case reports suggest that chlorambucil can be of benefit for NXG. In general, chlorambucil is better tolerated than melphalan and is the preferred first-line treatment.

Examples of studies documenting the effects of chlorambucil on NXG include:

●In a review of 19 patients with NXG, 9 of 10 patients who were alive at the time of a follow-up study had received chlorambucil (2 to 4 mg per day) for various periods. Of the 9 patients, 3 reported that chlorambucil induced near-complete clearing of cutaneous NXG, 4 reported some improvement, 1 reported stable disease, and 1 did not note an impact of chlorambucil on the disease [9].

●In a retrospective study of 17 patients with NXG, 4 received chlorambucil with prednisone. Of these, 2 patients had an excellent response, and 2 patients failed to respond [8].

●In a retrospective study of 22 patients treated for NXG with multiple modalities, 3 patients treated with chlorambucil monotherapy improved [11].

Multiple case reports also document responses of NXG to chlorambucil as monotherapy or in combination with prednisone [10,31,35-37].

Chlorambucil is administered orally and is usually given for NXG at the relatively low dose of 2 to 4 mg per day. Potential adverse effects include gastrointestinal distress, hepatotoxicity, myelosuppression, central nervous system injury, pulmonary toxicity, amenorrhea, azoospermia, and secondary malignancy.

Melphalan is another alkylating agent that has been reported in retrospective studies and case reports to be effective for NXG when given as monotherapy or in combination with other agents [8,9,30,38,39]. Optimal dosing is unknown. Regimens associated with clinical improvement in case reports have included 10 mg of melphalan given with 60 mg of prednisolone for four consecutive days every three weeks for two cycles prior to skin grafting of NXG ulcers with additional cycles to maintain remission [39] and 10 mg (0.15 mg/kg) of melphalan given with allopurinol for five consecutive days every four weeks for three cycles with additional cycles as needed [30]. Melphalan failures are also documented [11,36,40]. Potential adverse effects of melphalan are gastrointestinal distress, myelosuppression, secondary malignancy, and hypersensitivity.

Oral cyclophosphamide (1 mg/kg per day) is an acceptable alternative alkylating agent based upon clinical experience. The duration of treatment is typically six months. Treatment beyond one year is not advised due to the risk of permanent myelosuppression and secondary myelodysplasia. Case reports also describe successful use of cyclophosphamide and dexamethasone pulsed therapy for NXG [41,42].

There are reports of improvement in the cutaneous manifestations of NXG but not the gammopathy [30,43], and vice-versa [40], during treatment with alkylating agents.

Second-line therapy — For patients with an underlying malignancy, treatment should be directed based upon treatment protocols for that malignancy. For patients with NXG and no underlying malignancy, a variety of second-line therapies have been examined. Several reports document efficacy of systemic glucocorticoids and IVIG for NXG, suggesting that these treatments may be reasonable second-line therapies. Choosing between the two approaches is largely based upon consideration of toxicity and reimbursement (particularly for IVIG).

Systemic glucocorticoids — Treatment with pulsed dexamethasone (32 mg for days 1 to 3, 16 mg on day 4, 8 mg on day 5, 4 mg on days 6 and 7) has been associated with improvement in NXG in individual patients [8,44,45]. In addition, treatment with prednisone was associated with healing of NXG ulcers in a patient given 60 mg of prednisone per day [13]. Prednisone also was associated with improvement of NXG in 3 of 11 patients in a retrospective study [11]. Side effects of systemic glucocorticoids are reviewed in detail separately. (See "Major adverse effects of systemic glucocorticoids".)

Intravenous immune globulin — Several case reports suggest that intravenous immune globulin (IVIG) can be beneficial for NXG [3,46-49]. In one multicenter, cross-sectional study that included nine patients treated with IVIG, all had a partial or complete response to treatment [3]. IVIG is typically administered in a cyclical manner with three- to four-week intervals between treatments. Optimal dosing for NXG is unknown. The cost of IVIG may be a limiting factor. Side effects of IVIG are reviewed in detail separately. (See "Intravenous immune globulin: Adverse effects".)

Other therapies — A few reports document benefit of other therapeutic interventions for NXG in small numbers of patients. These include thalidomide [8,50], autologous stem cell transplantation [8,51], lenalidomide [52,53], interferon alfa-2a [54], plasmapheresis [55], dapsone [56], antimalarials [3], psoralen plus ultraviolet A [57], topical nitrogen mustard [58], and topical glucosides of peony [59]. In addition, a patient with small lymphocytic lymphoma, Sjögren syndrome, and periocular NXG treated with fludarabine, cyclophosphamide, and rituximab experienced resolution of NXG and sicca symptoms [60]. Rituximab monotherapy demonstrated efficacy in one patient with bilateral orbital NXG and no underlying paraproteinemia [61]. Poor results from treatment with azathioprine, methotrexate, and systemic nitrogen mustard have occurred in individual patients [11].

Selection amongst the above agents is largely based upon consideration of toxicity and comorbidities. Lenalidomide (favored over thalidomide due to toxicity profile) is a reasonable option in NXG associated with monoclonal gammopathy, even if there is no evidence of overt multiple myeloma. Interferon is a reasonable option if a monoclonal gammopathy is not present or if there is a lack of response to lenalidomide given the activity of interferon in other histiocyte disorders and scattered case reports documenting efficacy in NXG. Dapsone and plasmapheresis are reserved for more refractory cases.

Procedural therapies have been employed for the treatment of NXG. Intralesional steroids have very little toxicity and are a reasonable approach for patients with a small number of easily accessible lesions. Both efficacy and inefficacy of intralesional corticosteroid therapy have been reported [3,8,11,62]. Surgical excision of NXG has been linked to improvement in NXG when used as monotherapy [63,64], following radiation [8], or preceding melphalan therapy [65]. However, the use of surgical excision for NXG is controversial because of concern for high risk of recurrence. Excision is generally not recommended unless the disease is exerting a mass effect that requires immediate debulking (particularly if prior systemic or local therapy has not been effective) [11,19].

Radiation has been used with success in some cases [8,11,66]. In addition, case reports document improvement in NXG after treatment with a carbon dioxide laser [28] and improvement in facial hyperpigmentation secondary to NXG after treatment with a Q-switched 650 nm wavelength laser [67].

PROGNOSIS AND FOLLOW-UP — Patients with NXG are at an increased risk for hematologic disorders. In a retrospective study of 48 patients with NXG, 13 percent developed a malignancy, including leukemia and lymphoma [9].

There are no standard recommendations regarding monitoring of these patients. Given the high association with a monoclonal gammopathy and the low but existing risk for progression of monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma, Waldenström macroglobulinemia, amyloidosis, or a malignant lymphoproliferative disorder [68], patients need to have regular follow-up, including a complete blood count, complete metabolic panel, and immunofixation electrophoresis, at least every six months. The course of the paraproteinemia often does not parallel the course of skin disease [11]; thus, flaring of skin disease is not a reliable indicator of worsening proteinemia.

No characteristics have been identified to predict which patients with NXG will develop a malignancy. Recommendations for monitoring patients with MGUS for progression to a malignant plasma cell dyscrasia or lymphoproliferative disorder are reviewed separately. (See "Clinical course and management of monoclonal gammopathy of undetermined significance".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology and pathogenesis – Necrobiotic xanthogranuloma is a rare non-Langerhans histiocytosis that often occurs in association with monoclonal gammopathy. NXG typically occurs in adults. The average age of onset is in the sixth decade. The pathogenesis is unclear. (See 'Epidemiology' above and 'Pathogenesis' above.)

●Clinical manifestations – NXG usually begins as yellow-orange, red-brown, or violaceous papules or nodules that evolve into infiltrated plaques (picture 1A-B). The plaques may exhibit central atrophy or telangiectasias. Ulceration and scarring are common. Extracutaneous involvement may occur in the respiratory tract, heart, or other tissues. (See 'Clinical manifestations' above.)

●Associated disorders – Most patients with NXG have a monoclonal gammopathy. Other hematologic disorders, including malignancies, may also occur in patients with NXG. Hematologic disorders may precede or follow the development of NXG. (See 'Associated disorders' above.)

●Diagnosis – The diagnosis of NXG is made by the recognition of consistent clinical and histologic findings. A skin biopsy characteristically demonstrates palisading histiocytic xanthogranulomas, bands of necrobiosis that extend to the subcutaneous fat, Touton-giant cells, and large, bizarre-appearing foreign-body giant cells. (See 'Histopathology' above.)

●Additional evaluation – The evaluation of patients with NXG should include a review of systems and laboratory studies to look for evidence of systemic involvement and underlying disease. Follow-up for the development of hematologic disorders is necessary for patients with NXG. (See 'Diagnosis' above and 'Further evaluation' above and 'Prognosis and follow-up' above.)

●Treatment – Data on the treatment of NXG are limited, preventing definitive guidelines for the best approach to treatment:

•Patients with associated malignancy – In patients with NXG associated with an underlying malignancy, treatment should be directed at the underlying malignancy.

•Patients without associated malignancy – For patients with NXG that is not associated with an underlying malignancy, we suggest treatment with chlorambucil or melphalan as first-line treatment (Grade 2C). We prefer chlorambucil because the drug is better tolerated than melphalan. Cyclophosphamide is an alternative alkylating agent. Patients who cannot receive an alkylating agent or fail to respond may benefit from systemic glucocorticoids, intravenous immune globulin, or other treatments. (See 'Treatment' above.)