Necrobiotic xanthogranuloma is a type of non-Langerhans cell histiocytosis. It is a chronic granulomatous multisystem disease that mainly affects the skin and tissues around the eye. It was first reported by Kossard and Winkelmann in 1980.1)
It most often begins in the 60s, and there is no difference between men and women.1) Lesions outside the skin can also involve the heart, lungs, bronchi, liver, spleen, oropharynx, and digestive tract.
Its most notable feature is a strong association with blood disorders.
It is also generally known that multiple myeloma (a neoplastic proliferation of plasma cells) can rarely cause skin xanthomas. A granuloma is a proliferative chronic inflammation characterized by small nodular lesions made up of macrophage-derived epithelioid cells and multinucleated giant cells, and necrobiotic xanthogranuloma is one form of it.
It is said that 77–84% of patients with necrobiotic xanthogranuloma develop a blood disorder at some point in their lives, so it does not happen in every case, but it is common. Because progression to multiple myeloma has been reported up to 6 years after the onset of necrobiotic xanthogranuloma, regular screening for blood disorders is important.
Skin and periorbital findings
Characteristic skin lesions: yellow to orange papules, nodules, and plaques with induration. They are usually multiple and most often periorbital.
Progression: atrophy, telangiectasia, ulceration, and scarring may occur. New lesions often develop in scarred areas.
Periorbital complications: can cause cicatricial ectropion and lagophthalmos.
Distribution: in addition to the face, it can also occur on the trunk and proximal limbs.
Ocular symptoms
Orbital lesions: orbital mass, proptosis, restrictive strabismus, ptosis.
Conjunctival and scleral lesions: conjunctival lesions, episcleritis, scleritis, diffuse conjunctival hyperemia.
Corneal lesions: keratitis, punctate superficial keratitis, corneal ulcer.
Ocular surface complications: subepithelial fibrosis of the cornea and conjunctiva.
About 50% of patients with necrobiotic xanthogranuloma have eye symptoms. In addition to orbital lesions such as orbital masses, proptosis, restrictive strabismus, and ptosis, a variety of findings can occur, including conjunctival lesions, scleritis, keratitis, incomplete eyelid closure (lagophthalmos), and cicatricial ectropion. See the “Clinical findings” section for details.
The direct cause of necrobiotic xanthogranuloma is unknown. A strong association with paraproteinemia is known, but the exact causal relationship has not been clarified.
Multiple myeloma is a disease caused by the neoplastic proliferation of plasma cells, occurs more often in men over 50, and mainly affects the bones and bone marrow.
The diagnostic criteria proposed by Nelson et al. (2020) are as follows. Apply only when there is no foreign body, infection, or other identifiable cause.
Major criteria (both required)
Skin lesions: presence of papules, patches, or nodules (often yellow to orange).
Pathological findings: palisading granulomas with lymphoplasmacytic infiltration and necrobiotic areas. Cholesterol clefts and giant cells vary by case.
Minor criteria (one or more)
Hematologic disorder: associated paraproteinemia (most often IgG-κ), plasma cell disease, and/or lymphoproliferative disease.
Lesion distribution: skin lesions are distributed around the orbit.
The significance of each test is shown below.
| Test item | Findings/Purpose |
|---|---|
| Serum protein electrophoresis | Screening for hematologic disorders (strongly recommended) |
| Complement level (C4) | Low C4 in 64% |
| Lipid panel (HDL-3C) | Confirmation of low HDL cholesterolemia |
| Cryoglobulin level | Cryoglobulinemia in 23% |
| Vitamin D panel | Low 25-OH vitamin D, normal to high 1,25-(OH)₂D |
In the diagnosis of multiple myeloma, urinary detection of Bence Jones protein and bone marrow biopsy are important.
It must be differentiated from the following conditions.
Based on the diagnostic criteria of Nelson et al. (2020), both major criteria (characteristic skin lesions + histopathologic findings) and at least one minor criterion (paraproteinemia or periorbital distribution) must be met. Serum protein electrophoresis is strongly recommended if there is no history of hematologic disease.
There are no consensus guidelines for specific treatment of necrobiotic xanthogranuloma. Randomized controlled trials have not been conducted because it is a rare disease1), and treatment decisions are made by taking into account whether there is an associated malignancy.
The response rates for each drug based on a systematic review (175 cases) are shown below (complete response: CR, partial response: PR).1)
| Treatment | Number of cases | Complete response + partial response | Median duration of response |
|---|---|---|---|
| Intravenous immunoglobulin therapy | 26 cases | 81% (complete 27%, partial 54%) | 12 months (range 6-48 months) |
| Corticosteroids | 45 cases | 31% (complete 11%, partial 20%) | 12 months (range 2-24 months) |
| Lenalidomide ± steroids | 22 cases | 50% (complete 18%, partial 32%) | — |
Overall, 128 of 175 cases (73%) improved (complete response + partial response), 25 were stable, and 22 cases (13%) progressed. 1) Intravenous immunoglobulin therapy and corticosteroids are recommended as first-line treatment for necrobiotic xanthogranuloma. 1)
For treatment of multiple myeloma, radiation therapy (20–40 Gy) is used for orbital infiltration. Systemic therapy includes melphalan, steroid + melphalan combination therapy, and hematopoietic stem cell transplantation. Molecularly targeted agents used include bortezomib, thalidomide, and the thalidomide derivative lenalidomide (to reduce side effects).
Several drugs have been reported, including cyclosporine, antimetabolites, infliximab, plasmapheresis, alkylating agents (chlorambucil, cyclophosphamide, melphalan), and cladribine.
The recurrence rate after surgical removal is as high as 40%. It is recommended only when severe cicatricial ectropion or lagophthalmos affects vision.
A systematic review found that intravenous immunoglobulin therapy had the highest response rate (complete response + partial response) at 81%, and it is recommended as a first-line treatment along with corticosteroids.1) Steroid monotherapy has a response rate of only 31%, but combination with intravenous immunoglobulin therapy is standard.
The pathophysiology of necrobiotic xanthogranuloma is not fully understood. Based on its association with paraproteinemia, the following hypotheses have been proposed.
Granulomas are proliferative chronic inflammation characterized by small nodular lesions made up of macrophage-derived epithelioid cells and multinucleated giant cells. The characteristic findings in necrobiotic xanthogranuloma are as follows.
These histological features are thought to reflect a distinctive disease state in which abnormal lipid metabolism and paraproteinemia are combined.
Steinhelfer et al. (2022) systematic review (175 cases) is the largest analysis of necrobiotic xanthogranuloma, but it is mostly based on case reports and case series. A fundamental issue is that there is no severity scale for necrobiotic xanthogranuloma, making standardized assessment of treatment response difficult. 1) A prospective randomized controlled trial is needed, but it is considered difficult to carry out because the number of cases is small.
Individual case reports are accumulating for bortezomib, rituximab, adalimumab, mycophenolate mofetil, and clofazimine. 1) Because the number of cases is small, none of these has reached the point of being established as standard treatment.
In addition, a case has been reported in which long-term remission was achieved with combination therapy of monthly intravenous immunoglobulin therapy plus daily thalidomide, cyclophosphamide, and low-dose oral prednisone.
