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Necrobiotic xanthogranuloma-rapid progression under treatment with melphalan

European Journal of Dermatology. Volume 15, Numéro 5, 363-5, September-October 2005, Therapy

Summary

Auteur(s) : Mirjana Ziemer, Ulrich Wedding, Christina S Sander, Peter Elsner , Department of Dermatology, Friedrich-Schiller-University of Jena, Erfurter Strasse 35, 07743 Jena GermanyFax: (+49) 3641 937423., Department of Internal Medicine, Haematology and Oncology, Friedrich-Schiller-University of Jena, Germany, Dermatology Department, The Churchill Hospital, Oxford, UK.

Illustrations

ARTICLE

Auteur(s) : Mirjana Ziemer¹, Ulrich Wedding², Christina S Sander³, Peter Elsner¹

¹Department of Dermatology, Friedrich-Schiller-University of Jena, Erfurter Strasse 35, 07743 Jena GermanyFax: (+49) 3641 937423.
²Department of Internal Medicine, Haematology and Oncology, Friedrich-Schiller-University of Jena, Germany
³Dermatology Department, The Churchill Hospital, Oxford, UK

accepté le 13 Avril 2005

Necrobiotic xanthogranuloma (NXG) is a systemic, locally destructive disease, first described by Kossard and Winkelmann in 1980 [1]. The indurated yellow-red plaques or nodules, involving the face and, less frequently, the trunk and extremities, are histologically composed of highly characteristic xanthogranulomas with giant cells of the Touton and foreign body type and degenerate collagen accompanied by a lymphocytic and plasma cell infiltrate. NXG is usually associated with paraproteinaemia, less often bone marrow examination shows frank multiple myeloma [2]. Although the causative role of the paraproteinaemia is discussed, the pathogenesis of this disease remains unknown. No first-line treatment has been established. The patient’s prognosis depends on the degree of extracutaneous involvement and the presence of visceral malignancies [2, 3].

Case report

We report the case of a now 65-year-old woman presenting with a 28-year history of multiple indurated, yellow-red plaques initially involving her left arm and back. Besides the slowly progressive lesions on her trunk and extremities, she also developed facial plaques. Her condition was initially misdiagnosed as systemic scleroderma. Later biopsy specimens were interpreted to show granulomatosis disciformis chronica et progressiva Miescher-Leder or cutaneous sarcoidosis. In the period from 1994 to 2000 the patient was treated with clofazimine, prednisolone, dapsone, and minocycline without any therapeutical effect. Bath-PUVA was also of no benefit. In 1994 an associated monoclonal gammopathy IgG kappa of undetermined significance was observed for the first time but only after repeated cutaneous biopsy in December 2002, was the diagnosis of NXG established. At this time, clinical examination revealed multiple, extensive, sharply demarcated, yellow to red plaques with smooth surface and elevated erythematous margins on the trunk, thighs, neck and face (( figure 1 )A). Histologically, distinctive zones of degenerated collagen with intervening granulomatous foci composed mainly of foamy histiocytes and multinucleated giant cells in the superficial and deep dermis and septa of the subcutis were present (( figure 2 )A and B). Lymphocytic infiltrates with plasma cells were found within and at the periphery of the granulomatous foci. However, cholesterol clefts were not seen. Immunoperoxidase stains demonstrated that most histiocytes were not Langerhans cells (CD1a negative, CD74 positive). Gram, Gomeri-methenamin silver and acid-fast stains were negative. Monoclonal immune globulins were not identified in tissue specimen, using immunohistochemistry. Serum immunofixation revealed monoclonal IgG kappa bands. A monoclonal protein in the urine was not found. Furthermore, laboratory investigation had shown anaemia (3.7/nl) and elevated C-reactive protein (29.5 mg/l). The following parameters were within the normal range: lipids, glucose, renal and liver function tests, and antinuclear antibodies. The findings of chest computer-tomography scan and sonography of the abdomen were normal. A bone marrow biopsy revealed an increase of plasma cells (15%) but without evidence of plasmocytoma. Due to the extensive skin involvement and the supposed causative significance of the paraprotein, treatment of the NXG was started with melphalan (0.25 mg/kg) and prednisolone (50 mg) over 4 days every 4 weeks, a standard regimen for the treatment of multiple myeloma. The treatment was continued over 4 courses within 5 months. Under the therapy we observed a rapid enlargement of the cutaneous plaques (( figure 1B )). However, as demonstrated in table 1( Table 1 ), IgG kappa light chains and the total amount of gamma globulins decreased.

Table 1 Levels of IgG kappa light chains and gamma globulins in the course of treatment with melphalan and prednisolone

Date	Gamma globulin – serum [%]	IgG – serum [g/l]	Kappa light chains – serum [g/l]	Kappa light chains – urine [g/l]	Therapy
03.02.03	17.2%	11.7	12.4	< 0.018	1. Course 04/03
					2. Course 05/03
23.06.03	13.6%	7.5	9.5	-	3. Course 06/03
08.08.03	16.2%	7.9	8.6	< 0.018	4. Course 08/03
18.09.03	11.1%	6.8	7.5	< 0.018

Discussion

NXG is a rare disease with only about 80 reported cases so far. Although regarded as a dermatosis occurring exclusively in association with paraproteinaemia, there are cases without or late developing monoclonal gammopathy [2, 4]. Patients with NXG may develop systemic involvement [2, 5, 6]. Pulmonary and myocardial lesions of NXG, as well as xanthogranulomas of the spleen or giant cell myocarditis have been described [3, 7]. The mechanism for the formation of xanthoma in NXG has not yet been clarified. It is suggested that paraproteins have the functional features of a lipoprotein, which may bind to the lipoprotein receptors of histiocytes, thereby inducing xanthoma formation [8]. The phagocytotic ability of monocytes was shown to be enhanced in a patient with NXG [9]. Furthermore, it is possible that the deposition of immunoglobulin/lipid complexes might lead to a xanthogranulomatous reaction [10]. Diverse treatment concepts have been attempted, none of which is guaranteed to be curative [5]. The use of antiblastic, cytotoxic agents associated with steroids recommended for multiple myeloma, and certain alkylating agents (chlorambucil, melphalan and cyclophosphamide) have been used in cases of necrobiotic xanthogranuloma with paraproteinaemia [7, 8, 11, 12]. Other treatments such as plasmapheresis or interferon α are reported, although NXG can be resistant [13, 14] (table 2( Table 2 )).

In our patient the late occurrence of the paraproteinaemia in the course of NXG suggest that the paraproteinaemia may rather be an attendant symptom of NXG than the originating cause. The rapid and distinct progression of the xanthogranulomatous plaques during therapy with melphalan and prednisolone despite lowering of the serum levels of monoclonal Ig supports this thesis. The therapeutical concepts that have been proposed so far, in most instances concentrated on treating the paraproteinaemia, should be critically revised.
Table 2 Therapeutic options for necrobiotic xanthogranuloma

Therapeutic agents	Effect on skin lesions	Effect on paraproteinaemia
Antiblastic, cytotoxic drugs [15, 11]
– Chlorambucil (most frequent among these)	From total clearing of lesions to some improvement or halted disease process	Often unmodified
– Melphalan
– Cyclophosphamide
Systemic corticosteroids [1, 9]
– Prednisolone	Not effective alone	Not effective alone
– Dexamethasone (high-dose oral)	Response	No response
Serial plasmapheresis [13]	Lesions not resolved, but ulceration improved	Lowered
Interferons
– Interferon alpha [14, 16]	Remission	Remission

References

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11 Machado S, Alves R, Lima M, Leal I, Massa A. Cutaneous necrobiotic xanthogranuloma (NXG) – successfully treated with low dose chlorambucil. Eur J Dermatol 2001; 11: 458-62.

12 Finan MC, Winkelmann RK. Histopathology of necrobiotic xanthogranuloma with paraproteinemia. J Cutan Pathol 1987; 14: 92-9.

13 Finelli LG, Ratz JL. Plasmapheresis, a treatment modality for necrobiotic xanthogranuloma. J Am Acad Dermatol 1987; 17: 351-4.

14 Venencie PY, Le Bras P, Toan ND, Tchernia G, Delfraissy JF. Recombinant interferon alfa-2b treatment of necrobiotic xanthogranuloma with paraproteinemia. J Am Acad Dermatol 1995; 32: 666-7.

15 Finan MC, Winkelmann RK. Necrobiotic xanthogranuloma with paraproteinemia. A review of 22 cases. Medicine (Baltimore) 1986; 65: 376-88.

16 Georgiou S, Monastirli A, Kapranos N, Pasmatzi E, Sakkis T, Tsambaos D. Interferon alpha-2a monotherapy for necrobiotic xanthogranuloma. Acta Derm Venereol 1999; 79: 484-5.