Xanthogranuloma necrobiotic with paraproteinemia D76.3

Rare, normolipemic, infiltrative and destructive, localized or disseminated, histioproliferative neoplasm (systemic disease), often (>70%) combined with monoclonal gammopathy, belonging to the adult non-Langerhans cell hist iocytoses (see histiocytoses below).

Very rare disease. Currently, less than one hundred and fifty cases of this syndrome have been described in the literature worldwide. Incidence and prevalences are not known.

Unexplained. Associations with monoclonal gammopathies (MGUS) are observed in about 70% of cases (e.g. plasmocytomas in 50% of cases, sometimes also association with multiple myeloma), furthermore there are associations with other lymphoproliferative (e.g. Waldenström's disease, Hodgkin's disease, chronic lymphocytic leukemia) diseases.

Average age of illness: 6th decade of life. The youngest patient reported was 17 years old. Men and women are equally affected.

The skin lesions in NXG can occur anywhere on the body. However, about two-thirds of patients are affected periorbitally, particularly on the upper and/or lower eyelids or other parts of the face. The second most commonly affected area was the trunk, especially the chest. However, many skin lesions first appear on the trunk or extremities and subsequently affect the periorbital area. In approximately 90% of published cases, more than one body area was affected. In isolated cases, the occurrence of NXG has been noted within scars, after trauma, or in an area previously irradiated with X-rays.

Usually multiple, disseminated or also grouped, slowly growing over months to years, 0.3-20 cm large, reddish-brownish, or reddish-yellowish, sometimes also livid, plaques or nodules (rare) with atrophic surface. Consistency derb-elastic.

Ulceration of the lesions was observed in about 50% of patients and was usually extensive and progressive.

The lesions may be asymptomatic; however, more than half of the patients interviewed reported various symptoms, mainly itching, but also burning, tenderness, and even pain. Periorbital skin lesions are often associated with ophthalmologic manifestations, especially scleritis, choroiditis, or conjunctivitis, and with complications such as blepharoptosis, limited ocular motility, and proptosis.

Extracutaneous lesions most commonly occur in the respiratory tract, including the lungs and larynx, followed by the myocardium, oral cavity, skeletal muscles, kidneys, ovaries, intestines, and other sites. Extracutaneous involvement has been reported in less than 20% of cases.

BSG accelerated significantly. Frequently monoclonal gammopathy of the IgG or IgA type, cryoglobulinemia, leukopenia, neutropenia or hypocomplementemia (C4 decreased).

Destructive granulomatous tissue reaction involving the entire dermis, possibly also the subcutaneous adipose tissue and underlying organs. Histiocytes, lymphocytes, bizarre giant cells of foreign body and touton type; necrobiosis zones similar to necrobiosis lipoidica. These may be ribbon- or star-shaped, and not infrequently extend into the subcutaneous adipose tissue. Cholesterol deposits within the granulomas.

As with all non-Langerhans cell histiocytoses, no expression of CD1a, and S100B. No Birbeck granules. However, numerous CD68 (macrophage) - positive cells were detected (see CD classification).

In patients without known myeloproliferative disorder, bone marrow biopsy may reveal atypical or increased plasma cells and very rarely true multiple myeloma .

Necrobiosis lipoidica, cutaneous B-cell lymphoma, non-Langerhans cell histiocytoses such as:

• papular xanthomatosis
• granuloma anulare
• plane xanthomas
• multicentric reticulohistiocytosis
• xanthoma disseminatum
• juvenile xanthogranuloma.

Coincidental occurrence of diffuse planar xanthomas and NXG was reported in 5 cases from the literature.

An effective causal therapy is not known. Randomized controlled trials and studies of long-term outcomes after treatment do not yet exist.

Individual troublesome granulomas can be excised. Intralesional injections of triamcinolone acetonide (e.g., Volon A) have been tried without much success. Frequent recurrences.

Treatment options include topical and systemic corticosteroids, thalidomide, high-dose intravenous immunoglobulin (IVIG), chlorambucil, fludarabine, rituximab, melphalan, infliximab, interferon alpha, cladribine, hydroxychloroquine, azathioprine, methotrexate, laser therapy, radiotherapy, surgery, PUVA and extracorporeal photopheresis, and autologous bone marrow transplantation.

Alternative: pulse therapy with cyclophosphamide and dexamethasone.

Alternative: Therapy trial with DADPS, (e.g. dapsone-fatol) initially 100 -150 mg/day. Dose reduction after clinic to 50 mg/day. If necessary, discontinuation trial. Sporadic therapeutic success with plasmapheresis, especially for lowering high paraprotein levels.

Controversial therapeutic results after application of melphalan, thalidomide, fumaric acid ester or radiotherapy, especially in localized skin lesions with ocular symptoms. Methotrexate appears to be ineffective.

Local therapy, including local steroids, CO2 laser, or radiotherapy, results in partial improvement. Skin lesions that recur or do not respond to treatment can be surgically removed and the defects restored with skin grafts.

The hematologic disorders may occur many years before or after the onset of skin lesions (even up to 11 years). According to the available literature data, the course of the disease is usually chronic and slowly progressive, and the prognosis is relatively good if malignant hematologic disorders do not occur simultaneously.

A 57-year-old woman developed yellow-reddish xanthomatous nodules and plaques mimicking xanthomas within three months, mainly affecting the periorbital area and breast. Her serum cholesterol and triglyceride levels were normal.

Detailed laboratory analysis revealed the presence of monoclonal gammopathy with the presence of immunoglobulin G (IgG) kappa light chains, but this did not require therapy after internal medicine consultation.

Imaging examination and ultrasonography showed no specific involvement of internal organs.

Skin biopsy showed a diffuse dermal infiltrate of epithelioid, foamy histiocytes in addition to conspicuous giant Touton-type and foreign body-type cells and variable numbers of lymphocytes, plasma cells, and neutrophils. Furthermore, necrobiotic areas were evident, alternating throughout the reticular dermis with extension into the subcutaneous tissue. Lipid vacuoles were seen within the necrobiotic foci and xanthogranulomatous infiltration. Two months after the initial evaluation, necrotic areas appeared in the lesions. This evolution led to the diagnosis: "necrobiotic xanthogranuloma".

In this patient, the extremely late onset of the disease, the aggressive course, the absence of malignant hematologic disease were remarkable.

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