A Multicenter Cross-Sectional Study and Systematic Review of Necrobiotic Xanthogranuloma With Proposed Diagnostic Criteria | Dermatology | JAMA Dermatology | JAMA Network
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Figure.  Flowchart of Selected Studies for the Systematic Review
Flowchart of Selected Studies for the Systematic Review
Table 1.  Demographics and Comorbidities of Necrobiotic Xanthogranuloma
Demographics and Comorbidities of Necrobiotic Xanthogranuloma
Table 2.  Clinical Features of Necrobiotic Xanthogranulomaa
Clinical Features of Necrobiotic Xanthogranulomaa
Table 3.  Treatment Response for Necrobiotic Xanthogranuloma in the Multicenter Cohort
Treatment Response for Necrobiotic Xanthogranuloma in the Multicenter Cohort
1.
Kossard  S, Winkelmann  RK.  Necrobiotic xanthogranuloma.  Australas J Dermatol. 1980;21(2):85-88. doi:10.1111/j.1440-0960.1980.tb00148.xPubMedGoogle ScholarCrossref
2.
Lipsker  D.  Monoclonal gammopathy of cutaneous significance: review of a relevant concept.  J Eur Acad Dermatol Venereol. 2017;31(1):45-52. doi:10.1111/jdv.13847PubMedGoogle ScholarCrossref
3.
Hunter  L, Burry  AF.  Necrobiotic xanthogranuloma: a systemic disease with paraproteinemia.  Pathology. 1985;17(3):533-536. doi:10.3109/00313028509105517PubMedGoogle ScholarCrossref
4.
Winkelmann  RK, Litzow  MR, Umbert  IJ, Lie  JT.  Giant cell granulomatous pulmonary and myocardial lesions in necrobiotic xanthogranuloma with paraproteinemia.  Mayo Clin Proc. 1997;72(11):1028-1033. doi:10.4065/72.11.1028PubMedGoogle ScholarCrossref
5.
Ugurlu  S, Bartley  GB, Gibson  LE.  Necrobiotic xanthogranuloma: long-term outcome of ocular and systemic involvement.  Am J Ophthalmol. 2000;129(5):651-657. doi:10.1016/S0002-9394(99)00469-9PubMedGoogle ScholarCrossref
6.
Bolognia  JL, Schaffer  JV, Cerroni  L.  Dermatology. 4th ed. Philadelphia: Elsevier Saunders; 2018.
7.
Szalat  R, Arnulf  B, Karlin  L,  et al.  Pathogenesis and treatment of xanthomatosis associated with monoclonal gammopathy.  Blood. 2011;118(14):3777-3784. doi:10.1182/blood-2011-05-356907PubMedGoogle ScholarCrossref
8.
Szalat  R, Pirault  J, Fermand  JP,  et al.  Physiopathology of necrobiotic xanthogranuloma with monoclonal gammopathy.  J Intern Med. 2014;276(3):269-284. doi:10.1111/joim.12195PubMedGoogle ScholarCrossref
9.
Wood  AJ, Wagner  MV, Abbott  JJ, Gibson  LE.  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.2008.583PubMedGoogle ScholarCrossref
10.
Sfeir  JG, Zogala  RJ, Popii  VB.  Hypercalcemia in necrobiotic xanthogranuloma: first reported case and insight into treatment.  J Bone Miner Res. 2017;32(4):784-787. doi:10.1002/jbmr.3047PubMedGoogle ScholarCrossref
11.
Al-Bermani  A, Figueiredo  F, Speight  EL, Jackson  GH, Pandit  R.  Necrobiotic xanthogranuloma masquerading as posterior scleritis.  Eye (Lond). 2009;23(1):239-240. doi:10.1038/eye.2008.37PubMedGoogle ScholarCrossref
12.
Al-Niaimi  FA, Dawn  G, Cox  NH.  Necrobiotic xanthogranuloma without paraproteinaemia: marked improvement with psoralen ultraviolet A treatment.  Clin Exp Dermatol. 2010;35(3):275-277. doi:10.1111/j.1365-2230.2009.03447.xPubMedGoogle ScholarCrossref
13.
AlGain  M, Szalat  R, Vignon-Pennamen  MD,  et al.  A rare case of disseminated skin and mucosal necrobiotic xanthogranuloma and xanthoma.  J Eur Acad Dermatol Venereol. 2017;31(1):e3-e5. doi:10.1111/jdv.13577PubMedGoogle ScholarCrossref
14.
Ali  FR, Green  R, Chularojanamontri  L, Young  HS, Motta  L.  Recurrent posterior scleritis and a ‘sebaceous cyst’: Extrafacial necrobiotic xanthogranuloma.  Br J Dermatol. 2012;167:18-19.Google Scholar
15.
Amer  R, Pe’er  J, Pappo  O, Dotan  S.  Necrobiotic xanthogranuloma associated with choroidal infiltration and syncytial giant cell hepatitis.  J Neuroophthalmol. 2005;25(3):189-192. doi:10.1097/01.wno.0000177299.44845.65PubMedGoogle ScholarCrossref
16.
Bain  EE  III, Meehan  SA, Hale  EK.  Solitary necrobiotic xanthogranuloma of an upper extremity in association with multiple myeloma.  J Drugs Dermatol. 2014;13(5):598-600.PubMedGoogle Scholar
17.
Balagula  Y, Straus  DJ, Pulitzer  MP, Lacouture  ME.  Necrobiotic xanthogranuloma associated with immunoglobulin m paraproteinemia in a patient with Waldenström macroglobulinemia.  J Clin Oncol. 2011;29(11):e305-e307. doi:10.1200/JCO.2010.32.4921PubMedGoogle ScholarCrossref
18.
Barzilai  A, Trau  H, Shpiro  D, Yorav  S.  Necrobiotic xanthogranuloma with paraproteinemia.  Cutis. 1996;57(5):320-322.PubMedGoogle Scholar
19.
Betts  CM, Pasquinelli  G, Costa  AM, Fanti  PA, Misciali  C, Varotti  C.  Necrobiotic xanthogranuloma without periorbital involvement: an ultrastructural investigation.  Ultrastruct Pathol. 2001;25(6):437-444. doi:10.1080/019131201753343476PubMedGoogle ScholarCrossref
20.
Bhari  N, Chiramel  MJ, Vedi  KK,  et al.  Necrobiotic xanthogranuloma with multiple myeloma.  Clin Exp Dermatol. 2015;40(7):811-814. doi:10.1111/ced.12620PubMedGoogle ScholarCrossref
21.
Bortolani  A, Barisoni  D, Bontempini  L.  Necrobiotic xanthogranuloma of the eyelids with paraproteinemia.  Eur J Plast Surg. 1999;22(1):36-39. doi:10.1007/s002380050141Google ScholarCrossref
22.
Bullock  JD, Bartley  GB, Campbell  RJ, Yanes  B, Connelly  PJ, Funkhouser  JW.  Necrobiotic xanthogranuloma with paraproteinemia: case report and a pathogenetic theory.  Trans Am Ophthalmol Soc. 1986;84:342-354.PubMedGoogle Scholar
23.
Burdick  AE, Sanchez  J, Elgart  GW.  Necrobiotic xanthogranuloma associated with a benign monoclonal gammopathy.  Cutis. 2003;72(1):47-50.PubMedGoogle Scholar
24.
Butterfield  JH, Bartley  GB.  Atypical periorbital xanthogranulomas associated with systemic benign lymphoepithelial lesions.  Ophthalmic Plast Reconstr Surg. 1994;10(4):287-292. doi:10.1097/00002341-199412000-00014PubMedGoogle ScholarCrossref
25.
Carabelli  A, Cecca  E, Crovetti  G,  et al.  IgG lambda multiple myeloma and diffuse necrobiotic xanthogranuloma association: a case report.  Eur J Dermatol. 1997;7(7):519-521.Google Scholar
26.
Chandra  S, Finklestein  E, Gill  D.  Necrobiotic xanthogranuloma occurring within linear morphoea.  Australas J Dermatol. 2002;43(1):52-54. doi:10.1046/j.1440-0960.2002.00553.xPubMedGoogle ScholarCrossref
27.
Chang  SE, Lee  WS, Lee  MW,  et al.  A case of necrobiotic xanthogranuloma without paraproteinemia presenting as a solitary tumor on the thigh.  Int J Dermatol. 2003;42(6):470-472. doi:10.1046/j.1365-4362.2003.01716_1.xPubMedGoogle ScholarCrossref
28.
Char  DH, LeBoit  PE, Ljung  BM, Wara  W.  Radiation therapy for ocular necrobiotic xanthogranuloma.  Arch Ophthalmol. 1987;105(2):174-175. doi:10.1001/archopht.1987.01060020028014PubMedGoogle ScholarCrossref
29.
Chave  TA, Chowdhury  MM, Holt  PJ.  Recalcitrant necrobiotic xanthogranuloma responding to pulsed high-dose oral dexamethasone plus maintenance therapy with oral prednisolone.  Br J Dermatol. 2001;144(1):158-161. doi:10.1046/j.1365-2133.2001.03967.xPubMedGoogle ScholarCrossref
30.
Chave  TA, Hutchinson  PE.  Necrobiotic xanthogranuloma with two monoclonal paraproteins and no periorbital involvement at presentation.  Clin Exp Dermatol. 2001;26(6):493-496. doi:10.1046/j.1365-2230.2001.00873.xPubMedGoogle ScholarCrossref
31.
Chen  KY, Leslie  W, Mahon  B, Venugopal  P.  A patient with necrobiotic xanthogranuloma presenting with an anterior mediastinal mass, plasma cell dyscrasia, and a lymphoproliferative disorder.  Clin Adv Hematol Oncol. 2011;9(9):696-700.PubMedGoogle Scholar
32.
Codère  F, Lee  RD, Anderson  RL.  Necrobiotic xanthogranuloma of the eyelid.  Arch Ophthalmol. 1983;101(1):60-63. doi:10.1001/archopht.1983.01040010062009PubMedGoogle ScholarCrossref
33.
Cornblath  WT, Dotan  SA, Trobe  JD, Headington  JT.  Varied clinical spectrum of necrobiotic xanthogranuloma.  Ophthalmology. 1992;99(1):103-107. doi:10.1016/S0161-6420(92)32031-7PubMedGoogle ScholarCrossref
34.
Criado  PR, Vasconcellos  C, Pegas  JR,  et al.  Necrobiotic xanthogranuloma with lambda paraproteinemia: case report of successful treatment with melphalan and prednisone.  J Dermatolog Treat. 2002;13(2):87-89. doi:10.1080/095466302317584458PubMedGoogle ScholarCrossref
35.
Criton  S, Asokan  PU, Pailey  S, Kuttappan  SS, Rodriguez  FP; Remani.  Necrobiotic xanthogranuloma with paraproteinaemia.  Indian J Dermatol Venereol Leprol. 1996;62(6):383-385.PubMedGoogle Scholar
36.
Dabiri  S, Morales  A, Ma  L,  et al.  The frequency of dual TCR-PCR clonality in granulomatous disorders.  J Cutan Pathol. 2011;38(9):704-709. doi:10.1111/j.1600-0560.2011.01727.xPubMedGoogle ScholarCrossref
37.
Davies  MJ, Whitehead  K, Quagliotto  G, Wood  D, Patheja  RS, Sullivan  TJ.  Adult orbital and adnexal xanthogranulomatous disease.  Asia Pac J Ophthalmol (Phila). 2017;6(5):435-443.PubMedGoogle Scholar
38.
DeLuca  IJ, Grossman  ME.  Vulvar necrobiotic xanthogranuloma.  J Am Acad Dermatol. 2014;71(6):e247-e248. doi:10.1016/j.jaad.2014.04.039PubMedGoogle ScholarCrossref
39.
Dholaria  BR, Cappel  M, Roy  V.  Necrobiotic xanthogranuloma associated with monoclonal gammopathy: successful treatment with lenalidomide and dexamethasone.  Ann Hematol. 2016;95(4):671-672. doi:10.1007/s00277-016-2604-3PubMedGoogle ScholarCrossref
40.
Dilnawaz  M.  An unusual skin presentation of necrobiotic xanthogranuloma.  J Coll Physicians Surg Pak. 2010;20(4):274-275.PubMedGoogle Scholar
41.
Dupré  A, Viraben  R.  Necrobiotic xanthogranuloma: a case without paraproteinemia but with transepithelial elimination.  J Cutan Pathol. 1988;15(2):116-119. doi:10.1111/j.1600-0560.1988.tb00530.xPubMedGoogle ScholarCrossref
42.
Efebera  Y, Blanchard  E, Allam  C, Han  A, Lee  S, Munshi  N.  Complete response to thalidomide and dexamethasone in a patient with necrobiotic xanthogranuloma associated with monoclonal gammopathy: a case report and review of the literature.  Clin Lymphoma Myeloma Leuk. 2011;11(3):298-302. doi:10.1016/j.clml.2011.03.020PubMedGoogle ScholarCrossref
43.
Elner  VM, Mintz  R, Demirci  H, Hassan  AS.  Local corticosteroid treatment of eyelid and orbital xanthogranuloma.  Ophthalmic Plast Reconstr Surg. 2006;22(1):36-40. doi:10.1097/01.iop.0000192645.24814.e8PubMedGoogle ScholarCrossref
44.
Esmaeli  N, Ghanadan  A, Mansouri  P, Ghaedi  F.  Necrobiotic xanthogranuloma after penicillin injection: A case report.  Iranian J Dermatol. 2017;20(1):26-28.Google Scholar
45.
Ferrara  G, Palombi  N, Lipizzi  A, Zalaudek  I, Argenziano  G.  Nonnecrobiotic necrobiotic xanthogranuloma.  Am J Dermatopathol. 2007;29(3):306-308. doi:10.1097/DAD.0b013e3180332b8bPubMedGoogle ScholarCrossref
46.
Finelli  LG, Ratz  JL.  Plasmapheresis, a treatment modality for necrobiotic xanthogranuloma.  J Am Acad Dermatol. 1987;17(2 Pt 2):351-354. doi:10.1016/S0190-9622(87)70211-4PubMedGoogle ScholarCrossref
47.
Fink  C, Schneiderbauer  R, Hartschuh  W, Enk  A, Toberer  F.  Necrobiotic xanthogranuloma associated with chronic lymphocytic leukemia.  Int J Dermatol. 2018;57(6):719-720. doi:10.1111/ijd.13951PubMedGoogle ScholarCrossref
48.
Flann  S, Wain  EM, Halpern  S, Andrews  V, Whittaker  S.  Necrobiotic xanthogranuloma with paraproteinaemia.  Clin Exp Dermatol. 2006;31(2):248-251. doi:10.1111/j.1365-2230.2005.02042.xPubMedGoogle ScholarCrossref
49.
Fortson  JS, Schroeter  AL.  Necrobiotic xanthogranuloma with IgA paraproteinemia and extracutaneous involvement.  Am J Dermatopathol. 1990;12(6):579-584. doi:10.1097/00000372-199012000-00008PubMedGoogle ScholarCrossref
50.
Fu  T, Zwerner  J, Kim  J, Tang  J.  Subcutaneous nodules in an elderly patient. Necrobiotic xanthogranuloma.  Arch Dermatol. 2011;147(10):1215-1220. doi:10.1001/archdermatol.2011.285-aPubMedGoogle ScholarCrossref
51.
Furner  BB, Stevens  CS.  Diffuse, ulcerating plaques and nodules. Necrobiotic xanthogranuloma (NXG) with paraproteinemia.  Arch Dermatol. 1989;125(2):287-288, 290. doi:10.1001/archderm.1989.01670140139028PubMedGoogle ScholarCrossref
52.
Gacto  P, Barrera  F, Pereyra  JJ, Fernández-Ortega  P.  [Necrobiotic xanthogranuloma: efficacy of surgery in 2 patients]  [in Spanish].  Actas Dermosifiliogr. 2009;100(6):499-502. doi:10.1016/S0001-7310(09)71597-2PubMedGoogle ScholarCrossref
53.
Georgiou  S, Monastirli  A, Kapranos  N, Pasmatzi  E, Sakkis  Th, Tsambaos  D.  Interferon alpha-2a monotherapy for necrobiotic xanthogranuloma.  Acta Derm Venereol. 1999;79(6):484-485. doi:10.1080/000155599750010030PubMedGoogle ScholarCrossref
54.
Gergen  N, Biebl  K, Berg  BC, Suwattee  P.  Slowly growing yellow nodules: challenge. Necrobiotic xanthogranuloma.  Am J Dermatopathol. 2011;33(1):92-93, 103-104. doi:10.1097/DAD.0b013e3181d435a0PubMedGoogle ScholarCrossref
55.
Ghani  S, Al Ustwani  O, Khalid  B,  et al.  Periorbital necrobiotic xanthogranuloma treated successfully with novel multiple myeloma therapy.  Clin Adv Hematol Oncol. 2013;11(10):678-680.PubMedGoogle Scholar
56.
Ghiasi  N, Alavi  A, Coutts  PM, Ghazarian  D, Sibbald  RG.  Necrobiotic xanthogranuloma as an unusual cause of refractive chronic bilateral leg ulceration.  Int J Low Extrem Wounds. 2012;11(4):293-295. doi:10.1177/1534734612465434PubMedGoogle ScholarCrossref
57.
Girisha  BS, Holla  AP, Fernandes  M, Noronha  TM.  Necrobiotic xanthogranuloma.  J Cutan Aesthet Surg. 2012;5(1):43-45. doi:10.4103/0974-2077.94341PubMedGoogle ScholarCrossref
58.
Goede  JS, Misselwitz  B, Taverna  C,  et al.  Necrobiotic xanthogranuloma successfully treated with autologous stem cell transplantation.  Ann Hematol. 2007;86(4):303-306. doi:10.1007/s00277-006-0231-0PubMedGoogle ScholarCrossref
59.
Gonzales  JA, Haemel  A, Gross  AJ, Acharya  NR.  Management of uveitis and scleritis in necrobiotic xanthogranuloma.  J Ocul Pharmacol Ther. 2017;33(4):325-333. doi:10.1089/jop.2016.0135PubMedGoogle ScholarCrossref
60.
Goyal  A, O’Leary  D, Vercellotti  G, Miller  D, McGlave  P.  Intravenous immunoglobulin for treatment of necrobiotic xanthogranuloma.  Dermatol Ther. 2019;32(1):e12744. doi:10.1111/dth.12744PubMedGoogle Scholar
61.
Gün  D, Demirçay  Z, Demirkesen  C.  Necrobiotic xanthogranuloma in a burn scar.  Int J Dermatol. 2004;43(4):293-295. doi:10.1111/j.1365-4632.2004.01858.xPubMedGoogle ScholarCrossref
62.
Hallermann  C, Tittelbach  J, Norgauer  J, Ziemer  M.  Successful treatment of necrobiotic xanthogranuloma with intravenous immunoglobulin.  Arch Dermatol. 2010;146(9):957-960. doi:10.1001/archdermatol.2010.236PubMedGoogle ScholarCrossref
63.
Hamilton  HK, Dover  JS, Arndt  KA.  Successful treatment of disfiguring hemosiderin-containing hyperpigmentation with the Q-switched 650-nm wavelength laser.  JAMA Dermatol. 2014;150(11):1221-1222. doi:10.1001/jamadermatol.2014.1838PubMedGoogle ScholarCrossref
64.
Hashemi  P, Rashidi  A, Chapas  AM, Balfour  EM.  Necrobiotic xanthogranuloma of the extremities with paraproteinemia and without periorbital involvement at presentation.  Cutis. 2012;89(1):41-44.PubMedGoogle Scholar
65.
Hauser  C, Schifferli  J, Saurat  JH.  Complement consumption in a patient with necrobiotic xanthogranuloma and paraproteinemia.  J Am Acad Dermatol. 1991;24(5 pt 2):908-911. doi:10.1016/0190-9622(91)70145-RPubMedGoogle ScholarCrossref
66.
Herd  TJ, Fischer  R, Christensen  LC, Rajpara  A.  Irregular yellow-brown plaques on the trunk and thighs.  Cutis. 2018;101(1):12-15, 15.PubMedGoogle Scholar
67.
Holden  CA, Winkelmann  RK, Wilson Jones  E.  Necrobiotic xanthogranuloma: a report of four cases.  Br J Dermatol. 1986;114(2):241-250. doi:10.1111/j.1365-2133.1986.tb02804.xPubMedGoogle ScholarCrossref
68.
Inthasotti  S, Wanitphakdeedecha  R, Manonukul  J.  A 7-year history of necrobiotic xanthogranuloma following asymptomatic multiple myeloma: a case report.  Dermatol Res Pract. 2011;2011:927852. doi:10.1155/2011/927852PubMedGoogle Scholar
69.
Ito  Y, Nishimura  K, Yamanaka  K,  et al.  Necrobiotic xanthogranuloma with paraproteinemia; an atypical case.  J Dtsch Dermatol Ges. 2008;6(1):40-43.PubMedGoogle ScholarCrossref
70.
Jeziorska  M, Hassan  A, Mackness  MI,  et al.  Clinical, biochemical, and immunohistochemical features of necrobiotic xanthogranulomatosis.  J Clin Pathol. 2003;56(1):64-68. doi:10.1136/jcp.56.1.64PubMedGoogle ScholarCrossref
71.
Johnston  KA, Grimwood  RE, Meffert  JJ, Deering  KC.  Necrobiotic xanthogranuloma with paraproteinemia: an evolving presentation.  Cutis. 1997;59(6):333-336.PubMedGoogle Scholar
72.
Kadakia  S, Nadkarni  N, Sonavane  S, Ghate  S.  Spectacular skin nodules: cutaneous necrobiotic xanthogranuloma without paraproteinemia.  Indian J Dermatol. 2012;57(5):396-398. doi:10.4103/0019-5154.100499PubMedGoogle ScholarCrossref
73.
Kawakami  Y, Yamamoto  T.  Letter: Necrobiotic xanthogranuloma of extremities in an elderly patient successfully treated with low-dose prednisolone.  Dermatol Online J. 2011;17(6):13.PubMedGoogle Scholar
74.
Keorochana  N, Klanarongran  K, Satayasoontorn  K, Chaiamnuay  S.  Necrobiotic xanthogranuloma scleritis in a case of granulomatosis with polyangiitis (Wegener’s granulomatosis).  Int Med Case Rep J. 2017;10:323-328. doi:10.2147/IMCRJ.S145943PubMedGoogle ScholarCrossref
75.
Khan  IJ, Azam  NA, Sullivan  SC, Habboush  HW, Christian  A.  Necrobiotic xanthogranuloma successfully treated with a combination of dexamethasone and oral cyclophosphamide.  Can J Ophthalmol. 2009;44(3):335-336. doi:10.3129/i09-021PubMedGoogle ScholarCrossref
76.
Khan  M, Ahmed  I, Carr  R.  An unusual subcutaneous lump.  Clin Exp Dermatol. 2012;37(7):808-810. doi:10.1111/j.1365-2230.2011.04280.xPubMedGoogle ScholarCrossref
77.
Koch  D, Lucas  G, Durrington  P, Lear  JT.  Ulcerating necrobiotic xanthogranulomata and paraproteinaemia treated with thalidomide.  Br J Dermatol. 2008;159:16-17.Google Scholar
78.
Koch  PS, Goerdt  S, Géraud  C.  Erythematous papules, plaques, and nodular lesions on the trunk and within preexisting scars.  JAMA Dermatol. 2013;149(9):1103-1104. doi:10.1001/jamadermatol.2013.186PubMedGoogle ScholarCrossref
79.
Kossard  S, Chow  E, Wilkinson  B, Killingsworth  M.  Lipid and giant cell poor necrobiotic xanthogranuloma.  J Cutan Pathol. 2000;27(7):374-378. doi:10.1034/j.1600-0560.2000.027007374.xPubMedGoogle ScholarCrossref
80.
Kovalyshyn  I, Busam  KJ, Marghoob  AA.  Orange-yellow diffuse cutaneous eruption in an 82-year-old woman.  Arch Dermatol. 2009;145(10):1183-1188. doi:10.1001/archdermatol.2009.213-aPubMedGoogle ScholarCrossref
81.
Kunikata  N, Kikuchi  K, Hashimoto  A, Tagami  H.  Necrobiotic xanthogranuloma of the nose without paraproteinemia.  J Dermatol. 2006;33(11):809-812. doi:10.1111/j.1346-8138.2006.00184.xPubMedGoogle ScholarCrossref
82.
Lam  K, Brownstein  S, Jordan  DR, van der Jagt  R, Jastrzebski  A, Dionne  MA.  Bilateral necrobiotic xanthogranuloma of the eyelids followed by a diagnosis of multiple myeloma 20 years later.  Ophthalmic Plast Reconstr Surg. 2013;29(5):e119-e120. doi:10.1097/IOP.0b013e318279fdefPubMedGoogle ScholarCrossref
83.
Langlois  S, Brochot  P, Reguiai  Z,  et al.  Necrobiotic xanthogranuloma with multiple myeloma. Case report and pathogenic hypotheses.  Joint Bone Spine. 2006;73(1):120-122. doi:10.1016/j.jbspin.2005.03.008PubMedGoogle ScholarCrossref
84.
Le  AV, Fenske  NA.  An unusual granulomatous disease in the elderly.  Arch Dermatol. 1997;133(10):1303-1304, 1306-1307. doi:10.1001/archderm.1997.03890460129018PubMedGoogle ScholarCrossref
85.
Lebey  PB, Determer  I, Bazex  J, el Sayed  F, Marguery  MC.  Periorbital papules and nodules. Necrobiotic xanthogranuloma.  Arch Dermatol. 1997;133(1):99-102, 102. doi:10.1001/archderm.133.1.99PubMedGoogle ScholarCrossref
86.
Lee  HJ, Kim  JM, Kim  GW,  et al.  Necrobiotic xanthogranuloma treated with a combination of oral methylprednisolone and cyclosporin.  J Dermatol. 2017;44(10):1190-1191. doi:10.1111/1346-8138.13648PubMedGoogle ScholarCrossref
87.
Li  S, Chen  AJ, Fang  S, Li  H.  Successful treatment of necrobiotic xanthogranuloma with total glucosides of paeony.  Dermatol Ther. 2014;27(5):304-306. doi:10.1111/dth.12133PubMedGoogle ScholarCrossref
88.
Liszewski  W, Wisniewski  JD, Safah  H, Boh  EE.  Treatment of refractory necrobiotic xanthogranulomas with extracorporeal photopheresis and intravenous immunoglobulin.  Dermatol Ther. 2014;27(5):268-271. doi:10.1111/dth.12135PubMedGoogle ScholarCrossref
89.
Luck  J, Layton  A, Noble  BA.  Necrobiotic xanthogranuloma with orbital involvement.  J R Soc Med. 1992;85(6):357-358.PubMedGoogle Scholar
90.
Lukács  J, Goetze  S, Elsner  P.  Periocular necrobiotic xanthogranuloma successfully treated with intravenous immunoglobulin.  Acta Derm Venereol. 2017;97(6):754-755. doi:10.2340/00015555-2626PubMedGoogle ScholarCrossref
91.
Macfarlane  AW, Verbov  JL.  Necrobiotic xanthogranuloma with paraproteinaemia.  Br J Dermatol. 1985;113(3):339-343. doi:10.1111/j.1365-2133.1985.tb02087.xPubMedGoogle ScholarCrossref
92.
McGregor  JM, Miller  J, Smith  NP, Hay  RJ.  Necrobiotic xanthogranuloma without periorbital lesions.  J Am Acad Dermatol. 1993;29(3):466-469. doi:10.1016/0190-9622(93)70212-CPubMedGoogle ScholarCrossref
93.
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(5):458-462.PubMedGoogle Scholar
94.
Mahendran  P, Wee  J, Chong  H, Natkunarajah  J.  Necrobiotic xanthogranuloma treated with lenalidomide.  Clin Exp Dermatol. 2018;43(3):345-347. doi:10.1111/ced.13293PubMedGoogle ScholarCrossref
95.
Martínez Fernández  M, Rodríguez Prieto  MA, Ruiz González  I, Sánchez Sambucety  P, Delgado Vicente  S.  Necrobiotic xanthogranuloma associated with myeloma.  J Eur Acad Dermatol Venereol. 2004;18(3):328-331. doi:10.1111/j.1468-3083.2004.00906.xPubMedGoogle ScholarCrossref
96.
Mathias  M, Permi  HS, Shetty  P, Jayaprakash Shetty  K, Girish  BS.  Necrobiotic xanthogranuloma presenting as a clinical variant without paraproteinemia.  Nitte University Journal of Health Science. 2011;1(1-3):72-74.Google Scholar
97.
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)00260-3PubMedGoogle ScholarCrossref
98.
Meyer  S, Szeimies  RM, Landthaler  M, Hohenleutner  S.  Cyclophosphamide-dexamethasone pulsed therapy for treatment of recalcitrant necrobiotic xanthogranuloma with paraproteinemia and ocular involvement.  Br J Dermatol. 2005;153(2):443-445. doi:10.1111/j.1365-2133.2005.06737.xPubMedGoogle ScholarCrossref
99.
Minocha  R, Lee  S, Choi  JYJ, Mann  S.  Necrobiotic xanthogranuloma: a report of two fascinating cases.  Hong Kong J Dermat Venereol. 2017;25(2):84-89.Google Scholar
100.
Miszkiel  KA, Sohaib  SAA, Rose  GE, Cree  IA, Moseley  IF.  Radiological and clinicopathological features of orbital xanthogranuloma.  Br J Ophthalmol. 2000;84(3):251-258. doi:10.1136/bjo.84.3.251PubMedGoogle ScholarCrossref
101.
Mohsenin  A, Sinard  J, Huang  JJ.  Necrobiotic xanthogranuloma and chronic lymphocytic leukemia of the conjunctiva masquerading as scleritis and uveitis.  Clin Ophthalmol. 2012;6:2045-2047. doi:10.2147/OPTH.S35743PubMedGoogle ScholarCrossref
102.
Muscardin  LM, Mastroianni  A, Chistolini  A, Pulsoni  A.  Necrobiotic xanthogranuloma without periorbital lesions and without paraproteinaemia.  J Eur Acad Dermatol Venereol. 2003;17(2):233-235. doi:10.1046/j.1468-3083.2003.00577_6.xPubMedGoogle ScholarCrossref
103.
Naghashpour  M, Setoodeh  R, Moscinski  L,  et al.  Nonnecrobiotic necrobiotic xanthogranuloma as an initial manifestation of paraproteinemia and small lymphocytic lymphoma in a patient with Sjögren syndrome.  Am J Dermatopathol. 2011;33(8):855-857. doi:10.1097/DAD.0b013e3182051fcePubMedGoogle ScholarCrossref
104.
Nestle  FO, Hofbauer  G, Burg  G.  Necrobiotic xanthogranuloma with monoclonal gammopathy of the IgG lambda type.  Dermatology. 1999;198(4):434-435.PubMedGoogle Scholar
105.
Nishimura  M, Takano-Nishimura  Y, Yano  I, Hayashi  N, Toshitani  S.  Necrobiotic xanthogranuloma in a human T-lymphotropic virus type 1 carrier.  J Am Acad Dermatol. 1992;27(5 pt 2):886-889. doi:10.1016/0190-9622(92)70274-JPubMedGoogle ScholarCrossref
106.
Nockowski  P, Woźniak  Z, Reich  A, Maj  J.  Xanthoma-like skin changes in an elderly woman with a normal lipid profile.  Acta Dermatovenerol Croat. 2017;25(2):167-169.PubMedGoogle Scholar
107.
Novak  PM, Robbins  TO, Winkelmann  RK.  Necrobiotic xanthogranuloma with myocardial lesions and nodular transformation of the liver.  Hum Pathol. 1992;23(2):195-196. doi:10.1016/0046-8177(92)90244-WPubMedGoogle ScholarCrossref
108.
Oestreicher  J, Dookeran  R, Nijhawan  N, Kolin  A.  Necrobiotic xanthogranuloma with predominant periorbital involvement.  Ophthalmic Plast Reconstr Surg. 2010;26(6):473-475. doi:10.1097/IOP.0b013e3181d92955PubMedGoogle ScholarCrossref
109.
Olson  RM, Harrison  AR, Maltry  A, Mokhtarzadeh  A.  Periorbital necrobiotic xanthogranuloma successfully treated with intravenous immunoglobulin.  Case Rep Ophthalmol. 2018;9(1):70-75. doi:10.1159/000485913PubMedGoogle ScholarCrossref
110.
Omarjee  L, Janin  A, Etienne  G,  et al.  Necrobiotic xanthogranuloma: a paraneoplastic skin lesion of haematological malignancies?  Eur J Dermatol. 2018;28(3):384-386. doi:10.1684/ejd.2018.3256PubMedGoogle ScholarCrossref
111.
Oumeish  OY, Oumeish  I, Tarawneh  M, Salman  T, Sharaiha  A.  Necrobiotic xanthogranuloma associated with paraproteinemia and non-Hodgkin’s lymphoma developing into chronic lymphocytic leukemia: the first case reported in the literature and review of the literature.  Int J Dermatol. 2006;45(3):306-310. doi:10.1111/j.1365-4632.2006.02575.xPubMedGoogle ScholarCrossref
112.
Pedrosa  AF, Ferreira  O, Calistru  A,  et al.  Necrobiotic xanthogranuloma with giant cell hepatitis, successfully treated with intravenous immunoglobulins.  Dermatol Ther. 2015;28(2):68-70. doi:10.1111/dth.12211PubMedGoogle ScholarCrossref
113.
Peyman  A, Walsh  N, Green  P, Dorey  MW, Seamone  C, Pasternak  S.  Necrobiotic xanthogranuloma associated with necrotizing scleritis.  Am J Dermatopathol. 2012;34(6):644-647. doi:10.1097/DAD.0b013e318234e73cPubMedGoogle ScholarCrossref
114.
Plotnick  H, Taniguchi  Y, Hashimoto  K, Negendank  W, Tranchida  L.  Periorbital necrobiotic xanthogranuloma and stage I multiple myeloma: ultrastructure and response to pulsed dexamethasone documented by magnetic resonance imaging.  J Am Acad Dermatol. 1991;25(2 pt 2):373-377. doi:10.1016/0190-9622(91)70208-JPubMedGoogle ScholarCrossref
115.
Randell  PL, Heenan  PJ.  Necrobiotic xanthogranuloma with paraproteinaemia.  Australas J Dermatol. 1999;40(2):114-115. doi:10.1046/j.1440-0960.1999.00334.xPubMedGoogle ScholarCrossref
116.
Rashid  MM, Chowdhury  T, Sultana  A, Begum  R, Islam  S, Ahmed  I.  Necrobiotic xanthogranuloma—a case report.  J Pak Assoc Dermatol. 2009;19(3):175-177.Google Scholar
117.
Rayner  SA, Duncombe  AS, Keefe  M, Theaker  J, Manners  RM.  Necrobiotic xanthogranuloma occurring in an eyelid scar.  Orbit. 2008;27(3):191-194. doi:10.1080/01676830701804057PubMedGoogle ScholarCrossref
118.
Reddy  VC, Salomão  DR, Garrity  JA, Baratz  KH, Patel  SV.  Periorbital and ocular necrobiotic xanthogranuloma leading to perforation.  Arch Ophthalmol. 2010;128(11):1493-1494. doi:10.1001/archophthalmol.2010.254PubMedGoogle ScholarCrossref
119.
Reeder  CB, Connolly  SM, Winkelmann  RK.  The evolution of Hodgkin’s disease and necrobiotic xanthogranuloma syndrome.  Mayo Clin Proc. 1991;66(12):1222-1224. doi:10.1016/S0025-6196(12)62473-2PubMedGoogle ScholarCrossref
120.
Rose  GE, Patel  BC, Garner  A, Wright  JE.  Orbital xanthogranuloma in adults.  Br J Ophthalmol. 1991;75(11):680-684. doi:10.1136/bjo.75.11.680PubMedGoogle ScholarCrossref
121.
Rose  A, Robinson  M, Kamino  H, Latkowski  JA.  Necrobiotic xanthogranuloma.  Dermatol Online J. 2012;18(12):30.PubMedGoogle Scholar
122.
Rubinstein  A, Wolf  DJ, Granstein  RD.  Successful treatment of necrobiotic xanthogranuloma with intravenous immunoglobulin.  J Cutan Med Surg. 2013;17(5):347-350. doi:10.2310/7750.2013.13012PubMedGoogle ScholarCrossref
123.
Russo  GG.  Necrobiotic xanthogranuloma with scleroderma.  Cutis. 2002;70(6):311-316.PubMedGoogle Scholar
124.
Ryan  E, Warren  LJ, Szabo  F.  Necrobiotic xanthogranuloma: response to chlorambucil.  Australas J Dermatol. 2012;53(2):e23-e25. doi:10.1111/j.1440-0960.2010.00710.xPubMedGoogle Scholar
125.
Saeki  H, Tomita  M, Kai  H,  et al.  Necrobiotic xanthogranuloma with paraproteinemia successfully treated with melphalan, prednisolone and skin graft.  J Dermatol. 2007;34(11):795-797. doi:10.1111/j.1346-8138.2007.00387.xPubMedGoogle Scholar
126.
Sagiv  O, Thakar  SD, Morrell  G, Tetzlaff  MT, Esmaeli  B.  Rituximab monotherapy is effective in treating orbital necrobiotic xanthogranuloma.  Ophthalmic Plast Reconstr Surg. 2018;34(1):e24-e27. doi:10.1097/IOP.0000000000000988PubMedGoogle Scholar
127.
Santosaputri  E, Ellis  EJ, Nagiah  S, Chrispal  A, Thomas  A.  A multisystem granulomatous disease: necrobiotic xanthogranuloma with hepatic involvement.  Med J Aust. 2014;200(8):490-493. doi:10.5694/mja13.11303PubMedGoogle Scholar
128.
Schaudig  U, Al-Samir  K.  Upper and lower eyelid reconstruction for severe disfiguring necrobiotic xanthogranuloma.  Orbit. 2004;23(1):65-76. doi:10.1076/orbi.23.1.65.28989PubMedGoogle Scholar
129.
Scupham  RK, Fretzin  DF.  Necrobiotic xanthogranuloma with paraproteinemia.  Arch Pathol Lab Med. 1989;113(12):1389-1391.PubMedGoogle Scholar
130.
Seastrom  S, Bookout  A, Hogan  DJ.  Necrobiotic xanthogranuloma without a monoclonal gammopathy.  Cutis. 2014;94(6):293-296.PubMedGoogle Scholar
131.
Shah  KC, Poonnoose  SI, George  R, Jacob  M, Rajshekhar  V.  Necrobiotic xanthogranuloma with cutaneous and cerebral manifestations. case report and review of the literature.  J Neurosurg. 2004;100(6):1111-1114. doi:10.3171/jns.2004.100.6.1111PubMedGoogle Scholar
132.
Silapunt  S, Chon  SY.  Generalized necrobiotic xanthogranuloma successfully treated with lenalidomide.  J Drugs Dermatol. 2010;9(3):273-276.PubMedGoogle Scholar
133.
Singh  K, Rajan  KD, Eberhart  C.  Orbital necrobiotic xanthogranuloma associated with systemic IgG4 disease.  Ocul Immunol Inflamm. 2010;18(5):373-378. doi:10.3109/09273948.2010.490629PubMedGoogle Scholar
134.
Smith  HG, Sargent  LA, Lundgrin  DB.  Necrobiotic xanthogranuloma of the chest wall.  Dermatol Online J. 2006;12(1):12.PubMedGoogle Scholar
135.
Stork  J, Kodetová  D, Vosmík  F, Krejca  M.  Necrobiotic xanthogranuloma presenting as a solitary tumor.  Am J Dermatopathol. 2000;22(5):453-456. doi:10.1097/00000372-200010000-00013PubMedGoogle Scholar
136.
Sutton  L, Sutton  S, Sutton  M.  Treatment of necrobiotic xanthogranuloma with 2-chlorodeoxyadenosine.  Skinmed. 2013;11(2):121-123.PubMedGoogle Scholar
137.
Torabian  SZ, Fazel  N, Knuttle  R.  Necrobiotic xanthogranuloma treated with chlorambucil.  Dermatol Online J. 2006;12(5):11.PubMedGoogle Scholar
138.
Tucker  NA, Discepola  MJ, Blanco  G, Burnier  MN  Jr.  Necrobiotic xanthogranuloma without dermatologic involvement.  Can J Ophthalmol. 1997;32(6):396-399.PubMedGoogle Scholar
139.
Umbert  I, Winkelmann  RK.  Necrobiotic xanthogranuloma with cardiac involvement.  Br J Dermatol. 1995;133(3):438-443. doi:10.1111/j.1365-2133.1995.tb02674.xPubMedGoogle Scholar
140.
Valentine  EA, Friedman  HD, Zamkoff  KW, Streeten  BW.  Necrobiotic xanthogranuloma with IgA multiple myeloma: a case report and literature review.  Am J Hematol. 1990;35(4):283-285. doi:10.1002/ajh.2830350414PubMedGoogle Scholar
141.
Venencie  PY, Puissant  A, Verola  O,  et al.  Necrobiotic xanthogranuloma with myeloma: a case report.  Cancer. 1987;59(3):588-592. doi:10.1002/1097-0142(19870201)59:3<588::AID-CNCR2820590339>3.0.CO;2-CPubMedGoogle Scholar
142.
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(4):666-667. doi:10.1016/0190-9622(95)90370-4PubMedGoogle Scholar
143.
Vieira  V, Del Pozo  J, Martínez  W, Veiga-Barreiro  JA, Fonseca  E.  Necrobiotic xanthogranuloma associated with lymphoplasmacytic lymphoma. Palliative treatment with carbon dioxide laser.  Eur J Dermatol. 2005;15(3):182-185.PubMedGoogle Scholar
144.
Vignon  M, Placais  L, Malphettes  M,  et al.  Non-cirrhotic portal hypertension in necrobiotic xanthogranuloma associated with monoclonal gammopathy.  J Eur Acad Dermatol Venereol. 2017;31(9):e403-e405. doi:10.1111/jdv.14213PubMedGoogle Scholar
145.
Vu  K, Gupta  R, Frater  J, Atkinson  J, Ranganathan  P.  A 55-year-old man with periorbital and inguinal masses, pericarditis, and pleuritis.  Arthritis Care Res (Hoboken). 2017;69(5):730-736. doi:10.1002/acr.22843PubMedGoogle Scholar
146.
Wee  SA, Shupack  JL.  Necrobiotic xanthogranuloma.  Dermatol Online J. 2005;11(4):24.PubMedGoogle Scholar
147.
Wei  YH, Cheng  JJ, Wu  YH,  et al.  Necrobiotic xanthogranuloma: response to dapsone.  Dermatol Ther. 2015;28(1):7-9. doi:10.1111/dth.12179PubMedGoogle Scholar
148.
Wells  J, Gillespie  R, Zardawi  I.  Case of recalcitrant necrobiotic xanthogranuloma.  Australas J Dermatol. 2004;45(4):213-215. doi:10.1111/j.1440-0960.2004.00099.xPubMedGoogle Scholar
149.
Wolz  M, Peters  MS.  Necrobiotic xanthogranuloma of the extremities.  J Drugs Dermatol. 2012;11(1):122-123.PubMedGoogle Scholar
150.
Wruhs  M, Feldmann  R, Sawetz  I, Breier  F, Steiner  A.  Necrobiotic xanthogranuloma in a patient with multiple myeloma.  Case Rep Dermatol. 2016;8(3):350-353. doi:10.1159/000452826PubMedGoogle Scholar
151.
Yang  CY, Chung  WH, Rosaline  CYH, Kuo  TT, Yang  CH.  Necrobiotic xanthogranuloma with paraproteinemia without periorbital involvement - a case report.  Zhonghua Pifuke Yixue Zazhi. 2010;28(3):125-129. doi:10.1016/S1027-8117(10)60027-4Google Scholar
152.
Yasukawa  K, Kato  N, Hamasaka  A, Hata  H.  Necrobiotic xanthogranuloma: isolated skeletal muscle involvement and unusual changes.  J Am Acad Dermatol. 2005;52(4):729-731. doi:10.1016/j.jaad.2004.12.016PubMedGoogle Scholar
153.
Yoon  SY, Park  HJ, Lee  JY, Cho  BK.  Necrobiotic xanthogranuloma with multiple myeloma and no periorbital involvement.  Ann Dermatol. 2007;19(1):22-24. doi:10.5021/ad.2007.19.1.22Google Scholar
154.
Zainal  A, Razif  MY, Makhashen  M, Swaminathan  M, Mazita  A.  Necrobiotic xanthogranuloma of the parotid gland.  J Laryngol Otol. 2010;124(5):569-571. doi:10.1017/S0022215109991563PubMedGoogle Scholar
155.
Ziemer  M, Wedding  U, Sander  CS, Elsner  P.  Necrobiotic xanthogranuloma-rapid progression under treatment with melphalan.  Eur J Dermatol. 2005;15(5):363-365.PubMedGoogle Scholar
156.
Ziemer  M, Norgauer  J, Simon  JC, Koehler  MJ.  An unusual histologic variant of necrobiotic xanthogranuloma.  Am J Dermatopathol. 2012;34(2):e22-e26. doi:10.1097/DAD.0b013e3182222aa8PubMedGoogle Scholar
157.
Higgins  LS, Go  RS, Dingli  D,  et al.  Clinical features and treatment outcomes of patients with necrobiotic xanthogranuloma associated with monoclonal gammopathies.  Clin Lymphoma Myeloma Leuk. 2016;16(8):447-452. doi:10.1016/j.clml.2016.04.009PubMedGoogle Scholar
158.
Hilal  T, DiCaudo  DJ, Connolly  SM, Reeder  CB.  Necrobiotic xanthogranuloma: a 30-year single-center experience.  Ann Hematol. 2018;97(8):1471-1479. doi:10.1007/s00277-018-3301-1PubMedGoogle Scholar
159.
Carroll  MD. Frayar  CD, Nguyen  DT. Total and high-density lipoprotein cholesterol in adults: United States, 2015–2016; NCHS data brief, No. 290, October 2017. https://www.cdc.gov/nchs/data/databriefs/db290.pdf. Published 2017. Accessed November 19, 2019.
160.
Sodhi  A, Aldrich  T.  Vitamin D supplementation: not so simple in sarcoidosis.  Am J Med Sci. 2016;352(3):252-257. doi:10.1016/j.amjms.2016.05.027PubMedGoogle Scholar
161.
Miguel  D, Lukacs  J, Illing  T, Elsner  P.  Treatment of necrobiotic xanthogranuloma—a systematic review.  J Eur Acad Dermatol Venereol. 2017;31(2):221-235. doi:10.1111/jdv.13786PubMedGoogle Scholar
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    Original Investigation
    January 15, 2020

    A Multicenter Cross-Sectional Study and Systematic Review of Necrobiotic Xanthogranuloma With Proposed Diagnostic Criteria

    Author Affiliations
    • 1Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
    • 2Harvard Medical School, Boston, Massachusetts
    • 3Perelman School of Medicine, University of Pennsylvania, Philadelphia
    • 4Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
    • 5University of Iowa Carver College of Medicine, Iowa City
    • 6Perelman School of Medicine at the University of Pennsylvania, Department of Dermatology, Philadelphia
    • 7Perelman School of Medicine at the University of Pennsylvania, Department of Medicine, Philadelphia
    • 8Department of Dermatology, University of Iowa Carver College of Medicine, Iowa City
    JAMA Dermatol. 2020;156(3):270-279. doi:10.1001/jamadermatol.2019.4221
    Key Points

    Question  What are the characteristics of necrobiotic xanthogranuloma, and what criteria should establish the diagnosis?

    Findings  This multicenter cross-sectional study and systematic review included 235 patients with necrobiotic xanthogranuloma. Informed by the results, 8 board-certified dermatologists participated in a consensus exercise; in the absence of foreign body, infection, or other identifiable cause, both major criteria (clinical and histopathological features) and at least 1 minor criterion (paraproteinemia, plasma-cell dyscrasia, and/or other associated lymphoproliferative disorder, or a periorbital distribution) were proposed to diagnose necrobiotic xanthogranuloma.

    Meaning  These findings and criteria have potential to advance clinical research and should be validated by further studies.

    Abstract

    Importance  Necrobiotic xanthogranuloma (NXG) is a non–Langerhans cell histiocytosis classically associated with paraproteinemia attributable to plasma-cell dyscrasias or lymphoproliferative disorders. Despite the morbidity of NXG, the literature is limited to case reports and small studies, and diagnostic criteria are lacking.

    Objective  To evaluate the characteristics of NXG and propose diagnostic criteria.

    Design, Setting, and Participants  This multicenter cross-sectional study was conducted at tertiary academic referral centers and followed by a systematic review and a consensus exercise. The multicenter cohort included patients with NXG diagnosed at the Brigham and Women’s and Massachusetts General Hospitals (2000-2018), the University of Iowa Hospitals and Clinics (2000-2018), and the University of Pennsylvania Health System (2008-2018). The systematic review was conducted in 2018 and included patients with NXG identified in the Cochrane, Ovid EMBASE, PubMed, and Web of Science databases. The consensus exercise was conducted by 8 board-certified dermatologists to identify diagnostic criteria.

    Main Outcomes and Measures  Demographic factors, comorbidities, clinical features, and treatment response.

    Results  Of 235 included patients with NXG (34 from the multicenter cohort and 201 from the systematic review results), the mean (SD) age at presentation was 61.6 (14.2) years; 147 (62.6%) were female. Paraproteinemia was detected in 193 patients (82.1%), most often IgG-κ (117 patients [50.0%]). A malignant condition was detected in 59 patients (25.1%), most often multiple myeloma (33 patients [14.0%]). The overall rate of paraproteinemia and/or a malignant condition was 83.8% (197 patients). In the multicenter cohort, evolution of paraproteinemia into multiple myeloma was observed up to 5.7 years (median [range], 2.4 [0.1-5.7] years) after NXG presentation. Cutaneous lesions consisted of papules, plaques, and/or nodules, typically yellow or orange in color (113 of 187 [60.4%]) with a periorbital distribution (130 of 219 [59.3%]). The eye was the leading site of extracutaneous involvement (34 of 235 [14.5%]). In the multicenter cohort, intravenous immunoglobulin had the best treatment response rate (9 of 9 patients [100%]), followed by antimalarial drugs (4 of 5 patients [80%]), intralesional triamcinolone (6 of 8 patients [75%]), surgery (3 of 4 patients [75%]), chemotherapy (8 of 12 patients [67%]), and lenalidomide or thalidomide (5 of 8 patients [63%]). The consensus exercise yielded 2 major criteria, which were (1) clinical and (2) histopathological features consistent with NXG, and 2 minor criteria, consisting of (1) paraproteinemia, plasma-cell dyscrasia, and/or other associated lymphoproliferative disorder and (2) periorbital distribution of cutaneous lesions. In the absence of foreign body, infection, or another identifiable cause, fulfillment of both major and at least 1 minor criterion were proposed to establish the diagnosis of NXG.

    Conclusions and Relevance  Necrobiotic xanthogranuloma is a multisystem disorder associated with paraproteinemia and malignant conditions. The proposed diagnostic criteria may advance clinical research and should be validated.

    Introduction

    Necrobiotic xanthogranuloma (NXG) is a non–Langerhans cell histiocytosis first described by Kossard and Winkelmann1 in 1980. It is typically associated with paraproteinemia attributable to plasma-cell dyscrasias or lymphoproliferative disorders.2 In addition to serving as a skin sign of systemic disease, NXG may result in cosmetic disfigurement. Extracutaneous involvement including the eye, heart, gastrointestinal tract, liver, and lung may result in organ dysfunction and death.1,3-5 Clinically, yellow-to-orange papules, plaques, and/or nodules in a periorbital distribution are classic; however, other morphological characteristics and sites have been described.6 Histopathologically, NXG demonstrates palisading granulomas with lymphoplasmacytic infiltrate and zones of necrobiosis. Cholesterol clefts and Touton or large, bizarre foreign body giant cells are other classical features.6 The pathogenesis of NXG remains unknown; however, a role for paraprotein-lipoprotein interaction has been hypothesized.7,8 Evaluation of 12 skin-biopsy specimens by Wood et al9 in 2009 found no evidence to support a monoclonal plasma-cell proliferation within the inflammatory infiltrate.

    The literature on NXG consists of case reports and small studies, and diagnostic criteria are currently unavailable. The first objective of this study was to evaluate the demographic features, comorbidities, clinical features, and treatment response of a large NXG cohort. The second objective was to propose diagnostic criteria for NXG.

    Methods
    Study Design, Setting, and Participants

    The institutional review boards of Partners Healthcare, the University of Iowa, and the University of Pennsylvania approved this study. The requirement for informed consent was waived because of the retrospective nature of the study.

    For the multicenter cohort, patients were identified from both the electronic health records and the dermatopathology databases at the Brigham and Women's Hospital, Massachusetts General Hospital, the University of Iowa Hospitals and Clinics, and the University of Pennsylvania Health System using International Classification of Diseases, Ninth Revision and Tenth Revision codes (273.2 and D76.3) and a free-text search for the terms necrobiotic xanthogranuloma and NXG. Patients were identified from 2000 through 2018 at the Brigham and Women's Hospital, Massachusetts General Hospital, and the University of Iowa Hospitals and Clinics and from 2008 through 2018 at the University of Pennsylvania Health System, with years selected based on availability of readily searchable electronic health records. The diagnosis was verified by consensus of the principal investigators (K.A.W., M.R., and A.M.) based on clinical and histopathological features. Exclusion criteria were an age younger than 18 years or a lack of histopathological features interpreted by a dermatopathologist as being consistent with NXG.

    For the systematic review, records were identified with the support of a medical librarian in the Cochrane, Ovid EMBASE, PubMed, and Web of Science databases on November 20, 2018, using the medical subject headings (MeSH) terms “necrobiotic disorders” AND “histiocytosis, non-Langerhans-cell” OR “necrobiotic xanthogranuloma” in PubMed and a free text search for “necrobiotic xanthogranuloma” OR “NXG” OR “periocular xanthogranuloma” OR “periorbital xanthogranuloma” in all databases. Titles and abstracts were independently reviewed by 2 authors (C.A.N. and C.S.Z.). Full texts of records deemed relevant were independently reviewed by both authors, and a consensus was reached to include or exclude each article. Exclusion criteria were a patient age younger than 18 years, a study with aggregated data, an alternative diagnosis, a patient duplicated in another study, a language other than English, a lack of histopathological features interpreted by a dermatopathologist as being consistent with NXG, or an excluded study design (a conference abstract or a case report with insufficient data).

    Data Collection

    Using a standardized data collection instrument, we abstracted patient demographics, comorbidities, and clinical features at the time of NXG presentation. For the multicenter cohort, we also abstracted body mass index (calculated as weight in kilograms divided by height in meters squared), timing of paraproteinemia and malignant conditions relative to NXG, and antilipemic therapy, characteristics inconsistently reported in the literature. In addition, we classified treatment response as a complete response, a partial response, no response, or worsening based on the assessment of the patient’s dermatologist. Response rates were calculated as the percentage of patients with a complete or partial response. We did not evaluate response rates in the literature out of a concern for positive outcome bias.

    Consensus Exercise

    After reviewing the results, 8 board-certified dermatologists (A.M., C.A.N., K.A.W., M.H.N., M.R., R.A.V., R.G.M., and S.I.) participated in a consensus exercise to propose diagnostic criteria for NXG. In the first online survey, participants identified all possible characteristics of NXG that could be considered for inclusion. In the second round, participants ranked the importance of each characteristic on a Likert scale ranging from 1 (not at all important) to 5 (very important), along with a free-response commentary. We used a mean importance ranking of 3.5 of 5 or greater as the numerical cutoff score for inclusion. In the third round, the participants reviewed the results of the previous survey and provided a free-response commentary on how to structure the criteria. In the final round, the participants reviewed draft criteria, indicated the level of agreement with each criterion using a Likert scale ranging from 1 (signaling strongly disagreement) to 5 (strong agreement), along with a free-response commentary, and indicated approval or disapproval. We required a mean agreement ranking of 3.5 of 5 or greater for each criterion and unanimous approval to establish consensus.

    Statistical Analysis

    Continuous variables were summarized with means and SDs. Categorical variables were reported as proportions and percentages. All statistical analyses were performed in Excel version 14.7.1 (Microsoft).

    Results
    Patient Characteristics

    For the multicenter cohort, the initial search yielded 71 patients at the Brigham and Women's Hospital and Massachusetts General Hospital (combined), 41 patients at the University of Iowa Hospitals and Clinics, and 61 patients at the University of Pennsylvania Health System. Fifteen patients (21%), 6 patients (15%), and 13 patients (21%) from these 3 centers, respectively, were included after review and verification, for a total of 34 patients.

    In the systematic review, the initial search yielded 1199 records, 151 of which were included3,4,7,8,10-156 (Figure). These reports described 201 patients with NXG, with demographics, comorbidities, and clinical features (detailed in the eTable in the Supplement).

    Overall, 235 patients with NXG were included in the study. The demographic features and comorbidities of patients with NXG are detailed in Table 1. The mean (SD) age at presentation was 61.6 (14.2) years; 147 patients (62.6%) were female. Most patients were white (78 of 90 for whom these data were available [87%]). Of the 235 patients, 193 (82.1%) had paraproteinemia. The most common subtype was IgG-κ, in 117 of 235 patients (50.0%); however, IgG-λ, IgM, and IgA subtypes were also observed (in 49 patients [20.8%], 5 patients [2.1%], and 2 patients [0.9%], respectively). Fifty-nine of 235 patients (25.1%) had a malignant condition. Multiple myeloma, in 33 patients (14.0%), was the most common type; however, lymphoma, leukemia, and Waldenstrom macroglobulinemia were also observed (in 1 patient [0.4%] each). Solid tumors were rare (2 of 235 [0.9%]) and observed exclusively in patients with coexistent paraproteinemia. The overall rate of paraproteinemia and/or a malignant conditions was 83.8% (affecting 197 patients). In the multicenter cohort, the timing of paraproteinemia relative to NXG was antecedent in 13 of 24 patients (54%), concurrent in 6 of 24 patients (25%), and subsequent in 4 of 24 patients (16.7%). Evolution of paraproteinemia into multiple myeloma was observed up to 5.7 years after NXG presentation (median [range], 2.4 [0.1-5.7] years); in contrast, lymphoma and leukemia preceded NXG presentation (by a median [range] of 5.25 [2.2-6.8] years).

    The clinical features of NXG are detailed in Table 2 and the eTable in the Supplement. Primary morphological characteristics were papules and plaques (163 of 212 patients [76.7%]) and/or nodules (52 of 212 [24.5%]). Ulceration (40 of 211 patients [19.0%]) was the most common secondary feature, followed by telangiectasia (30 of 211 [14.2%]), atrophy (29 of 211 [13.7%]), and induration (15 of 211 [7.1%]). Diverse colors were observed, from yellow or orange (113 of 187 patients [60.4%]) to red or pink (45 of 187 [24.1%]), brown (28 of 187 [14.9%]), and purple (21 of 187 [11.2%]). Pain and pruritus were reported by 27 of 88 patients (30.7%) and 15 of 88 patients (17.0%), respectively. Of 218 patients, 197 (90.4%) presented with multiple cutaneous lesions. The most common distribution was periorbital (130 of 219 [59.3%]); however, lesions were distributed elsewhere on the face (50 of 219 [22.8%]), trunk (116 of 219 [53.0%]), extremities (123 of 219 [56.1%]), and within scars (12 of 219 [5.5%]). The eye was the leading site of extracutaneous involvement. In the multicenter cohort, the rate of eye involvement in patients evaluated by ophthalmology was 27% (4 of 15 patients); however, this denominator was not reliably reported in the literature. Other sites were the brain, gastrointestinal tract, heart, liver, lung, lymphoreticular system, muscle, and parotid gland.

    Patients with NXG in the multicenter cohort had an overweight mean (SD) body mass index (27.0 [5.6]). Overall, 14 of 59 patients (24%) had a low high-density lipoprotein–cholesterol level; however, this rate in the multicenter cohort was higher (7 of 17 patients [41%]), even though 4 of 7 patients (38%) tested were taking 1 or more medications known to elevate high-density lipoprotein cholesterol levels. Thirty-three of 54 patients (61%) and 9 of 39 patients (23%) tested had low complement C4 levels and positive test results for cryoglobulins, respectively. Four of 11 patients (36%) tested had low 25-hydroxyvitamin D; however, 1,25-dihydroxyvitamin D was normal or high in half of these patients (2 of 4 [50%]).

    Treatment Response

    Treatment response rates in the multicenter cohort are presented in Table 3. Of treatments with response reported in more than 3 patients (10%), intravenous immunoglobulin had the best response rate (9 of 9 patients [100%]), followed by antimalarials (4 of 5 patients [80%]), intralesional triamcinolone (6 of 8 patients [75%]), surgery (3 of 4 patients [75%]), chemotherapy (8 of 12 patients [67%]), and lenalidomide or thalidomide (5 of 8 patients [63%]).

    Diagnostic Criteria

    The proposed diagnostic criteria for NXG are presented in the Box. The response rate for each round of the consensus exercise was 100%. Participants identified 13 characteristics in the first round and ranked their importance in the second round. In the third round, participants expressed preference for proposing major and minor criteria instead of a point-scoring system and requiring the exclusion of other causes, such as a foreign body and infection. Four characteristics that received mean importance rankings of 3.5 of 5 points or greater were drafted into major and minor criteria. In the final round, the major criteria received mean agreement rankings of 4.6 of 5 points and 4.5 of 5 points, respectively; the minor criteria received mean agreement rankings of 4.6 of 5 points and 3.9 of 5 points, respectively; and all participants approved the criteria, establishing consensus.

    Box Section Ref ID
    Box.

    Diagnostic Criteria for Necrobiotic Xanthogranulomaa

    Major Criteria
    1. Cutaneous papules, plaques, and/or nodules, most often yellow or orange in color.

    2. Histopathological 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
    1. Paraproteinemia, most often IgG-κ, plasma-cell dyscrasia, and/or other associated lymphoproliferative disorder.

    2. Periorbital distribution of cutaneous lesions.

    a Both major criteria and at least 1 minor criterion are required for diagnosis, applicable only in the absence of foreign body, infection, or other identifiable cause.

    Discussion

    To our knowledge, this study provides the largest review to date of the demographics, comorbidities, clinical features, and treatment response of NXG. In addition, it presents the outcome of a consensus exercise to propose the first diagnostic criteria for NXG.

    The mean age of 61.6 years in the cohort of 235 patients with NXG falls just above the range of 54 to 60 years reported in previous cohorts that included 10 or more patients.5,7,157,158 The female predominance in our cohort (63%) equates to an elevated female-to-male ratio of 1.7. While 1 study reported an elevated female-to-male ratio of 2.7,7 other studies reported an equal sex distribution157,158 or an elevated male-to-female ratio of 1.4.5 The rate of paraproteinemia in this cohort (82.1%) falls within the range of 77% to 84% reported by studies that did not require paraproteinemia as an inclusion criterion,5,158 and the rate of the IgG-κ subtype (50.0%) falls within the previously reported range of 50% to 60%.5,157 The rate of malignant conditions in this cohort (25.1%) is just less than the previously reported range of 26% to 45%, while the rate of multiple myeloma specifically (14%) falls within the previously reported range of 5% to 36%.5,7,157,158 The overall rate of paraproteinemia and/or malignant condition in this cohort was 83.8%. While paraproteinemia in the multicenter cohort most often preceded the presentation of NXG, evolution into multiple myeloma was observed up to 5.7 years afterwards, highlighting the importance of long-term hematologic surveillance.

    The primary morphology of papules and plaques (76.7%) and/or nodules (24.5%) in the cohort was consistent with the literature5,7; however, the ulceration rate of 19.0% was less than the rate of 42% reported in a prior study.5 In keeping with the classic description by Kossard and Winkelmann,1 the most frequently observed colors in the cohort were yellow or orange (60.4%). Interestingly, a subset of patients reported pain (30.7%) and/or pruritus (17.0%), symptoms of NXG that have not received attention in prior studies. The most common distribution of cutaneous lesions was periorbital (59.3%), which falls within the previously reported range of 35% to 78%,5,7,157,158 and the eye was the leading site of extracutaneous involvement. Based on the 27% rate of eye involvement in patients evaluated by ophthalmology in this multicenter cohort, we suggest that an ophthalmology referral be considered for all patients with NXG. In addition, these data highlight the potential for multiorgan involvement, including the brain, gastrointestinal tract, heart, liver, lung, lymphoreticular system, muscle, and parotid gland.

    Body mass index has been inconsistently reported in the literature; therefore, it is difficult to determine whether the overweight mean body mass index of 27.0 in the multicenter cohort is a reliable feature of NXG. Diagnosis with NXG has been associated with a low high-density lipoprotein–cholesterol phenotype,8 which was found in 24% of patients tested. In the multicenter cohort, 41% of patients tested had low high-density lipoprotein–cholesterol level, even though 38% were taking 1 or more medications known to elevate high-density lipoprotein–cholesterol levels. By comparison, approximately 18% of adults in the United States have low high-density lipoprotein–cholesterol levels.159 Interactions between the paraprotein and lipoproteins are hypothesized to impair macrophage-lipid homeostasis, promote systemic inflammation, and generate immune complexes. Necrobiotic xanthogranuloma has been associated with acquired early complement deficiencies and cryoglobulinemia.7,8 Of the patients tested in our cohort, 61% had low C4 levels, and 23% had cryoglobulinemia. Finally, we identified a pattern of low 25-hydroxyvitamin D with normal or high 1,25-dihydroxyvitamin D. Granuloma-mediated production of 1α-hydroxylase, a well-documented phenomenon in patients with sarcoidosis, may lead to increased synthesis of 1,25-dihydroxyvitamin D and subsequent hypercalcemia.10,160 Given small sample sizes, the associations between these abnormal results of laboratory tests and NXG merit further investigations.

    In the multicenter cohort, intravenous immunoglobulin had the best response rate (100%), followed by antimalarial drugs (80%), intralesional triamcinolone (75%), surgery (75%), chemotherapy (67%), and lenalidomide or thalidomide (63%). A diversity of treatments for NXG has been reported; however, the literature consists of case reports, case series, and retrospective studies.161 Prospective, controlled clinical studies are essential to guide practice.

    The participants in the consensus exercise to propose diagnostic criteria for NXG strongly agreed (mean ranking, 4.6 of 5 points) that cutaneous papules, plaques, and/or nodules should be a major criterion. Given that 60% of NXG lesions in the cohort were yellow or orange in color, this was included with the qualifier most often to indicate a helpful but not mandatory clinical feature. Whether histopathological testing should be required for diagnosis emerged as a key point of discussion. To differentiate NXG from clinical mimics, participants strongly agreed (mean ranking, 4.5 of 5 points) that palisading granulomas with lymphoplasmacytic infiltrate and zones of necrobiosis should be a major criterion. Cholesterol clefts and/or giant cells (Touton or foreign body) were included as characteristic but variably present histopathological features. A second key point of discussion was whether paraproteinemia, most often IgG-κ, plasma-cell dyscrasia, and/or other associated lymphoproliferative disorder should be required for diagnosis. Noting the absence of these associations in 16% of patients with NXG in our cohort, participants strongly agreed (mean ranking, 4.6 of 5 points) that this should be a minor criterion. Participants agreed (mean ranking, 3.9 of 5 points) that periorbital distribution of cutaneous lesions should be a minor criterion. Finally, whether the major criteria should be sufficient to establish the diagnosis of NXG emerged as a third key point of discussion. Participants expressed concern that necrobiosis lipoidica, given shared clinicopathological features, could be misdiagnosed as NXG. Therefore, in the absence of foreign body, infection, or other identifiable cause, both major criteria and at least 1 minor criterion were required for diagnosis. Ongoing research is necessary to validate these criteria so that they may guide clinical research efforts, such as selecting patients for clinical trials.

    Limitations

    These results should be interpreted in the context of the study design. The retrospective nature of the multicenter cross-sectional study and systematic review may lead to information bias, and the tertiary care setting may limit generalizability to other study populations. A standardized data-collection tool was used to minimize variability; however, data were collected from physician notes and the literature, creating the potential for inconsistent reporting. Moreover, data collected at initial presentation to a tertiary academic referral center may differ from that collected at NXG onset. Response rates are limited by an inability to determine individual response for concurrent treatments. Finally, a potential limitation of the consensus-exercise method was the lack of face-to-face discussion. However, we opted to maintain anonymity to enable participants to formulate and express opinions independently.

    Conclusions

    This study of 235 patients describes the largest NXG cohort in the published literature, to our knowledge. The results provide insight into the demographics, comorbidities, clinical features, and treatment response of NXG. Eight board-certified dermatologists informed by these results participated in a consensus exercise to propose the first diagnostic criteria for NXG. While these criteria require validation, they represent a step forward in standardizing the diagnosis of this rare disorder for use in clinical research.

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    Article Information

    Accepted for Publication: November 7, 2019.

    Corresponding Author: Arash Mostaghimi, MD, MPA, MPH, Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, 221 Longwood Ave, Boston, MA 02115 (amostaghimi@bwh.harvard.edu).

    Published Online: January 15, 2020. doi:10.1001/jamadermatol.2019.4221

    Author Contributions: Drs Mostaghimi and Nelson had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Wanat, Rosenbach, and Mostaghimi contributed equally and share senior authorship.

    Concept and design: Nelson, Hashemi, Noe, Vleugels, Rosenbach, Mostaghimi.

    Acquisition, analysis, or interpretation of data: Nelson, Zhong, Hashemi, Ashchyan, Brown-Joel, Imadojemu, Micheletti, Wanat, Rosenbach, Mostaghimi.

    Drafting of the manuscript: Nelson, Vleugels.

    Critical revision of the manuscript for important intellectual content: Zhong, Hashemi, Ashchyan, Brown-Joel, Noe, Imadojemu, Micheletti, Vleugels, Wanat, Rosenbach, Mostaghimi.

    Statistical analysis: Nelson, Hashemi, Ashchyan.

    Administrative, technical, or material support: Ashchyan, Brown-Joel, Micheletti, Wanat, Rosenbach, Mostaghimi.

    Supervision: Vleugels, Wanat, Rosenbach, Mostaghimi.

    Conflict of Interest Disclosures: Dr Brown-Joel reports grants from the National Center for Advancing Translational Sciences of the National Institutes of Health during the conduct of the study. Dr Rosenbach reports personal fees from Merck, grants and personal fees from Processa Pharma, and personal fees from aTyr Pharma outside the submitted work. Dr Vleugels reports research support from Pfizer outside the submitted work. Dr Mostaghimi reports personal fees from Pfizer and 3Derm, personal fees from and equity in Hims, equity in Lucid, and participation in clinical trials with Incyte, Aclaris, Concert, and Lilly, outside the submitted work. No other disclosures were reported.

    Funding/Support: For the use of electronic medical records data collection service at University of Iowa Hospitals and Clinics, research reported in this article was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health (grant UL1TR002537).

    Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Disclaimer: Dr Rosenbach is Deputy Editor and Dr Mostaghimi is Associate Editor of JAMA Dermatology, but they were not involved in any of the decisions regarding review of the manuscript or its acceptance. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

    Additional Contributions: We thank medical librarian Paul Bain, PhD, MLIS, Harvard Medical School, for his assistance in developing our search strategy for the systematic review. He was not compensated for his contributions.

    References
    1.
    Kossard  S, Winkelmann  RK.  Necrobiotic xanthogranuloma.  Australas J Dermatol. 1980;21(2):85-88. doi:10.1111/j.1440-0960.1980.tb00148.xPubMedGoogle ScholarCrossref
    2.
    Lipsker  D.  Monoclonal gammopathy of cutaneous significance: review of a relevant concept.  J Eur Acad Dermatol Venereol. 2017;31(1):45-52. doi:10.1111/jdv.13847PubMedGoogle ScholarCrossref
    3.
    Hunter  L, Burry  AF.  Necrobiotic xanthogranuloma: a systemic disease with paraproteinemia.  Pathology. 1985;17(3):533-536. doi:10.3109/00313028509105517PubMedGoogle ScholarCrossref
    4.
    Winkelmann  RK, Litzow  MR, Umbert  IJ, Lie  JT.  Giant cell granulomatous pulmonary and myocardial lesions in necrobiotic xanthogranuloma with paraproteinemia.  Mayo Clin Proc. 1997;72(11):1028-1033. doi:10.4065/72.11.1028PubMedGoogle ScholarCrossref
    5.
    Ugurlu  S, Bartley  GB, Gibson  LE.  Necrobiotic xanthogranuloma: long-term outcome of ocular and systemic involvement.  Am J Ophthalmol. 2000;129(5):651-657. doi:10.1016/S0002-9394(99)00469-9PubMedGoogle ScholarCrossref
    6.
    Bolognia  JL, Schaffer  JV, Cerroni  L.  Dermatology. 4th ed. Philadelphia: Elsevier Saunders; 2018.
    7.
    Szalat  R, Arnulf  B, Karlin  L,  et al.  Pathogenesis and treatment of xanthomatosis associated with monoclonal gammopathy.  Blood. 2011;118(14):3777-3784. doi:10.1182/blood-2011-05-356907PubMedGoogle ScholarCrossref
    8.
    Szalat  R, Pirault  J, Fermand  JP,  et al.  Physiopathology of necrobiotic xanthogranuloma with monoclonal gammopathy.  J Intern Med. 2014;276(3):269-284. doi:10.1111/joim.12195PubMedGoogle ScholarCrossref
    9.
    Wood  AJ, Wagner  MV, Abbott  JJ, Gibson  LE.  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.2008.583PubMedGoogle ScholarCrossref
    10.
    Sfeir  JG, Zogala  RJ, Popii  VB.  Hypercalcemia in necrobiotic xanthogranuloma: first reported case and insight into treatment.  J Bone Miner Res. 2017;32(4):784-787. doi:10.1002/jbmr.3047PubMedGoogle ScholarCrossref
    11.
    Al-Bermani  A, Figueiredo  F, Speight  EL, Jackson  GH, Pandit  R.  Necrobiotic xanthogranuloma masquerading as posterior scleritis.  Eye (Lond). 2009;23(1):239-240. doi:10.1038/eye.2008.37PubMedGoogle ScholarCrossref
    12.
    Al-Niaimi  FA, Dawn  G, Cox  NH.  Necrobiotic xanthogranuloma without paraproteinaemia: marked improvement with psoralen ultraviolet A treatment.  Clin Exp Dermatol. 2010;35(3):275-277. doi:10.1111/j.1365-2230.2009.03447.xPubMedGoogle ScholarCrossref
    13.
    AlGain  M, Szalat  R, Vignon-Pennamen  MD,  et al.  A rare case of disseminated skin and mucosal necrobiotic xanthogranuloma and xanthoma.  J Eur Acad Dermatol Venereol. 2017;31(1):e3-e5. doi:10.1111/jdv.13577PubMedGoogle ScholarCrossref
    14.
    Ali  FR, Green  R, Chularojanamontri  L, Young  HS, Motta  L.  Recurrent posterior scleritis and a ‘sebaceous cyst’: Extrafacial necrobiotic xanthogranuloma.  Br J Dermatol. 2012;167:18-19.Google Scholar
    15.
    Amer  R, Pe’er  J, Pappo  O, Dotan  S.  Necrobiotic xanthogranuloma associated with choroidal infiltration and syncytial giant cell hepatitis.  J Neuroophthalmol. 2005;25(3):189-192. doi:10.1097/01.wno.0000177299.44845.65PubMedGoogle ScholarCrossref
    16.
    Bain  EE  III, Meehan  SA, Hale  EK.  Solitary necrobiotic xanthogranuloma of an upper extremity in association with multiple myeloma.  J Drugs Dermatol. 2014;13(5):598-600.PubMedGoogle Scholar
    17.
    Balagula  Y, Straus  DJ, Pulitzer  MP, Lacouture  ME.  Necrobiotic xanthogranuloma associated with immunoglobulin m paraproteinemia in a patient with Waldenström macroglobulinemia.  J Clin Oncol. 2011;29(11):e305-e307. doi:10.1200/JCO.2010.32.4921PubMedGoogle ScholarCrossref
    18.
    Barzilai  A, Trau  H, Shpiro  D, Yorav  S.  Necrobiotic xanthogranuloma with paraproteinemia.  Cutis. 1996;57(5):320-322.PubMedGoogle Scholar
    19.
    Betts  CM, Pasquinelli  G, Costa  AM, Fanti  PA, Misciali  C, Varotti  C.  Necrobiotic xanthogranuloma without periorbital involvement: an ultrastructural investigation.  Ultrastruct Pathol. 2001;25(6):437-444. doi:10.1080/019131201753343476PubMedGoogle ScholarCrossref
    20.
    Bhari  N, Chiramel  MJ, Vedi  KK,  et al.  Necrobiotic xanthogranuloma with multiple myeloma.  Clin Exp Dermatol. 2015;40(7):811-814. doi:10.1111/ced.12620PubMedGoogle ScholarCrossref
    21.
    Bortolani  A, Barisoni  D, Bontempini  L.  Necrobiotic xanthogranuloma of the eyelids with paraproteinemia.  Eur J Plast Surg. 1999;22(1):36-39. doi:10.1007/s002380050141Google ScholarCrossref
    22.
    Bullock  JD, Bartley  GB, Campbell  RJ, Yanes  B, Connelly  PJ, Funkhouser  JW.  Necrobiotic xanthogranuloma with paraproteinemia: case report and a pathogenetic theory.  Trans Am Ophthalmol Soc. 1986;84:342-354.PubMedGoogle Scholar
    23.
    Burdick  AE, Sanchez  J, Elgart  GW.  Necrobiotic xanthogranuloma associated with a benign monoclonal gammopathy.  Cutis. 2003;72(1):47-50.PubMedGoogle Scholar
    24.
    Butterfield  JH, Bartley  GB.  Atypical periorbital xanthogranulomas associated with systemic benign lymphoepithelial lesions.  Ophthalmic Plast Reconstr Surg. 1994;10(4):287-292. doi:10.1097/00002341-199412000-00014PubMedGoogle ScholarCrossref
    25.
    Carabelli  A, Cecca  E, Crovetti  G,  et al.  IgG lambda multiple myeloma and diffuse necrobiotic xanthogranuloma association: a case report.  Eur J Dermatol. 1997;7(7):519-521.Google Scholar
    26.
    Chandra  S, Finklestein  E, Gill  D.  Necrobiotic xanthogranuloma occurring within linear morphoea.  Australas J Dermatol. 2002;43(1):52-54. doi:10.1046/j.1440-0960.2002.00553.xPubMedGoogle ScholarCrossref
    27.
    Chang  SE, Lee  WS, Lee  MW,  et al.  A case of necrobiotic xanthogranuloma without paraproteinemia presenting as a solitary tumor on the thigh.  Int J Dermatol. 2003;42(6):470-472. doi:10.1046/j.1365-4362.2003.01716_1.xPubMedGoogle ScholarCrossref
    28.
    Char  DH, LeBoit  PE, Ljung  BM, Wara  W.  Radiation therapy for ocular necrobiotic xanthogranuloma.  Arch Ophthalmol. 1987;105(2):174-175. doi:10.1001/archopht.1987.01060020028014PubMedGoogle ScholarCrossref
    29.
    Chave  TA, Chowdhury  MM, Holt  PJ.  Recalcitrant necrobiotic xanthogranuloma responding to pulsed high-dose oral dexamethasone plus maintenance therapy with oral prednisolone.  Br J Dermatol. 2001;144(1):158-161. doi:10.1046/j.1365-2133.2001.03967.xPubMedGoogle ScholarCrossref
    30.
    Chave  TA, Hutchinson  PE.  Necrobiotic xanthogranuloma with two monoclonal paraproteins and no periorbital involvement at presentation.  Clin Exp Dermatol. 2001;26(6):493-496. doi:10.1046/j.1365-2230.2001.00873.xPubMedGoogle ScholarCrossref
    31.
    Chen  KY, Leslie  W, Mahon  B, Venugopal  P.  A patient with necrobiotic xanthogranuloma presenting with an anterior mediastinal mass, plasma cell dyscrasia, and a lymphoproliferative disorder.  Clin Adv Hematol Oncol. 2011;9(9):696-700.PubMedGoogle Scholar
    32.
    Codère  F, Lee  RD, Anderson  RL.  Necrobiotic xanthogranuloma of the eyelid.  Arch Ophthalmol. 1983;101(1):60-63. doi:10.1001/archopht.1983.01040010062009PubMedGoogle ScholarCrossref
    33.
    Cornblath  WT, Dotan  SA, Trobe  JD, Headington  JT.  Varied clinical spectrum of necrobiotic xanthogranuloma.  Ophthalmology. 1992;99(1):103-107. doi:10.1016/S0161-6420(92)32031-7PubMedGoogle ScholarCrossref
    34.
    Criado  PR, Vasconcellos  C, Pegas  JR,  et al.  Necrobiotic xanthogranuloma with lambda paraproteinemia: case report of successful treatment with melphalan and prednisone.  J Dermatolog Treat. 2002;13(2):87-89. doi:10.1080/095466302317584458PubMedGoogle ScholarCrossref
    35.
    Criton  S, Asokan  PU, Pailey  S, Kuttappan  SS, Rodriguez  FP; Remani.  Necrobiotic xanthogranuloma with paraproteinaemia.  Indian J Dermatol Venereol Leprol. 1996;62(6):383-385.PubMedGoogle Scholar
    36.
    Dabiri  S, Morales  A, Ma  L,  et al.  The frequency of dual TCR-PCR clonality in granulomatous disorders.  J Cutan Pathol. 2011;38(9):704-709. doi:10.1111/j.1600-0560.2011.01727.xPubMedGoogle ScholarCrossref
    37.
    Davies  MJ, Whitehead  K, Quagliotto  G, Wood  D, Patheja  RS, Sullivan  TJ.  Adult orbital and adnexal xanthogranulomatous disease.  Asia Pac J Ophthalmol (Phila). 2017;6(5):435-443.PubMedGoogle Scholar
    38.
    DeLuca  IJ, Grossman  ME.  Vulvar necrobiotic xanthogranuloma.  J Am Acad Dermatol. 2014;71(6):e247-e248. doi:10.1016/j.jaad.2014.04.039PubMedGoogle ScholarCrossref
    39.
    Dholaria  BR, Cappel  M, Roy  V.  Necrobiotic xanthogranuloma associated with monoclonal gammopathy: successful treatment with lenalidomide and dexamethasone.  Ann Hematol. 2016;95(4):671-672. doi:10.1007/s00277-016-2604-3PubMedGoogle ScholarCrossref
    40.
    Dilnawaz  M.  An unusual skin presentation of necrobiotic xanthogranuloma.  J Coll Physicians Surg Pak. 2010;20(4):274-275.PubMedGoogle Scholar
    41.
    Dupré  A, Viraben  R.  Necrobiotic xanthogranuloma: a case without paraproteinemia but with transepithelial elimination.  J Cutan Pathol. 1988;15(2):116-119. doi:10.1111/j.1600-0560.1988.tb00530.xPubMedGoogle ScholarCrossref
    42.
    Efebera  Y, Blanchard  E, Allam  C, Han  A, Lee  S, Munshi  N.  Complete response to thalidomide and dexamethasone in a patient with necrobiotic xanthogranuloma associated with monoclonal gammopathy: a case report and review of the literature.  Clin Lymphoma Myeloma Leuk. 2011;11(3):298-302. doi:10.1016/j.clml.2011.03.020PubMedGoogle ScholarCrossref
    43.
    Elner  VM, Mintz  R, Demirci  H, Hassan  AS.  Local corticosteroid treatment of eyelid and orbital xanthogranuloma.  Ophthalmic Plast Reconstr Surg. 2006;22(1):36-40. doi:10.1097/01.iop.0000192645.24814.e8PubMedGoogle ScholarCrossref
    44.
    Esmaeli  N, Ghanadan  A, Mansouri  P, Ghaedi  F.  Necrobiotic xanthogranuloma after penicillin injection: A case report.  Iranian J Dermatol. 2017;20(1):26-28.Google Scholar
    45.
    Ferrara  G, Palombi  N, Lipizzi  A, Zalaudek  I, Argenziano  G.  Nonnecrobiotic necrobiotic xanthogranuloma.  Am J Dermatopathol. 2007;29(3):306-308. doi:10.1097/DAD.0b013e3180332b8bPubMedGoogle ScholarCrossref
    46.
    Finelli  LG, Ratz  JL.  Plasmapheresis, a treatment modality for necrobiotic xanthogranuloma.  J Am Acad Dermatol. 1987;17(2 Pt 2):351-354. doi:10.1016/S0190-9622(87)70211-4PubMedGoogle ScholarCrossref
    47.
    Fink  C, Schneiderbauer  R, Hartschuh  W, Enk  A, Toberer  F.  Necrobiotic xanthogranuloma associated with chronic lymphocytic leukemia.  Int J Dermatol. 2018;57(6):719-720. doi:10.1111/ijd.13951PubMedGoogle ScholarCrossref
    48.
    Flann  S, Wain  EM, Halpern  S, Andrews  V, Whittaker  S.  Necrobiotic xanthogranuloma with paraproteinaemia.  Clin Exp Dermatol. 2006;31(2):248-251. doi:10.1111/j.1365-2230.2005.02042.xPubMedGoogle ScholarCrossref
    49.
    Fortson  JS, Schroeter  AL.  Necrobiotic xanthogranuloma with IgA paraproteinemia and extracutaneous involvement.  Am J Dermatopathol. 1990;12(6):579-584. doi:10.1097/00000372-199012000-00008PubMedGoogle ScholarCrossref
    50.
    Fu  T, Zwerner  J, Kim  J, Tang  J.  Subcutaneous nodules in an elderly patient. Necrobiotic xanthogranuloma.  Arch Dermatol. 2011;147(10):1215-1220. doi:10.1001/archdermatol.2011.285-aPubMedGoogle ScholarCrossref
    51.
    Furner  BB, Stevens  CS.  Diffuse, ulcerating plaques and nodules. Necrobiotic xanthogranuloma (NXG) with paraproteinemia.  Arch Dermatol. 1989;125(2):287-288, 290. doi:10.1001/archderm.1989.01670140139028PubMedGoogle ScholarCrossref
    52.
    Gacto  P, Barrera  F, Pereyra  JJ, Fernández-Ortega  P.  [Necrobiotic xanthogranuloma: efficacy of surgery in 2 patients]  [in Spanish].  Actas Dermosifiliogr. 2009;100(6):499-502. doi:10.1016/S0001-7310(09)71597-2PubMedGoogle ScholarCrossref
    53.
    Georgiou  S, Monastirli  A, Kapranos  N, Pasmatzi  E, Sakkis  Th, Tsambaos  D.  Interferon alpha-2a monotherapy for necrobiotic xanthogranuloma.  Acta Derm Venereol. 1999;79(6):484-485. doi:10.1080/000155599750010030PubMedGoogle ScholarCrossref
    54.
    Gergen  N, Biebl  K, Berg  BC, Suwattee  P.  Slowly growing yellow nodules: challenge. Necrobiotic xanthogranuloma.  Am J Dermatopathol. 2011;33(1):92-93, 103-104. doi:10.1097/DAD.0b013e3181d435a0PubMedGoogle ScholarCrossref
    55.
    Ghani  S, Al Ustwani  O, Khalid  B,  et al.  Periorbital necrobiotic xanthogranuloma treated successfully with novel multiple myeloma therapy.  Clin Adv Hematol Oncol. 2013;11(10):678-680.PubMedGoogle Scholar
    56.
    Ghiasi  N, Alavi  A, Coutts  PM, Ghazarian  D, Sibbald  RG.  Necrobiotic xanthogranuloma as an unusual cause of refractive chronic bilateral leg ulceration.  Int J Low Extrem Wounds. 2012;11(4):293-295. doi:10.1177/1534734612465434PubMedGoogle ScholarCrossref
    57.
    Girisha  BS, Holla  AP, Fernandes  M, Noronha  TM.  Necrobiotic xanthogranuloma.  J Cutan Aesthet Surg. 2012;5(1):43-45. doi:10.4103/0974-2077.94341PubMedGoogle ScholarCrossref
    58.
    Goede  JS, Misselwitz  B, Taverna  C,  et al.  Necrobiotic xanthogranuloma successfully treated with autologous stem cell transplantation.  Ann Hematol. 2007;86(4):303-306. doi:10.1007/s00277-006-0231-0PubMedGoogle ScholarCrossref
    59.
    Gonzales  JA, Haemel  A, Gross  AJ, Acharya  NR.  Management of uveitis and scleritis in necrobiotic xanthogranuloma.  J Ocul Pharmacol Ther. 2017;33(4):325-333. doi:10.1089/jop.2016.0135PubMedGoogle ScholarCrossref
    60.
    Goyal  A, O’Leary  D, Vercellotti  G, Miller  D, McGlave  P.  Intravenous immunoglobulin for treatment of necrobiotic xanthogranuloma.  Dermatol Ther. 2019;32(1):e12744. doi:10.1111/dth.12744PubMedGoogle Scholar
    61.
    Gün  D, Demirçay  Z, Demirkesen  C.  Necrobiotic xanthogranuloma in a burn scar.  Int J Dermatol. 2004;43(4):293-295. doi:10.1111/j.1365-4632.2004.01858.xPubMedGoogle ScholarCrossref
    62.
    Hallermann  C, Tittelbach  J, Norgauer  J, Ziemer  M.  Successful treatment of necrobiotic xanthogranuloma with intravenous immunoglobulin.  Arch Dermatol. 2010;146(9):957-960. doi:10.1001/archdermatol.2010.236PubMedGoogle ScholarCrossref
    63.
    Hamilton  HK, Dover  JS, Arndt  KA.  Successful treatment of disfiguring hemosiderin-containing hyperpigmentation with the Q-switched 650-nm wavelength laser.  JAMA Dermatol. 2014;150(11):1221-1222. doi:10.1001/jamadermatol.2014.1838PubMedGoogle ScholarCrossref
    64.
    Hashemi  P, Rashidi  A, Chapas  AM, Balfour  EM.  Necrobiotic xanthogranuloma of the extremities with paraproteinemia and without periorbital involvement at presentation.  Cutis. 2012;89(1):41-44.PubMedGoogle Scholar
    65.
    Hauser  C, Schifferli  J, Saurat  JH.  Complement consumption in a patient with necrobiotic xanthogranuloma and paraproteinemia.  J Am Acad Dermatol. 1991;24(5 pt 2):908-911. doi:10.1016/0190-9622(91)70145-RPubMedGoogle ScholarCrossref
    66.
    Herd  TJ, Fischer  R, Christensen  LC, Rajpara  A.  Irregular yellow-brown plaques on the trunk and thighs.  Cutis. 2018;101(1):12-15, 15.PubMedGoogle Scholar
    67.
    Holden  CA, Winkelmann  RK, Wilson Jones  E.  Necrobiotic xanthogranuloma: a report of four cases.  Br J Dermatol. 1986;114(2):241-250. doi:10.1111/j.1365-2133.1986.tb02804.xPubMedGoogle ScholarCrossref
    68.
    Inthasotti  S, Wanitphakdeedecha  R, Manonukul  J.  A 7-year history of necrobiotic xanthogranuloma following asymptomatic multiple myeloma: a case report.  Dermatol Res Pract. 2011;2011:927852. doi:10.1155/2011/927852PubMedGoogle Scholar
    69.
    Ito  Y, Nishimura  K, Yamanaka  K,  et al.  Necrobiotic xanthogranuloma with paraproteinemia; an atypical case.  J Dtsch Dermatol Ges. 2008;6(1):40-43.PubMedGoogle ScholarCrossref
    70.
    Jeziorska  M, Hassan  A, Mackness  MI,  et al.  Clinical, biochemical, and immunohistochemical features of necrobiotic xanthogranulomatosis.  J Clin Pathol. 2003;56(1):64-68. doi:10.1136/jcp.56.1.64PubMedGoogle ScholarCrossref
    71.
    Johnston  KA, Grimwood  RE, Meffert  JJ, Deering  KC.  Necrobiotic xanthogranuloma with paraproteinemia: an evolving presentation.  Cutis. 1997;59(6):333-336.PubMedGoogle Scholar
    72.
    Kadakia  S, Nadkarni  N, Sonavane  S, Ghate  S.  Spectacular skin nodules: cutaneous necrobiotic xanthogranuloma without paraproteinemia.  Indian J Dermatol. 2012;57(5):396-398. doi:10.4103/0019-5154.100499PubMedGoogle ScholarCrossref
    73.
    Kawakami  Y, Yamamoto  T.  Letter: Necrobiotic xanthogranuloma of extremities in an elderly patient successfully treated with low-dose prednisolone.  Dermatol Online J. 2011;17(6):13.PubMedGoogle Scholar
    74.
    Keorochana  N, Klanarongran  K, Satayasoontorn  K, Chaiamnuay  S.  Necrobiotic xanthogranuloma scleritis in a case of granulomatosis with polyangiitis (Wegener’s granulomatosis).  Int Med Case Rep J. 2017;10:323-328. doi:10.2147/IMCRJ.S145943PubMedGoogle ScholarCrossref
    75.
    Khan  IJ, Azam  NA, Sullivan  SC, Habboush  HW, Christian  A.  Necrobiotic xanthogranuloma successfully treated with a combination of dexamethasone and oral cyclophosphamide.  Can J Ophthalmol. 2009;44(3):335-336. doi:10.3129/i09-021PubMedGoogle ScholarCrossref
    76.
    Khan  M, Ahmed  I, Carr  R.  An unusual subcutaneous lump.  Clin Exp Dermatol. 2012;37(7):808-810. doi:10.1111/j.1365-2230.2011.04280.xPubMedGoogle ScholarCrossref
    77.
    Koch  D, Lucas  G, Durrington  P, Lear  JT.  Ulcerating necrobiotic xanthogranulomata and paraproteinaemia treated with thalidomide.  Br J Dermatol. 2008;159:16-17.Google Scholar
    78.
    Koch  PS, Goerdt  S, Géraud  C.  Erythematous papules, plaques, and nodular lesions on the trunk and within preexisting scars.  JAMA Dermatol. 2013;149(9):1103-1104. doi:10.1001/jamadermatol.2013.186PubMedGoogle ScholarCrossref
    79.
    Kossard  S, Chow  E, Wilkinson  B, Killingsworth  M.  Lipid and giant cell poor necrobiotic xanthogranuloma.  J Cutan Pathol. 2000;27(7):374-378. doi:10.1034/j.1600-0560.2000.027007374.xPubMedGoogle ScholarCrossref
    80.
    Kovalyshyn  I, Busam  KJ, Marghoob  AA.  Orange-yellow diffuse cutaneous eruption in an 82-year-old woman.  Arch Dermatol. 2009;145(10):1183-1188. doi:10.1001/archdermatol.2009.213-aPubMedGoogle ScholarCrossref
    81.
    Kunikata  N, Kikuchi  K, Hashimoto  A, Tagami  H.  Necrobiotic xanthogranuloma of the nose without paraproteinemia.  J Dermatol. 2006;33(11):809-812. doi:10.1111/j.1346-8138.2006.00184.xPubMedGoogle ScholarCrossref
    82.
    Lam  K, Brownstein  S, Jordan  DR, van der Jagt  R, Jastrzebski  A, Dionne  MA.  Bilateral necrobiotic xanthogranuloma of the eyelids followed by a diagnosis of multiple myeloma 20 years later.  Ophthalmic Plast Reconstr Surg. 2013;29(5):e119-e120. doi:10.1097/IOP.0b013e318279fdefPubMedGoogle ScholarCrossref
    83.
    Langlois  S, Brochot  P, Reguiai  Z,  et al.  Necrobiotic xanthogranuloma with multiple myeloma. Case report and pathogenic hypotheses.  Joint Bone Spine. 2006;73(1):120-122. doi:10.1016/j.jbspin.2005.03.008PubMedGoogle ScholarCrossref
    84.
    Le  AV, Fenske  NA.  An unusual granulomatous disease in the elderly.  Arch Dermatol. 1997;133(10):1303-1304, 1306-1307. doi:10.1001/archderm.1997.03890460129018PubMedGoogle ScholarCrossref
    85.
    Lebey  PB, Determer  I, Bazex  J, el Sayed  F, Marguery  MC.  Periorbital papules and nodules. Necrobiotic xanthogranuloma.  Arch Dermatol. 1997;133(1):99-102, 102. doi:10.1001/archderm.133.1.99PubMedGoogle ScholarCrossref
    86.
    Lee  HJ, Kim  JM, Kim  GW,  et al.  Necrobiotic xanthogranuloma treated with a combination of oral methylprednisolone and cyclosporin.  J Dermatol. 2017;44(10):1190-1191. doi:10.1111/1346-8138.13648PubMedGoogle ScholarCrossref
    87.
    Li  S, Chen  AJ, Fang  S, Li  H.  Successful treatment of necrobiotic xanthogranuloma with total glucosides of paeony.  Dermatol Ther. 2014;27(5):304-306. doi:10.1111/dth.12133PubMedGoogle ScholarCrossref
    88.
    Liszewski  W, Wisniewski  JD, Safah  H, Boh  EE.  Treatment of refractory necrobiotic xanthogranulomas with extracorporeal photopheresis and intravenous immunoglobulin.  Dermatol Ther. 2014;27(5):268-271. doi:10.1111/dth.12135PubMedGoogle ScholarCrossref
    89.
    Luck  J, Layton  A, Noble  BA.  Necrobiotic xanthogranuloma with orbital involvement.  J R Soc Med. 1992;85(6):357-358.PubMedGoogle Scholar
    90.
    Lukács  J, Goetze  S, Elsner  P.  Periocular necrobiotic xanthogranuloma successfully treated with intravenous immunoglobulin.  Acta Derm Venereol. 2017;97(6):754-755. doi:10.2340/00015555-2626PubMedGoogle ScholarCrossref
    91.
    Macfarlane  AW, Verbov  JL.  Necrobiotic xanthogranuloma with paraproteinaemia.  Br J Dermatol. 1985;113(3):339-343. doi:10.1111/j.1365-2133.1985.tb02087.xPubMedGoogle ScholarCrossref
    92.
    McGregor  JM, Miller  J, Smith  NP, Hay  RJ.  Necrobiotic xanthogranuloma without periorbital lesions.  J Am Acad Dermatol. 1993;29(3):466-469. doi:10.1016/0190-9622(93)70212-CPubMedGoogle ScholarCrossref
    93.
    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(5):458-462.PubMedGoogle Scholar
    94.
    Mahendran  P, Wee  J, Chong  H, Natkunarajah  J.  Necrobiotic xanthogranuloma treated with lenalidomide.  Clin Exp Dermatol. 2018;43(3):345-347. doi:10.1111/ced.13293PubMedGoogle ScholarCrossref
    95.
    Martínez Fernández  M, Rodríguez Prieto  MA, Ruiz González  I, Sánchez Sambucety  P, Delgado Vicente  S.  Necrobiotic xanthogranuloma associated with myeloma.  J Eur Acad Dermatol Venereol. 2004;18(3):328-331. doi:10.1111/j.1468-3083.2004.00906.xPubMedGoogle ScholarCrossref
    96.
    Mathias  M, Permi  HS, Shetty  P, Jayaprakash Shetty  K, Girish  BS.  Necrobiotic xanthogranuloma presenting as a clinical variant without paraproteinemia.  Nitte University Journal of Health Science. 2011;1(1-3):72-74.Google Scholar
    97.
    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)00260-3PubMedGoogle ScholarCrossref
    98.
    Meyer  S, Szeimies  RM, Landthaler  M, Hohenleutner  S.  Cyclophosphamide-dexamethasone pulsed therapy for treatment of recalcitrant necrobiotic xanthogranuloma with paraproteinemia and ocular involvement.  Br J Dermatol. 2005;153(2):443-445. doi:10.1111/j.1365-2133.2005.06737.xPubMedGoogle ScholarCrossref
    99.
    Minocha  R, Lee  S, Choi  JYJ, Mann  S.  Necrobiotic xanthogranuloma: a report of two fascinating cases.  Hong Kong J Dermat Venereol. 2017;25(2):84-89.Google Scholar
    100.
    Miszkiel  KA, Sohaib  SAA, Rose  GE, Cree  IA, Moseley  IF.  Radiological and clinicopathological features of orbital xanthogranuloma.  Br J Ophthalmol. 2000;84(3):251-258. doi:10.1136/bjo.84.3.251PubMedGoogle ScholarCrossref
    101.
    Mohsenin  A, Sinard  J, Huang  JJ.  Necrobiotic xanthogranuloma and chronic lymphocytic leukemia of the conjunctiva masquerading as scleritis and uveitis.  Clin Ophthalmol. 2012;6:2045-2047. doi:10.2147/OPTH.S35743PubMedGoogle ScholarCrossref
    102.
    Muscardin  LM, Mastroianni  A, Chistolini  A, Pulsoni  A.  Necrobiotic xanthogranuloma without periorbital lesions and without paraproteinaemia.  J Eur Acad Dermatol Venereol. 2003;17(2):233-235. doi:10.1046/j.1468-3083.2003.00577_6.xPubMedGoogle ScholarCrossref
    103.
    Naghashpour  M, Setoodeh  R, Moscinski  L,  et al.  Nonnecrobiotic necrobiotic xanthogranuloma as an initial manifestation of paraproteinemia and small lymphocytic lymphoma in a patient with Sjögren syndrome.  Am J Dermatopathol. 2011;33(8):855-857. doi:10.1097/DAD.0b013e3182051fcePubMedGoogle ScholarCrossref
    104.
    Nestle  FO, Hofbauer  G, Burg  G.  Necrobiotic xanthogranuloma with monoclonal gammopathy of the IgG lambda type.  Dermatology. 1999;198(4):434-435.PubMedGoogle Scholar
    105.
    Nishimura  M, Takano-Nishimura  Y, Yano  I, Hayashi  N, Toshitani  S.  Necrobiotic xanthogranuloma in a human T-lymphotropic virus type 1 carrier.  J Am Acad Dermatol. 1992;27(5 pt 2):886-889. doi:10.1016/0190-9622(92)70274-JPubMedGoogle ScholarCrossref
    106.
    Nockowski  P, Woźniak  Z, Reich  A, Maj  J.  Xanthoma-like skin changes in an elderly woman with a normal lipid profile.  Acta Dermatovenerol Croat. 2017;25(2):167-169.PubMedGoogle Scholar
    107.
    Novak  PM, Robbins  TO, Winkelmann  RK.  Necrobiotic xanthogranuloma with myocardial lesions and nodular transformation of the liver.  Hum Pathol. 1992;23(2):195-196. doi:10.1016/0046-8177(92)90244-WPubMedGoogle ScholarCrossref
    108.
    Oestreicher  J, Dookeran  R, Nijhawan  N, Kolin  A.  Necrobiotic xanthogranuloma with predominant periorbital involvement.  Ophthalmic Plast Reconstr Surg. 2010;26(6):473-475. doi:10.1097/IOP.0b013e3181d92955PubMedGoogle ScholarCrossref
    109.
    Olson  RM, Harrison  AR, Maltry  A, Mokhtarzadeh  A.  Periorbital necrobiotic xanthogranuloma successfully treated with intravenous immunoglobulin.  Case Rep Ophthalmol. 2018;9(1):70-75. doi:10.1159/000485913PubMedGoogle ScholarCrossref
    110.
    Omarjee  L, Janin  A, Etienne  G,  et al.  Necrobiotic xanthogranuloma: a paraneoplastic skin lesion of haematological malignancies?  Eur J Dermatol. 2018;28(3):384-386. doi:10.1684/ejd.2018.3256PubMedGoogle ScholarCrossref
    111.
    Oumeish  OY, Oumeish  I, Tarawneh  M, Salman  T, Sharaiha  A.  Necrobiotic xanthogranuloma associated with paraproteinemia and non-Hodgkin’s lymphoma developing into chronic lymphocytic leukemia: the first case reported in the literature and review of the literature.  Int J Dermatol. 2006;45(3):306-310. doi:10.1111/j.1365-4632.2006.02575.xPubMedGoogle ScholarCrossref
    112.
    Pedrosa  AF, Ferreira  O, Calistru  A,  et al.  Necrobiotic xanthogranuloma with giant cell hepatitis, successfully treated with intravenous immunoglobulins.  Dermatol Ther. 2015;28(2):68-70. doi:10.1111/dth.12211PubMedGoogle ScholarCrossref
    113.
    Peyman  A, Walsh  N, Green  P, Dorey  MW, Seamone  C, Pasternak  S.  Necrobiotic xanthogranuloma associated with necrotizing scleritis.  Am J Dermatopathol. 2012;34(6):644-647. doi:10.1097/DAD.0b013e318234e73cPubMedGoogle ScholarCrossref
    114.
    Plotnick  H, Taniguchi  Y, Hashimoto  K, Negendank  W, Tranchida  L.  Periorbital necrobiotic xanthogranuloma and stage I multiple myeloma: ultrastructure and response to pulsed dexamethasone documented by magnetic resonance imaging.  J Am Acad Dermatol. 1991;25(2 pt 2):373-377. doi:10.1016/0190-9622(91)70208-JPubMedGoogle ScholarCrossref
    115.
    Randell  PL, Heenan  PJ.  Necrobiotic xanthogranuloma with paraproteinaemia.  Australas J Dermatol. 1999;40(2):114-115. doi:10.1046/j.1440-0960.1999.00334.xPubMedGoogle ScholarCrossref
    116.
    Rashid  MM, Chowdhury  T, Sultana  A, Begum  R, Islam  S, Ahmed  I.  Necrobiotic xanthogranuloma—a case report.  J Pak Assoc Dermatol. 2009;19(3):175-177.Google Scholar
    117.
    Rayner  SA, Duncombe  AS, Keefe  M, Theaker  J, Manners  RM.  Necrobiotic xanthogranuloma occurring in an eyelid scar.  Orbit. 2008;27(3):191-194. doi:10.1080/01676830701804057PubMedGoogle ScholarCrossref
    118.
    Reddy  VC, Salomão  DR, Garrity  JA, Baratz  KH, Patel  SV.  Periorbital and ocular necrobiotic xanthogranuloma leading to perforation.  Arch Ophthalmol. 2010;128(11):1493-1494. doi:10.1001/archophthalmol.2010.254PubMedGoogle ScholarCrossref
    119.
    Reeder  CB, Connolly  SM, Winkelmann  RK.  The evolution of Hodgkin’s disease and necrobiotic xanthogranuloma syndrome.  Mayo Clin Proc. 1991;66(12):1222-1224. doi:10.1016/S0025-6196(12)62473-2PubMedGoogle ScholarCrossref
    120.
    Rose  GE, Patel  BC, Garner  A, Wright  JE.  Orbital xanthogranuloma in adults.  Br J Ophthalmol. 1991;75(11):680-684. doi:10.1136/bjo.75.11.680PubMedGoogle ScholarCrossref
    121.
    Rose  A, Robinson  M, Kamino  H, Latkowski  JA.  Necrobiotic xanthogranuloma.  Dermatol Online J. 2012;18(12):30.PubMedGoogle Scholar
    122.
    Rubinstein  A, Wolf  DJ, Granstein  RD.  Successful treatment of necrobiotic xanthogranuloma with intravenous immunoglobulin.  J Cutan Med Surg. 2013;17(5):347-350. doi:10.2310/7750.2013.13012PubMedGoogle ScholarCrossref
    123.
    Russo  GG.  Necrobiotic xanthogranuloma with scleroderma.  Cutis. 2002;70(6):311-316.PubMedGoogle Scholar
    124.
    Ryan  E, Warren  LJ, Szabo  F.  Necrobiotic xanthogranuloma: response to chlorambucil.  Australas J Dermatol. 2012;53(2):e23-e25. doi:10.1111/j.1440-0960.2010.00710.xPubMedGoogle Scholar
    125.
    Saeki  H, Tomita  M, Kai  H,  et al.  Necrobiotic xanthogranuloma with paraproteinemia successfully treated with melphalan, prednisolone and skin graft.  J Dermatol. 2007;34(11):795-797. doi:10.1111/j.1346-8138.2007.00387.xPubMedGoogle Scholar
    126.
    Sagiv  O, Thakar  SD, Morrell  G, Tetzlaff  MT, Esmaeli  B.  Rituximab monotherapy is effective in treating orbital necrobiotic xanthogranuloma.  Ophthalmic Plast Reconstr Surg. 2018;34(1):e24-e27. doi:10.1097/IOP.0000000000000988PubMedGoogle Scholar
    127.
    Santosaputri  E, Ellis  EJ, Nagiah  S, Chrispal  A, Thomas  A.  A multisystem granulomatous disease: necrobiotic xanthogranuloma with hepatic involvement.  Med J Aust. 2014;200(8):490-493. doi:10.5694/mja13.11303PubMedGoogle Scholar
    128.
    Schaudig  U, Al-Samir  K.  Upper and lower eyelid reconstruction for severe disfiguring necrobiotic xanthogranuloma.  Orbit. 2004;23(1):65-76. doi:10.1076/orbi.23.1.65.28989PubMedGoogle Scholar
    129.
    Scupham  RK, Fretzin  DF.  Necrobiotic xanthogranuloma with paraproteinemia.  Arch Pathol Lab Med. 1989;113(12):1389-1391.PubMedGoogle Scholar
    130.
    Seastrom  S, Bookout  A, Hogan  DJ.  Necrobiotic xanthogranuloma without a monoclonal gammopathy.  Cutis. 2014;94(6):293-296.PubMedGoogle Scholar
    131.
    Shah  KC, Poonnoose  SI, George  R, Jacob  M, Rajshekhar  V.  Necrobiotic xanthogranuloma with cutaneous and cerebral manifestations. case report and review of the literature.  J Neurosurg. 2004;100(6):1111-1114. doi:10.3171/jns.2004.100.6.1111PubMedGoogle Scholar
    132.
    Silapunt  S, Chon  SY.  Generalized necrobiotic xanthogranuloma successfully treated with lenalidomide.  J Drugs Dermatol. 2010;9(3):273-276.PubMedGoogle Scholar
    133.
    Singh  K, Rajan  KD, Eberhart  C.  Orbital necrobiotic xanthogranuloma associated with systemic IgG4 disease.  Ocul Immunol Inflamm. 2010;18(5):373-378. doi:10.3109/09273948.2010.490629PubMedGoogle Scholar
    134.
    Smith  HG, Sargent  LA, Lundgrin  DB.  Necrobiotic xanthogranuloma of the chest wall.  Dermatol Online J. 2006;12(1):12.PubMedGoogle Scholar
    135.
    Stork  J, Kodetová  D, Vosmík  F, Krejca  M.  Necrobiotic xanthogranuloma presenting as a solitary tumor.  Am J Dermatopathol. 2000;22(5):453-456. doi:10.1097/00000372-200010000-00013PubMedGoogle Scholar
    136.
    Sutton  L, Sutton  S, Sutton  M.  Treatment of necrobiotic xanthogranuloma with 2-chlorodeoxyadenosine.  Skinmed. 2013;11(2):121-123.PubMedGoogle Scholar
    137.
    Torabian  SZ, Fazel  N, Knuttle  R.  Necrobiotic xanthogranuloma treated with chlorambucil.  Dermatol Online J. 2006;12(5):11.PubMedGoogle Scholar
    138.
    Tucker  NA, Discepola  MJ, Blanco  G, Burnier  MN  Jr.  Necrobiotic xanthogranuloma without dermatologic involvement.  Can J Ophthalmol. 1997;32(6):396-399.PubMedGoogle Scholar
    139.
    Umbert  I, Winkelmann  RK.  Necrobiotic xanthogranuloma with cardiac involvement.  Br J Dermatol. 1995;133(3):438-443. doi:10.1111/j.1365-2133.1995.tb02674.xPubMedGoogle Scholar
    140.
    Valentine  EA, Friedman  HD, Zamkoff  KW, Streeten  BW.  Necrobiotic xanthogranuloma with IgA multiple myeloma: a case report and literature review.  Am J Hematol. 1990;35(4):283-285. doi:10.1002/ajh.2830350414PubMedGoogle Scholar
    141.
    Venencie  PY, Puissant  A, Verola  O,  et al.  Necrobiotic xanthogranuloma with myeloma: a case report.  Cancer. 1987;59(3):588-592. doi:10.1002/1097-0142(19870201)59:3<588::AID-CNCR2820590339>3.0.CO;2-CPubMedGoogle Scholar
    142.
    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(4):666-667. doi:10.1016/0190-9622(95)90370-4PubMedGoogle Scholar
    143.
    Vieira  V, Del Pozo  J, Martínez  W, Veiga-Barreiro  JA, Fonseca  E.  Necrobiotic xanthogranuloma associated with lymphoplasmacytic lymphoma. Palliative treatment with carbon dioxide laser.  Eur J Dermatol. 2005;15(3):182-185.PubMedGoogle Scholar
    144.
    Vignon  M, Placais  L, Malphettes  M,  et al.  Non-cirrhotic portal hypertension in necrobiotic xanthogranuloma associated with monoclonal gammopathy.  J Eur Acad Dermatol Venereol. 2017;31(9):e403-e405. doi:10.1111/jdv.14213PubMedGoogle Scholar
    145.
    Vu  K, Gupta  R, Frater  J, Atkinson  J, Ranganathan  P.  A 55-year-old man with periorbital and inguinal masses, pericarditis, and pleuritis.  Arthritis Care Res (Hoboken). 2017;69(5):730-736. doi:10.1002/acr.22843PubMedGoogle Scholar
    146.
    Wee  SA, Shupack  JL.  Necrobiotic xanthogranuloma.  Dermatol Online J. 2005;11(4):24.PubMedGoogle Scholar
    147.
    Wei  YH, Cheng  JJ, Wu  YH,  et al.  Necrobiotic xanthogranuloma: response to dapsone.  Dermatol Ther. 2015;28(1):7-9. doi:10.1111/dth.12179PubMedGoogle Scholar
    148.
    Wells  J, Gillespie  R, Zardawi  I.  Case of recalcitrant necrobiotic xanthogranuloma.  Australas J Dermatol. 2004;45(4):213-215. doi:10.1111/j.1440-0960.2004.00099.xPubMedGoogle Scholar
    149.
    Wolz  M, Peters  MS.  Necrobiotic xanthogranuloma of the extremities.  J Drugs Dermatol. 2012;11(1):122-123.PubMedGoogle Scholar
    150.
    Wruhs  M, Feldmann  R, Sawetz  I, Breier  F, Steiner  A.  Necrobiotic xanthogranuloma in a patient with multiple myeloma.  Case Rep Dermatol. 2016;8(3):350-353. doi:10.1159/000452826PubMedGoogle Scholar
    151.
    Yang  CY, Chung  WH, Rosaline  CYH, Kuo  TT, Yang  CH.  Necrobiotic xanthogranuloma with paraproteinemia without periorbital involvement - a case report.  Zhonghua Pifuke Yixue Zazhi. 2010;28(3):125-129. doi:10.1016/S1027-8117(10)60027-4Google Scholar
    152.
    Yasukawa  K, Kato  N, Hamasaka  A, Hata  H.  Necrobiotic xanthogranuloma: isolated skeletal muscle involvement and unusual changes.  J Am Acad Dermatol. 2005;52(4):729-731. doi:10.1016/j.jaad.2004.12.016PubMedGoogle Scholar
    153.
    Yoon  SY, Park  HJ, Lee  JY, Cho  BK.  Necrobiotic xanthogranuloma with multiple myeloma and no periorbital involvement.  Ann Dermatol. 2007;19(1):22-24. doi:10.5021/ad.2007.19.1.22Google Scholar
    154.
    Zainal  A, Razif  MY, Makhashen  M, Swaminathan  M, Mazita  A.  Necrobiotic xanthogranuloma of the parotid gland.  J Laryngol Otol. 2010;124(5):569-571. doi:10.1017/S0022215109991563PubMedGoogle Scholar
    155.
    Ziemer  M, Wedding  U, Sander  CS, Elsner  P.  Necrobiotic xanthogranuloma-rapid progression under treatment with melphalan.  Eur J Dermatol. 2005;15(5):363-365.PubMedGoogle Scholar
    156.
    Ziemer  M, Norgauer  J, Simon  JC, Koehler  MJ.  An unusual histologic variant of necrobiotic xanthogranuloma.  Am J Dermatopathol. 2012;34(2):e22-e26. doi:10.1097/DAD.0b013e3182222aa8PubMedGoogle Scholar
    157.
    Higgins  LS, Go  RS, Dingli  D,  et al.  Clinical features and treatment outcomes of patients with necrobiotic xanthogranuloma associated with monoclonal gammopathies.  Clin Lymphoma Myeloma Leuk. 2016;16(8):447-452. doi:10.1016/j.clml.2016.04.009PubMedGoogle Scholar
    158.
    Hilal  T, DiCaudo  DJ, Connolly  SM, Reeder  CB.  Necrobiotic xanthogranuloma: a 30-year single-center experience.  Ann Hematol. 2018;97(8):1471-1479. doi:10.1007/s00277-018-3301-1PubMedGoogle Scholar
    159.
    Carroll  MD. Frayar  CD, Nguyen  DT. Total and high-density lipoprotein cholesterol in adults: United States, 2015–2016; NCHS data brief, No. 290, October 2017. https://www.cdc.gov/nchs/data/databriefs/db290.pdf. Published 2017. Accessed November 19, 2019.
    160.
    Sodhi  A, Aldrich  T.  Vitamin D supplementation: not so simple in sarcoidosis.  Am J Med Sci. 2016;352(3):252-257. doi:10.1016/j.amjms.2016.05.027PubMedGoogle Scholar
    161.
    Miguel  D, Lukacs  J, Illing  T, Elsner  P.  Treatment of necrobiotic xanthogranuloma—a systematic review.  J Eur Acad Dermatol Venereol. 2017;31(2):221-235. doi:10.1111/jdv.13786PubMedGoogle Scholar
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