Introduction
Necrobiotic xanthogranuloma (NXG) is a rare CD68-positive, CD1a-negative non-Langerhans cell histiocytosis presenting most commonly as yellow to red-brown indurated, atrophic papules, plaques and nodules with prominent telangiectasias. 1 The periorbital area is involved in 80% to 85% of cases, although lesions can be distributed over the face, trunk, and extremities. 2 Neither the incidence nor prevalence of NXG are known, but a multicenter cross-sectional study including 235 patients with NXG reported the average age of onset to be 62 years. 3 Classically, NXG is associated with paraproteinemia secondary to plasma cell dyscrasias, with immunoglobulin G (IgG) kappa being the most prevalent. 3 We present a patient with NXG in the setting of an initial monoclonal gammopathy of undetermined significance (MGUS), who later developed increasing painful ulceration of skin lesions prompting evaluation for progression of his MGUS to smoldering multiple myeloma. Ultimately, ulcerations healed only after treatment of his myeloma.
Case
A 72-year-old male with a history of large granular lymphocytic (LGL) leukemia, being observed without treatment, presented for evaluation of nonhealing wounds over the abdomen, first originating within scars from abdominal surgery 4 years prior. He had received oral antibiotics and wound care without any significant improvement. On physical exam, there were 2-8 centimeter orange-red plaques with overlying telangiectasias and inflammatory borders ( Fig 1 , A ).
There were also red-brown nodules over his extremities and face (sparing the periorbital area). Dermatopathology obtained from punch biopsies of affected skin demonstrated dermal lymphohistiocytic and granulomatous inflammation with multinucleated giant cells, collagen degeneration, and necrobiotic changes, consistent with NXG. Additional stains were negative for microorganisms. Complete blood count was notable only for leukopenia (2.1 K/mcL).
Serum protein electrophoresis panel (SPEP) with immunofixation revealed a monoclonal gammopathy with an IgG lambda paraprotein. A subsequent bone marrow biopsy revealed CD138(+) plasma cells with lambda light chain restriction accounting for 5% of the marrow population, consistent with MGUS. Involvement of his LGL leukemia was not appreciated. Urine protein electrophoresis was unremarkable. He was started on topical clobetasol ointment and intravenous immunoglobulin (IVIg) every 4 weeks. Based on multidisciplinary discussions with his oncologist, his large granular lymphocytic (LGL) was also treated with cyclophosphamide in the event it could be contributing.
Routine clinical and myeloma laboratory monitoring remained stable over 2 years, however the patient then developed increasing painful ulceration of prior plaques. Exam was significant for enlargement of prior plaques as well as several new orange-red indurated plaques with central ulceration and overlying crust ( Fig 1 , B ). Yellow and plum-colored papules and nodules, some with telangiectasias, were appreciated over the face, back, and extremities. Biopsy was obtained from a nodule on the back and was again consistent with NXG ( Fig 2 , A-C ).
The significant clinical progression of his NXG raised concern his MGUS had progressed to multiple myeloma. Monoclonal gammopathy with IgG lambda paraprotein (2381 mg/dL) were found on repeat SPEP, and a bone marrow biopsy demonstrated an increased plasma cell population (10% of marrow cells) with excess lambda light chain expression. These findings were consistent with smoldering multiple myeloma. The patient continued IVIg and began lenalidomide, ixazomib, and dexamethasone directed at his myeloma. Four months later, IgG decreased to 1814 mg/dL, and there was significant improvement of his skin lesions, which now consisted of orange-red atrophic plaques without ulceration or inflammation ( Fig 1 , C ).
Discussion
We report a novel case of a patient with NXG associated initially with MGUS, who 2 years later developed increasing painful ulceration of skin lesions coinciding with MGUS transitioning to smoldering multiple myeloma. Ultimately, his painful ulcerations only healed after initiating myeloma treatment.
While the exact pathogenesis of NXG is not known, there are multiple theories: a foreign-body giant cell reaction secondary to deposition of serum immunoglobulins complexed with lipids, 4 complement reaction promoting monocyte activation, 5 or a systemic inflammatory response with impaired macrophage lipid homeostasis. 6 Of patients with NXG, 67% to 84% have a MGUS. 7 , 8 IgG, with IgG-kappa more frequently than IgG-lambda, is the most common isotype. 3 Approximately, 14% of NXG patients have multiple myeloma. 3 In one study of 235 patients with NXG, there were only 3 patients with nonmyeloid hematologic malignancies, accounting for less than 1% of cases. 3 We had low suspicion the patient’s LGL was related to his NXG, given absence of features of LGL on bone marrow biopsy at the time of skin lesion progression and lack of response of his NXG to LGL monotherapy. However, the cyclophosphamide used to treat the patient’s LGL may well have delayed progression of his MGUS. 9
NXG has the potential for significant morbidity and cosmetic disfigurement and is generally a cutaneous sign of underlying systemic disease. Additionally, MGUS in the setting of NXG is a monoclonal gammopathy of cutaneous significance and may warrant treatment to prevent disfigurement or pain from skin lesions; destruction of the end organ of skin is of clinical significance. The diagnostic criteria of multiple myeloma includes clonal bone marrow plasma cells ≥ 10% plus the presence of related organ or tissue impairment, classically involving anemia, hypercalcemia, renal insufficiency, or bone lesions (“CRAB”). 10 Non-CRAB end-organ damage, however, is currently viewed as both nonspecific and nondiagnostic. 10 Whether or not destruction of the skin should be considered to fulfill the diagnostic criterion of organ or tissue impairment, treatment of myeloma is still warranted.
Although there are limited data comparing treatment efficacy for NXG, when an underlying malignancy is present, management of the cancer is primary. Further research is needed to determine whether targeting MGUS itself in the setting of NXG is more efficacious than other commonly used treatments in the absence of malignancy, such as IVIg, antimalarials, intralesional triamcinolone, surgery, or chemotherapy. 3
MGUS in the setting of ulcerating or otherwise progressive NXG should prompt evaluation for progression to a malignant plasma cell dyscrasia. Dermatologists can play a vital role in facilitating the work-up of cutaneous findings that may herald an underlying or progressive systemic disease. Ultimately, the ability to promptly diagnose and appropriately treat an associated underlying malignancy may be paramount for maximizing patient quality of life and cancer outcomes.
Conflicts of interest
The authors declare no conflicts of interest with respect to the research, authorship, and/or publication of this article. Nicole R. LeBoeuf is a consultant and has received honoraria from Bayer, Seattle Genetics, Sanofi, Silverback, Fortress Biotech, and Synox Therapeutics outside the scope of the submitted work.
Footnotes
Funding sources: None.
Patient consent: Consent for the publication of all patient photographs and medical information was provided by the authors at the time of article submission to the journal stating that all patients gave consent for their photographs and medical information to be published in print and online and with the understanding that this information may be publicly available.
IRB approval status: This study was approved by the Mass General Brigham IRB.
References
1. Wood A.J., Wagner M.V., Abbott J.J., Gibson L.E. Necrobiotic xanthogranuloma: a review of 17 cases with emphasis on clinical and pathologic correlation. Arch Dermatol. 2009;145(3):279–284. doi: 10.1001/archdermatol.2008.583.
2. Fernandez-Herrera J., Pedraz J. Necrobiotic xanthogranuloma. Semin Cutan Med Surg. 2007;26(2):108–113. doi: 10.1016/j.sder.2007.02.008.
3. Nelson C.A., Zhong C.S., Hashemi D.A., et al. A multicenter cross-sectional study and Systematic review of necrobiotic xanthogranuloma with proposed diagnostic criteria. JAMA Dermatol. 2020;156(3):270–279. doi: 10.1001/jamadermatol.2019.4221.
4. Bullock J.D., Bartley G.B., Campbell R.J., Yanes B., Connelly P.J., Funkhouser J.W. Necrobiotic xanthogranuloma with paraproteinemia. Case report and a pathogenetic theory. Ophthalmology. 1986;93(9):1233–1236. doi: 10.1016/s0161-6420(86)33605-4.
5. 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. doi: 10.1016/s0021-9150(98)00260-3.
6. Szalat R., Pirault J., Fermand J.P., et al. Physiopathology of necrobiotic xanthogranuloma with monoclonal gammopathy. J Intern Med. 2014;276(3):269–284. doi: 10.1111/joim.12195.
7. Mehregan D.A., Winkelmann R.K. Necrobiotic xanthogranuloma. Arch Dermatol. 1992;128(1):94–100.
8. Hilal T., DiCaudo D.J., Connolly S.M., Reeder C.B. Necrobiotic xanthogranuloma: a 30-year single-center experience. Ann Hematol. 2018;97(8):1471–1479. doi: 10.1007/s00277-018-3301-1.
9. Notermans N.C., Lokhorst H.M., Franssen H., et al. Intermittent cyclophosphamide and prednisone treatment of polyneuropathy associated with monoclonal gammopathy of undetermined significance. Neurology. 1996;47(5):1227–1233. doi: 10.1212/wnl.47.5.1227.
10. Laubach J.P. UpToDate; 2023. Multiple Myeloma: Clinical Features, Laboratory Manifestations, and Diagnosis.