Juvenile xanthogranuloma

Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports

The non-Langerhans cell histiocytosis juvenile xanthogranuloma (JXG) is a benign disease common in infancy and early childhood but may affect adults as well. JXG presents as single or multiple rubbery, firm, round to oval yellow-red to orange cutaneous papules or nodules. The most common sites are the head and neck followed by the upper trunk and extremities.

JXG is usually limited to the skin and is self-healing within months to years. Treatment is recommended for systemic lesions if their location interferes with organ function.

Management Strategy

The clinical and radiological presentation is non-specific. Correlation with histopathology is the gold standard for the diagnosis.

In approximately 5% of children, JXG may be a systemic disease with involvement of ≥ two organs. Skin lesions may precede the development of other organ complications with a latent period of months to years. Clinicians should remain alert to the development of suspicious clinical or laboratory findings needing further investigation (see below).

1.
Eye involvement. The eye is the most frequent site of extracutaneous involvement. Ocular JXG seems to occur more commonly as an isolated site. Only 0.3–0.5% of patients with cutaneous JXG develop ocular JXG (usually during the first 2 years of life). Most frequent complications are hyphema, glaucoma, and anterior uveitis, with the risk of loss of visual acuity. Ocular JXG is the most frequent cause of spontaneous hyphema in children.
2.
Systemic juvenile xanthogranuloma. Systemic JXG accounts for 4–10% of JXG cases, but only 50% of systemic JXG cases demonstrate skin lesions. Age under 2 years and having multiple cutaneous lesions may be risk factors for systemic involvement, and these may give a high degree of clinical suspicion. The disease may involve internal organs such as the lungs, kidneys, heart, central nervous system, adrenal glands, pituitary gland, bones, and bone marrow.
3.
An association between JXG, neurofibromatosis type 1 (NF1), and juvenile myelomonocytic leukemia (JMML). The presence of JXG in patients with NF1 is considered a warning sign for JMML. A study by Zvulunov et al. concluded that the risk of JMML was 20–32 times greater in children with NF1 and JXG as in those without JXG. Because JMML is an aggressive disease with a median survival of approximately 1 year if not treated with stem cell transplantation, early diagnosis may be crucial for a positive outcome.
4.
Other diseases associated with JXG: urticaria pigmentosa, insulin-dependent diabetes mellitus, aquagenic pruritus, cytomegalovirus infection, cutaneous tuberculosis, and neoplasia. A case of tuberculosis presenting with generalized xanthogranulomas in an adult Filipino male by Caro-Chang and Cubillan concluded that tuberculosis, together with other infectious disorders, should also be investigated in patients presenting with generalized xanthogranulomas.

Specific Investigations

In most cases, no specific investigations are required
Correlation with histopathology and immunostaining
Ophthalmology evaluation (recommended for <2 yo with multiple micronodular lesions)
Dermoscopy
Reflectance confocal microscopy
Fine-needle aspiration cytology (FNAC) smears
Further evaluation warranted for symptoms of affected organs

The various clinical spectra of juvenile xanthogranuloma: imaging for two case reports and review of literature

Höck M, Zelger B, Schweigmann G, et al. BMC Pediatr 2019. doi https://doi.org/10.1186/s12887-019-1490-y .

Immunostaining is important in establishing the diagnosis: JXG stains positive for factor XIIIa, CD68, CD163, CD14, and fascin, and is mostly negative for S100 protein and regularly negative for CD1a and anti-langerin (CD207), which are specific for Langerhans cells.

Giant juvenile xanthogranuloma: case report, literature review, and algorithm for classification

Ladha MA, Haber RM. J Cutan Med Surg 2018; 22(5): 488-94. 10.1177/1203475418777734.

The dermoscopic features of classic JXG were first reported by Palmer and Bowling: (1) an orange-yellow base called setting sun sign; (2) clouds of diffuse yellow deposits, likely histiocytes; and (3) branched linear vessels at the periphery.

Reflectance confocal microscopy for the noninvasive diagnosis of cutaneous juvenile xanthogranuloma

Pimenta R, Leal-Filipe P, Oliveira A. Skin Res Technol 2018. https://doi.org/10.1111/srt.12616 .

Epidermal examination revealed a normal honeycomb pattern. At the dermal–epidermal junction level, dilated papillae filled with clustered, large and refractile, multinucleated roundish structures were found. They were also found at the superficial dermis, together with discoid-shaped structures with a peripheral bright ring. The former atypical cells corresponded to Touton cells, while the latter corresponded to foamy histiocytes. These in vivo features allowed the diagnosis of cutaneous juvenile xanthogranuloma. A skin biopsy was no longer required.

Cytological diagnosis of juvenile xanthogranuloma: a rare histiocytic disorder

Chauhan S, Diwaker P, Singh A, et al. 2019. Wiley Periodicals. https://doi.org/10.1002/dc.24310 .

FNAC smears may be another option and may save patients from unnecessary surgical biopsy or excision. FNAC shows foamy macrophages along with mixed inflammatory infiltrate and few Touton giant cells. This cytological diagnosis requires a high index of suspicion by a cytopathologist.

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