Dermatologic Manifestations of Juvenile Xanthogranuloma 

Updated: Oct 17, 2019
Author: Sally H Monahan, MD; Chief Editor: William D James, MD 

Overview

Background

Juvenile xanthogranulomas (JXGs) are benign; usually asymptomatic; self-healing; red, yellow, or brown papules and nodules composed of histiocytic cells that predominantly occur in infancy and childhood. Papules or nodules occur in the skin, eyes, and viscera. JXG is the most common form of non–Langerhans cell histiocytosis.[1, 2]

See the image below.

Smooth, domed, yellow-brown, 5-mm papule on right Smooth, domed, yellow-brown, 5-mm papule on right arm of a 6-month-old boy.

Adamson first reported JXG in the English literature in 1905. He presented a child who developed numerous yellow-white papules on the body in the first 2 weeks of life. He named the entity congenital xanthoma multiplex.

In 1912, McDonagh presented the first case review and renamed the condition nevoxanthoendothelioma (although the condition is not associated with nevi or endothelial cells). In 1954, Helwig and Hackney again retermed it juvenile xanthogranuloma, reflecting its histopathologic appearance. Laurb and Lain first reported JXG with visceral involvement in 1937. Blank et al first described ocular involvement in 1949.

Pathophysiology

The etiology of juvenile xanthogranuloma (JXG) is not fully known. The papules and nodules of JXG represent collections of differentiated non–Langerhans cell histiocytes. The consensus is that the cells of origin are dermal dendrocytes. As postulated, JXG may be a granulomatous reaction of histiocytes to an unidentified stimulus, possibly of either physical or infectious etiology. Evidence from Kraus et al,[3] however, suggests a possible CD4+ plasmacytoid monocyte origin. Inhibition of cellular apoptosis appears to play a minor role in the growth of xanthogranulomas.[4]

The appearance of giant cells and foamy lipid-laden histiocytes generally occurs late and apparently is a secondary event, possibly in response to cytokine production by histiocytes. Serum lipid levels are normal and remain normal.

Etiology

Coexistence of café au lait macules and juvenile xanthogranuloma (JXG) has been associated with epilepsy.

Niemann-Pick disease has been associated with JXG.

Urticaria pigmentosa has been associated with JXG.

Neurofibromatosis type 1 (NF1) has been associated with JXG.[5, 6, 7, 8, 9] A recent study found a prevalence of 37.5% of JXGs in young children with NF1.[10] Another recent study also found a high frequency (30%) of JXGs in children with NF1 who were younger than 2 years.[11] These JXG lesions were often multiple. It has been proposed that JXG may be a helpful diagnostic criterion for NF1.

Juvenile chronic myelogenous leukemia, now primarily referred to as juvenile myelomonocytic leukemia (JMML), has been observed in association with multiple JXGs,[7, 8, 12] and the prevalence is especially high in patients with coexistent neurofibromatosis. Statistics regarding this triple association are controversial; estimates indicate that patients with NF1 and JXG have a 20- to 32-times increased risk of developing JMML than patients with NF1 alone. Patients have also been diagnosed with JMML and JXG, but without NF1.

Epidemiology

Race

Juvenile xanthogranuloma (JXG) occurs in whites approximately 10 times more frequently than in African Americans.

Sex

In childhood, juvenile xanthogranuloma (JXG) occurs predominately in males (1.5:1). Equal incidence occurs in adult males and females. Multiple cutaneous lesions occur predominantly in males (12:1).

Age

Approximately 35% of cases of juvenile xanthogranuloma (JXG) occur at birth, with as many as 71% of cases occurring in the first year. The mean age at presentation is 22 months. Most JXGs resolve by age 5 years. Despite the term juvenile in the disease name, 10% of cases manifest in adulthood.

Prognosis

In the absence of therapeutic intervention, juvenile xanthogranulomas (JXGs) flatten with time. Both cutaneous and extracutaneous lesions involute spontaneously within 3-6 years.

Hyperpigmentation, mild atrophy, or anetoderma may persist.

Lesions can recur after resection. The relapse rate is approximately 7%.

In the absence of neurofibromatosis, no systemic health implications are involved, with a few rare exceptions.

Vigilantly screen patients with neurofibromatosis and JXG for leukemia.

Ocular, neurologic, and hepatic disease are rare but may have serious long-term consequences.

Patient Education

Reassure patients and their families. Instruct patients concerning associations related to clinical situations (neurofibromatosis, ocular findings in diffuse JXG, JMML), and direct patient education toward these conditions.

 

Presentation

History

Patients with juvenile xanthogranuloma (JXG) usually present in infancy or early childhood with an asymptomatic; smooth; round; yellow, red, or brown papule or papules. Lesions are usually asymptomatic.

Physical Examination

The most frequent site of juvenile xanthogranuloma (JXG) occurrence is on the head and neck,[13, 14] followed by the trunk and upper extremities; however, JXG may occur anywhere on the skin.

When viewed under dermoscopy, an orange-yellow background with “clouds” of pale yellow interspersed within the lesion has been described. This is usually accompanied by an erythematous halo with linear and branching vessels extending from the periphery to the center of the lesion.[15, 16]

Up to 81% of cutaneous JXG cases manifest as a solitary lesion. This form is also more common in cases of adult xanthogranulomas.

Involvement is rare on mucous membranes, the tongue, palms, and soles.

Both papular and nodular forms of JXG have been described. The papular form consists of multiple, 2- to 5-mm, smooth, firm papules that initially are red-brown, then quickly change to yellow. The rarer nodular form consists of round, 0.5- to 2-cm, translucent, red-to-yellow, rubbery nodules with telangiectasias (nodules change to yellow-brown with time).

Giant JXG refers to nodules and masses greater than 2 cm (largest reported mass was 10 X 5 cm).[17, 18]

Rarer variants include a mixed form characterized by both papular and nodular lesions, in which grouped papules coalesce, and a subcutaneous form (approximately 5%), with a single deep nodule or mass formation.

Extracutaneous JXG is rare (3.9%) and most commonly involves the eye (< 1%) and periorbital region.[19] Ocular JXG most commonly manifests in the iris.[20] Cutaneous findings are absent at the time of diagnosis in approximately 50% of cases of ocular JXG. Risk factors for eye involvement include multiple skin lesions and age younger than 2 years. Most cases of ocular JXG present with acute eye changes such as erythema, uveitis, or hyphema.[19]

Following in frequency of ocular involvement are lung and liver manifestations of JXG.[21] Even more rarely, lesions occur in the adrenal gland, appendix, bones, bone marrow,[21, 22] central nervous system,[23] gonads, kidney, larynx, myocardium, pericardium, retroperitoneum, small and large intestines, and spleen. Only 50% of systemic lesions are accompanied by cutaneous JXG, and these cutaneous lesions tend to appear as multiple, rather than solitary, papules or nodules. The size of a cutaneous lesion does not correlate with the presence or absence of systemic JXG.

Café au lait macules occur in approximately 20% of patients with papular JXG.

Several other morphological presentations have been described, including clustered, hyperkeratotic, pedunculated, plaquelike, and linear arrangements.

Complications

Complications associated with juvenile xanthogranulomas (JXGs) are rare and are dependent on the site of involvement and associated conditions.

Ocular involvement may progress to ocular hemorrhage, glaucoma, or retinal detachment. These complications are best prevented through early detection.

CNS involvement is a very rare complication.

Hepatic failure is a rare, but potentially fatal, complication of systemic JXG.[24]

 

DDx

Diagnostic Considerations

Also consider the following:

  • Non–Langerhans cell histiocytosis
  • Benign cephalic histiocytosis [25]
  • Generalized eruptive histiocytoma
  • Self-healing reticulohistiocytoma
  • Tuberous xanthoma
  • Papular xanthoma
  • Xanthoma disseminatum
  • Mastocytosis (urticaria pigmentosa)

Differential Diagnoses

 

Workup

Procedures

While the diagnosis is typically clinical in most cases, a skin biopsy may be performed, both for diagnosis and cosmesis. The specimen usually consists of a complete excision of the papule or nodule.

Histologic Findings

Histological examination of juvenile xanthogranuloma (JXG) demonstrates a variety of findings. A time-dependent progression exists in the development of the characteristic histological features of JXG, which correlates with the age of the lesion. Early biopsy specimens reveal a dense monomorphous histiocytic infiltrate in the dermis. Extension into subcutaneous tissue, fascia, and muscle occurs in approximately one third of cases.[26] Older lesions contain foam cells, Touton giant cells, and foreign body giant cells. A mixed cellular infiltrate of neutrophils, lymphocytes, eosinophils, and (rarely) mast cells may be noted. Old lesions demonstrate fibrosis. No histological difference is reported between cutaneous and systemic JXG. Because of the difficulty in diagnosing JXG and because of the transient presence of Touton giant cells in JXG lesions, these classic elements may not be present in every case.

The histiocytes contain pleomorphic nuclei, with few or absent mitotic figures, and irregular dense bodies. Clustered comma-shaped bodies occasionally are observed on electron microscopy but are not specific. Use of special stains is important to differentiate JXG from Langerhans and non–Langerhans cell histiocytoses.[27] In JXG, histiocytes are positive to antibodies against factor XIIIa, HAM56, HHF35, KP1 (CD68), Ki-M1P, and Vimentin, and are generally negative to CD1a and S-100. They always stain negatively to langerin (CD207). New reports have also demonstrated a CD4 positivity, which has been used as evidence that plasmacytic monocytes may be the normal cell type of the major constituent of JXG, instead of the dermal dendrocyte.

 

Treatment

Medical Care

Anticipatory care, with patient reassurance, is appropriate because of the self-limiting benign nature of juvenile xanthogranulomas (JXGs). Ocular and systemic lesions may respond to steroids or radiotherapy. Rare cases of severe systemic JXG have required single or multiagent chemotherapy regimens.

Surgical Care

Lesions may be excised for diagnostic and cosmetic reasons. Ocular and systemic lesion excision usually is curative. A 2008 case report describes a newborn with multiple cutaneous and hepatic juvenile xanthogranulomas (JXGs) requiring liver transplantation secondary to cholestasis and portal hypertension.[28]

Consultations

Routine referral of patients with a juvenile xanthogranuloma (JXG) is unnecessary.

Patients younger than 2 years with multiple skin lesions comprise 92% of associated cases of ocular involvement. Refer these patients to an ophthalmologist, and continue screening every 6 months through the second year of life. Some have also recommended an ophthalmologist referral for those with periocular JXGs.

When presented with children diagnosed with both JXG and type 1 neurofibromatosis (NF1), physicians should be on alert for possible juvenile myelomonocytic leukemia (JMML). Whether screening for JMML is necessary remains controversial, and little evidence supports performing hematological panels for detecting malignancy. Instead, physicians should look first for clinical signs of JMML in patients with NF1 and JXG, particularly hepatosplenomegaly, lymphadenopathy, and/or pallor.

Long-Term Monitoring

Follow-up visits may be scheduled at regular intervals for reassurance and to monitor associated complications. For patients with juvenile xanthogranulomas (JXGs) and type 1 neurofibromatosis (NF1), physicians should watch for signs and symptoms of juvenile myelomonocytic leukemia (JMML).[29]

Patients with ocular involvement should be checked regularly by an ophthalmologist to prevent rare complications, such as glaucoma.[30]

 

Medication

Medication Summary

Systemic steroids may be used for problematic visceral juvenile xanthogranulomas (JXGs).[31]

Corticosteroids

Class Summary

Corticosteroids function to shrink the size of visceral nodules. These agents have anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli.

Prednisone (Deltasone, Meticorten, Orasone)

Prednisone is the drug of choice for visceral lesions. It may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.