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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. Published online January 15, 2020. 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.

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