Are You Confident of the Diagnosis?
Characteristic findings on physical examination
Juvenile xanthogranuloma (JXG) is a non-Langerhans histiocytosis that typically presents as dome-shaped red-brown or yellow papules and nodules (Figure 1, Figure 2, Figure 3, Figure 4, Figure 5, Figure 6). Two major clinical variants, large nodular and small nodular, have been described. The most common morphology is the large nodular form, which presents as either a solitary nodule or a few nodules. The small nodular form is the next most common variant presenting with multiple smaller papules. These two forms often coexist.
JXGs are generally asymptomatic. The most common location is the head and neck, followed by the upper torso and proximal extremities. Spontaneous involution over a period of several months to years is typical. Residual atrophy, anetoderma, or hyperpigmentation are not uncommon after lesions resolve.
Expected results of diagnostic studies
There is no dyslipidema associated with JXGs. There are no known associated laboratory anomalies.
Histopathology reveals a foamy histiocytic dermal infiltrate, often in association with epidermal flattening and ulceration (Figure 7). Touton giant cells, typified by a wreath-like arrangement of nuclei, are a characteristic finding. There are often admixed lymphocytes, eosinophils, and sometimes neutrophils. CD68, HAM36, and factor XIIIa stain positively in JXG. Although generally negative for S-100, early lesions have been shown to be S-100 positive. CD1a and CD34 stains, which are positive in Langerhans cell histiocytosis, are negative in JXG.
The differential diagnosis includes other histiocytoses such as benign cephalic histiocytosis, generalized eruptive histiocytosis, papular xanthoma, xanthoma disseminatum, Langerhans cell histiocytosis (LCH), and other miscellaneous disorders such as pyogenic granuloma, Spitz nevus, mastocytosis, and molloscum contagiousum.
Benign cephalic histiocytosis affects infants and toddlers up to age three, tends to present with multiple flatter lesions that are confined to the head and neck, and spares the mucous membranes. Touton giant cells are absent in benign cephalic histiocytosis.
Generalized eruptive histiocytosis is more common in adults, presents with hundreds of red-brown papules, and can be differentiated histopathologically by the absence of cellular lipidization and giant cells.
Xanthoma disseminatum is characterized by the triad of mucous membrane involvement, generalized symmetric eruption of cutaneous xanthomas, and associatied diabetes insipidus.
Nodular lesions of LCH may mimic JXG clinically and must be distinguished by histology and immunohistochemistry. Of particular note is the presence of Birbeck granules, and S-100 and CD1a positivity in LCH. Some authors believe that these histiocytic disorders fall within a spectrum, as opposed to rather that representing and do not representindividual diseases, as there are reports of various histiocytoses co-existing in the same patient.
Dermatoscopy may aid in establishing the diagnosis. A characteristic finding is an orange-yellow color with a surrounding rim of erythema. This has been likened to a setting sun. White streaks may also be present representing fibrosis.
Who is at Risk for Developing this Disease?
JXG is generally a disease of infancy and early childhood, with 40%-70% presenting in the first year of life. Between 5% and 17% are congenital. Approximately 1%-2% of children are affected, with a slight male predominance. Xanthogranulomas have been described in adults in whom the typical presentation is that of a large solitary nodule.
What is the Cause of the Disease?
The etiology is unknown. Some have postulated that JXG represents a reactive histiocytic process to an as yet unidentified stimulus.
Systemic Implications and Complications
JXGs may affect multiple organ systems. Extracutaneous disease has been reported in 4%-5% of patients with cutaneous lesions. Common sites of extracutaneous disease include the eyes, subcutaneous tissue, central nervous system, liver, spleen, lung, oropharynx, and muscle. Bone marrow, heart, kidney, gastrointestinal tract, bone, pancreas, adrenal gland, gonadal, and laryngeal involvement have also been described.
Fatalities are very rare, with only six cases reported, and most of these were in neonates with congenital disease. In general, routine screening for systemic involvement is not indicated unless symptoms or suggestive findings are present.
Ocular involvement is the most common extracutaneous manifestation, and this occurs in approximately 0.3%-0.4% of patients with cutaneous JXG. The iris is most frequently affected. Anterior chamber hemorrhage (hyphema) can cause glaucoma and subsequent blindness. Other sites include the cornea, sclera, conjunctiva, ciliary body, limbus, and optic nerve. Signs and symptoms of ocular involvement may include hyphema, eye redness, and photophobia.
Ocular involvement has been described only in children with multiple JXGs and more commonly occurs in children less than two years old.
There exists an association of JXG with neurofibromatosis 1 (NF-1). Importantly, the presence of JXGs in the setting of NF confers a higher risk (20-30 times) for developing juvenile myelomonocytic leukemia (JMML). Patients with NF and JXG should therefore be monitored closely for the development of JMML with serial complete hematologic evaluations, and referral to a hematologist.
Other hematologic malignancies have been reported in association with JXGs, including acute lymphoblastic leukemia, monocytic leukemia, hemophagocytic lymphohistiocytosis, and histiomonocytic reticulosis.
In adults, there have been six reported cases of xanthogranulomas linked to hematologic malignancies, including essential thrombocytosis, chronic lymphocytic leukemia, large B cell lymphoma, and monoclonal gammopathy. Some authors have advocated for hematologic evaluation in all adults who present with xanthogranulomas.
Treatment is not necessary for isolated cutaneous disease, as JXGs spontaneously involute and are usually asymptomatic.
Intraocular involvement often requires treatment with injectable or topical corticosteroids to prevent anterior chamber hemorrhage and glaucoma. Only when organ function is compromised in the context of systemic involvement is treatment indicated. Systemic therapy is similar to that for LCH and may include steroids, vinca alkaloid chemotherapeutics, and radiotherapy.
The diagnosis of JXG can be made clinically in the vast majority of patients, and a biopsy is generally not indicated. Histology can be a useful adjunct to rule out occasional clinical mimickers such as Spitz nevi or solitary mastocytoma. A biopsy may also be indicated to rule out more serious disease processes such as LCH if multiple lesions are present.
Optimal Therapeutic Approach for this Disease
As noted above, treatment is not indicated for asymptomatic cutaneous JXGs. If ulcerated, wound care with topical antibiotics or emollients is often adequate. Depending on location, size, and symptoms, excision may be indicated for ulcerated JXGs refractive to topical wound care, or very large JXGs in functionally critical sites such as the eyelid. Recurrences have been reported after excision.
Routine screening for extracutaneous disease is not indicated unless findings suggestive of systemic disease are present. A complete history, review of systems, and physical examination should be performed in all patients with JXG. A thorough history and physical exam is all that is required in cases of single JXG.
Given the risk of JMML in patients with NF and JXG, evaluate closely for stigmata of neurofibromatosis. Refer children less than two years old with multiple (two or more) JXGs located anywhere on the body to an ophthalmologist to evaluate for ocular involvement. For children who have a normal screening ophthalmologic exam, serial exams every six months until the child reaches age two are generally recommended.
Unusual Clinical Scenarios to Consider in Patient Management
Less common morphologic variants of JXG include subcutaneous, plaque-like, giant, clustered, keratotic, pedunculated, and disseminated. Subcutaneous JXG is the most common extracutaneous site and presents as an asymptomatic soft subcutaneous mass that is not attached to the overlying skin. Giant JXGs may be as large as 10cm and are typically congenital.
Disseminated juvenile xanthogranulomatosis is a term used to describe neonates with multiple JXGs and systemic involvement.
As previously stated, various hematologic malignancies have been reported in association with JXGs in both children and adults.
What is the Evidence?
Hernandez-Martin, A, Baselga, E, Drolet, BA, Esterly, NB. “Juvenile xanthogranuloma”. J Am Acad Dermatol. vol. 36. 1997. pp. 355-67. (JAAD continuing medical education review that thoroughly discusses all aspects of diagnosis and management of JXG)
Azorin, D. “Systemic juvenile xanthogranuloma with fatal outcome”. Pediatr Dermatol. vol. 26. 2009. pp. 709-12. (Case report and complete review of the literature on systemic involvement of JXG and reported associated fatalities)
Zvulunov, A, Barak, Y, Metzker, A. “Juvenile xanthogranuloma, neurofibromatosis, and juvenile chronic myeloid leukemia: world statistical analysis”. Arch Dermatol. vol. 131. 1995. pp. 904-8. (Review of the literature confirming the association of JMML in patient with NF and JXG)
Haughton, AM, Horii, KA, Shao, L, Daniel, J, Nopper, AJ. “Disseminated juvenile xanthogranulomatosis in a newborn resulting in liver transplantation”. J Am Acad Dermatol. vol. 58. 2008. pp. S12-5. (Case report of congenital disseminated juvenile xanthogranulomatosis and review of the literature)
Chang, MW, Frieden, IJ, Good, W. “The risk of intraocular juvenile xanthogranuloma: survey of current practices and assessment of risk”. J Am Acad Dermatol. vol. 34. 1996. pp. 445-9. (Survey of dermatologists and ophthalmologists that addresses prevalence, presentation, and management of ocular involvement in children with cutaneous JXG)
Hussain, SH, Kozic, H, Lee, J. “The utility of dermatoscopy in the evaluation of xanthogranulomas”. Pediatric dermatology. vol. 25. 2008. pp. 505-6. (Discusses typical dermatoscopic features of JXG)
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