Necrobiotic Xanthogranuloma

Are You Confident of the Diagnosis?

Necrobiotic xanthogranuloma (NXG) is chronic, progressive, granulomatous disorder with the potential to affect multiple organs, with a notable strong association with paraproteinemias and/or lymphoproliferative disease that demands lifelong monitoring and vigilance.

Characteristic findings on physical examination

On physical examination, there are yellowish to red-orange papules and nodules that coalesce into indurated plaques, typically 0.5 to 2 cm (Figure 1). Lesions often have overlying telangiectasias; scarring and ulceration occur in 40-50% of patients.

Figure 1.

Ocular lesions are found in 80-85% of all patients and are considered the classic cutaneous location, but these are not required for the diagnosis. The extent of periorbital involvement can be severe, and can contribute to ocular symptoms and complications. Many skin lesions initially start on the trunk or extremities (60-70% of cases) and subsequently involve the periorbital area. Oral mucosal erosions are occasionally present.

Most cases are asymptomatic, although burning and pain may occur. Periorbital lesions may lead to pain and blurred vision depending on the location and size.

Extracutaneous sites can be involved including the lung, myocardium, larynx, pharynx, skeletal muscle, kidney, intestine, and ovary. Hepatomegaly and/or splenomegaly can occur in 20% of patients. Most importantly, patients with NXG frequently display a paraproteinemia and have a high risk for developing a lymphoproliferative disease.

Expected results of diagnostic studies

Histopathologically, NXG is characterized by a granulomatous inflammation in the dermis extending into the subcutaneous fat. There are large zones of necrobiosis (altered collagen with sheets of histiocytes and inflammatory cells) surrounded by granulomas composed of macrophages with some foreign body-type and Touton giant cells (Figure 2). A moderate lymphocytic infiltrate and plasma cells can be seen. Degenerated collagen is common, and mucin deposition can occur. Cholesterol clefts within the necrobiosis are characteristic of NXG (Figure 3, Figure 4).

Figure 2.

Figure 3.

Figure 4.

Laboratory studies should include the following: completew blood count (CBC), comprehensive metabolic panel (CMP), lipid panel, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), complement levels, cryoglobulins, and serum protein electrophoresis (SPEP). If SPEP is negative, then immunofixation may be considered, as it is a much more sensitive test for detection of specific monoclonal proteins compared with screening serum protein electrophoresis.

These tests are evaluating for anemia, leukopenia, hypocomplementemia, glucose intolerance and other organ involvement and underlying hematologic/ lymphoproliferative malignancies and paraproteinemia. Paraproteinemia is found in 80-90% of cases, with IgG kappa monoclonal gammopathy being the most common.

Patients require lifelong monitoring for the development of paraproteinemia and lymphoproliferative disease, and studies may need to be repeated regularly. No clear guidelines exist for frequency of monitoring, although annual monitoring is appropriate. If new symptoms or laboratory abnormalities develop, then more frequent monitoring may be necessary in some patients.

Imaging studies may include magnetic resonance or axial computed tomography of the orbit, which may demonstrate soft tissue densities within the orbit, extraocular muscle involvement, or diffuse orbital inflammation. Baseline echocardiography and dynamic cardiac imaging should be considered in all patients to evaluate for NXG involvement of the heart.

Referral to an oncologist for bone marrow biopsy should be considered in all patients with monoclonal gammopathy given the association with multiple myeloma and potential for myeloproliferative/lymphoproliferative disorders.

Diagnosis confirmation

The clinical differential diagnosis includes necrobiosis lipoidica, granuloma annulare, xanthelasma, and sarcoidosis; however, NXG often can be differentiated based upon the characteristic yellow-orange plaque morphology, clinical distribution pattern, and associated paraproteinemia, which is not present in other entities.

The most common entities to differentiate against include: necrobiosis lipoidica (pretibial location), xanthelasma (periorbital but less infiltrating plaques), sarcoidosis (less typically yellow/orange in color), and granuloma annulare (flesh and pink/red in color with more annular appearance, rarely periorbital). Normolipemic plane xanthoma also can be difficult to distinguish because it also can have a yellowish hue, normal serum lipids, and an upper body distribution pattern, but it typically lacks induration and never ulcerates.

A rare entity, adult-onset asthma with periocular xanthogranuloma (AAPOX) also is in the differential diagnosis and clinically presents with periocular infiltrative nodules. Although AAPOX has Touton giant cells and lipid-laden histiocytes, it characteristically has large lyphoid aggregates with germinal centers on histopathologic examination, which distinguishes it from NXG.

Histopathologic examination also can help differentiate between entities, but diagnosis may be difficult based on pathologic features alone. The histopathologic differential diagnosis includes necrobiosis lipoidica, granuloma annulare, juvenile xanthogranuloma, erythema induratum, foreign body granuloma, atypical sarcoidosis, and other xanthomatous disorders.

Who is at Risk for Developing this Disease?

NXG is an uncommon disease with approximately 100 cases reported in the literature since 1980, when it was first described.

A review of 48 cases found the age range to be 17 to 85 years with a mean age of onset in the sixth decade. Men and women are affected equally. The periorbital area is the most frequently involved site.

NXG typically follows a chronic and progressive but indolent course with a generally good prognosis. Prognosis is highly dependent on the extent of extracutaneous involvement and the presence of visceral malignancies. One study followed patients with NXG and multiple myeloma where there was 100% patient survival at 10 years and 90% at 15 years.

What is the Cause of the Disease?

Etiology

Pathophysiology

The pathogenesis of NXG is poorly understood. The role of the paraprotein has been investigated, and some hypothesize it functions as a lipoprotein, which allows it to bind to lipoprotein receptors of monocytes and cause xanthoma formation. Another theory is that the activation of monocytes in vivo may contribute to an intracellular accumulation of lipoprotein derived lipids in the skin.

Overall, the deposition of paraprotein and immune complexes is generally thought to elicit a granulomatous response, and hypoxia/ischemia induces necrobiosis. More recently, rare spirochetal organisms were identified in Germany, suggesting a potential role for an infectious etiology. Further investigation is required to determine the underlying etiology and pathophysiology.

Systemic Implications and Complications

In the skin, NXG can ulcerate and scar, either spontaneously or as a result of iatrogenic intervention, leading to disfigurement. NXG can have multiple systemic associations, leading to extracutaneous complications:

Ophthalmologic complications: Ophthalmologic symptoms include burning, itching, or painful eyes. Less commonly, diplopia has been reported. Reported findings include blepharitis, keratitis, conjunctivitis, restricted ocular motility and proptosis with some complication occurs in 50-80% of patients. These patients should be co-managed with ophthalmology to evaluate and manage these complications. Regular, life-long follow-up is recommended.

Lymphoproliferative/hematologic diseases: Serum monoclonal gammopathy, usually IgG-kappa, is found in 80% of patients, but only 10% of these will develop multiple myeloma. Due to the high frequency of monoclonal gammopathy, bone marrow biopsies are often performed to evaluate for evaluate for multiple myeloma.

Reported associations include multiple myeloma, chronic lymphocytic leukemia, non-Hodgkin’s lymphoma, and nonspecific myeloproliferative or lymphoproliferative diagnoses. These disorders may occur before or after the onset of skin lesions (8 years prior to onset to at least 11 years after). Patients with NXG require lifelong follow-up care and regular laboratory monitoring.

Heart involvement: Giant-cell myocardial disease can occur in these patients. Because of this, baseline routine echocardiography and dynamic cardiac imaging are recommended in all patients. If abnormalities are noted, then aggressive, systemic therapy should be considered. If cardiac symptoms at any point, then repeat imaging should be considered on an individual basis.

Other systemic involvement: Multiple extracutaneous sites have been reported with NXG. These include lung, liver, spleen (up to 20% with hepatosplenic involvement in one report), myocardium (above), larynx, pharynx, skeletal muscle, kidney, intestine, and ovary. Regular, long-term follow-up is recommended with these patients to evaluate for any systemic involvement.

Treatment Options

NXG is a rare disease and there is no treatment algorithm or accepted therapeutic ladder. Most of the treatments discussed are limited to case reports and small retrospective cases series. Due to the rarity of this disease, large-scale studies are lacking.

The treatment is varied and often times unsuccessful, although limited reports for some therapies have been reported to be successful. However, when lesions improve, the length of remission often is not reported. The treatment approach depends on whether the physician is treating NXG alone, or NXG in association with multiple myeloma, or NXG with extensive visceral/systemic involvement.

Treatment options are summarized in Table I.