Juvenile Xanthogranuloma

Juvenile xanthogranuloma (JXG) is primarily a self-limited dermatologic disorder that is associated rarely with systemic manifestations. Infants and small children are mainly affected.

Histiocytic disorders can be divided broadly into two categories: Langerhans cell histiocytosis (LCH) and non-LCH. JXG is a benign cutaneous disorder and is the most common form of non-LCH.

JXG consists of lesions that may be single or multiple and appear as firm, slightly raised papulonodules several millimeters in diameter. They are tan-orange in color and occur frequently on the head and neck, but many extracutaneous sites have been reported. See the image below.

Juvenile xanthogranuloma. Photograph of an 18-month-old presenting with a firm, nodular, tan-yellow lesion that has grown since first noticed 6 months ago. An examination under anesthesia did not reveal any ocular abnormalities. Excision of the lesion confirmed that this was a juvenile xanthogranuloma.

The eye, particularly the uveal tract, is the most frequent site of extracutaneous involvement. Approximately one half of patients with ocular involvement have skin lesions. JXG is the most frequent cause of spontaneous hyphema in children and can result in secondary glaucoma and eventual blindness.

In 1948, Fry first described iris involvement in association with juvenile xanthogranuloma (JXG) at a meeting of the Ophthalmic Pathology Club in Washington, DC (the case was later published by Blank et al a year later). Subsequently, major contributions were by Sanders in 1960 (a multicenter series of 20 cases of iris JXG) and Zimmerman in 1965 (53 cases of ocular JXG). Zimmerman demonstrated that the iris and eyelid were the two most common ocular sites involved.

The etiology of JXG is unknown. JXG is believed to result from a disordered macrophage response to a nonspecific tissue injury, resulting in a granulomatous reaction. JXG is on a spectrum of histiocytic disorders that includes benign cephalic histiocytosis, generalized eruptive histiocytosis, adult xanthogranuloma, and progressive nodular histiocytosis. These diseases are less common than the related Langerhans cell histiocytoses.[1]

Frequency

United States

The frequency is unknown, but it may be higher than reported, since lesions occur early in life, may be misdiagnosed, and spontaneously regress. In those affected, 92% of ocular involvement occurs before age 2 years.[2]

Mortality/Morbidity

Cutaneous lesions generally are self-limited and rarely require treatment. The risk of morbidity is high with ocular involvement and can include hyphema, glaucoma, corneal blood staining, cataract, vascular occlusion, and retinal detachment, all of which can lead to amblyopia in childhood. Rarely, death has been reported among children with visceral JXG.

Race

No reported predilection of race exists in JXG, although few African American patients have been described.

Sex

Cutaneous JXG is reported 1.5 times more in male children, but no sex predilection exists in adults. Both sexes are equally at risk for ocular involvement.

Age

JXG may be present at birth (in about 10%) but most often arises in infancy. Children younger than 6 months are more likely to have multiple lesions.[2] Zimmerman reported 64% of cutaneous lesions to be present by age 7 months and 85% before 1 year. Adult onset is reported infrequently.[3]

Spontaneous regression of skin lesions is the natural course, but in ocular disease, regression has only been infrequently documented.

JXG is an important cause of spontaneous hyphema in childhood, the sequelae of which include secondary glaucoma and blindness.

Visual prognosis of iris JXG depends upon prompt diagnosis and treatment prior to intraocular hemorrhage. Once hyphema occurs, visual morbidity increases substantially.

In patients with other ocular or orbital involvement, prognosis varies with the extent of the disease and its response to treatment.

Patients with cutaneous lesions should be made aware of the importance of a screening eye examination and regular follow-up care.

Patients with known ocular disease should undergo prompt treatment as appropriate. They should avoid any situation where ocular trauma could occur until resolution of the ocular disease is achieved.

Patients should be made aware of the signs and symptoms of spontaneous hyphema and seek ophthalmic attention as soon as possible if these are noted to occur.

Most individuals with juvenile xanthogranuloma (JXG) are asymptomatic. JXG predominantly affects the skin. Although a minority of patients with JXG have ocular involvement, recognition of this condition is important because a treatment delay can lead to complications such as glaucoma and hyphema.

Ocular lesions usually are discovered incidentally or following spontaneous hyphema. They may be noted by observant parents or primary care physicians. Among children with JXG, 10%-40% demonstrate cutaneous lesions characteristic of the condition.

Screening for ocular involvement generally is not performed because of its low incidence. The eye probably is affected in only about 0.5% of patients with cutaneous JXG,[4] although some early studies found an incidence as high as 10%.[5, 6]

Those at greatest risk are children younger than 2 years with multiple skin lesions.[2]

The most common ocular presentation involves the iris. Iris tumors may be diffuse or localized and lead to heterochromia, uveitis, spontaneous hyphema, and secondary glaucoma.[7]

Other ocular tissues are involved much less frequently, and orbital tumors are rare.

Nearly all cases are unilateral, and spontaneous regression of lesions is uncommon.

An association with neurofibromatosis type 1 (NF-1) and juvenile chronic myelogenous leukemia (JCML) has been reported. A recent retrospective review by Cambiaghi of 77 patients younger than 3 years with NF-1 yielded 17 (22%) with JXG, but none developed JCML or other hematologic abnormalities.[8]

Conjunctival, eyelid, and orbital JXG are rare and are more benign than iris JXG.

Skin lesions are well demarcated, rubbery, tan-orange papulonodules ranging from 1-20 mm in size. They may be single or multiple and usually occur on the head and neck, but they may appear at any site on the body surface.[9] See the image below.

Juvenile xanthogranuloma. Photograph of an 18-month-old presenting with a firm, nodular, tan-yellow lesion that has grown since first noticed 6 months ago. An examination under anesthesia did not reveal any ocular abnormalities. Excision of the lesion confirmed that this was a juvenile xanthogranuloma.

Extracutaneous involvement occurs in 4% of children and in 5-10% overall. Extracutaneous involvement has been reported in every organ system in the body, including central nervous system,[10] eye, salivary glands, larynx, lung, pericardium, myocardium, liver, spleen, colon, retroperitoneum, kidney, adrenal gland, gonads, bone, periosteum, muscle, and mucous membranes.

Ocular lesions usually involve the iris, but they may occasionally be seen in the eyelids, conjunctiva, cornea, limbal tissue, sclera, retina, choroid, optic nerve, and orbit. Cases are usually unilateral, but bilateral cases have been reported.

Iris lesions most often resemble isolated cutaneous lesions in color and appearance. They may be single or multiple and localized or diffuse. Tumors have been described to increase in thickness and lighten in color with maturation.

Iris JXG also may present as diffuse conjunctival injection with uveitis, congenital or acquired heterochromia iridis, spontaneous hyphema, or secondary glaucoma. Involvement of other uveal tissue is very uncommon.

The second most commonly affected ocular site is the eyelid.[11] Lesions appear as typical cutaneous tumors. Subcutaneous forms are rare, but they can mimic a recurrent/nonresolving chalazion. They can cause deprivational amblyopia or refractive amblyopia if they induce significant astigmatism.

Intraocular lesions rarely have been reported in the posterior pole.

Cutaneous lesions may appear before or after an ocular diagnosis has been made, with a delay of up to 8-10 months. Cutaneous and iris JXG present at a mean age of 3.3 years. Periocular JXG presents later, at a mean age of 6.5 years.

Although ocular involvement in patients with cutaneous JXG is rare, visual sequelae can lead to loss of vision. Therefore, all patients who present with typical JXG cutaneous lesions should be referred for a complete ophthalmologic examination.

Spontaneous hyphema is a common presenting sign in iris JXG. The differential diagnoses of hyphema in childhood include trauma, neoplastic conditions such as retinoblastoma, medulloepithelioma, leukemia, retinopathy of prematurity, and blood dyscrasias. These disorders should be excluded before JXG can be diagnosed.

When a spontaneous hyphema is the presenting finding, iris JXG appearing as nodular or diffuse lesions can be seen. Nodular iris JXG appears as a well-circumscribed, thickened, orange-colored lesion. Diffuse iris JXG appears as a thin coating or film on the iris surface, blunting the normal iris crypts.

Orbital lesions are extremely uncommon. They usually appear as infiltrative soft tissue tumors and often cause proptosis of the globe. At least one case has been described as a locally aggressive lesion causing bony destruction with intracranial extension.

The etiology of JXG is unknown, but a genetic basis has been suggested given the multiple sites of occurrence. However, familial cases have not been observed.

The transformation of benign cephalic histiocytosis (a related disorder) into JXG has been reported infrequently. A recent report postulated this progression could be virally mediated.

The primary complication of ocular JXG is spontaneous hyphema and its sequelae, especially glaucoma and amblyopia.

Management of iris JXG should be prompt to avoid the development of iritis with photophobia, advanced hyphema, secondary glaucoma, neovascularization-related complications, loss of vision, and, even, loss of the eye. 

Juvenile xanthogranuloma (JXG) is mainly a clinical diagnosis, which can be confirmed histologically. Histology of excised lesions and cytology of aqueous fluid may be used.

Routine screening for metabolic or hematologic abnormalities is not recommended.

High-frequency ultrasound of the anterior segment can aid in identifying lesions, which typically appear as solid homogeneous masses, especially when hyphema is present. Ocular ultrasound may also be used to help confirm the location of the intraocular or orbital lesions.

CT scanning and MRI are rarely indicated.

Anterior-segment optical coherence tomography (OCT) can help confirm a diagnosis of juvenile xanthogranuloma (JXG) by demonstrating the thin flat iris lesion.

Biomicroscopy is the main technique used in ocular diagnosis.

Anterior chamber paracentesis to obtain cytologic material has been described and can be useful in cases where the diagnosis is uncertain.

Gonioscopy is helpful to identify peripheral lesions and to look for causes of secondary glaucoma.

Fine-needle aspiration biopsy can also be helpful, especially when typical cutaneous lesions are absent.

Lesions contain dense polyhedral histiocytes with large amounts of cytoplasm that often contain vacuoles. Touton giant cells are present in 85% of cases.[2] They have a wreath of nuclei surrounding a homogenous eosinophilic cytoplasmic center. See the image below.

Touton giant cell in juvenile xanthogranuloma. Touton giant cell with a wreath of nuclei surrounding a homogenous eosinophilic cytoplasmic center in juvenile xanthogranuloma. Touton cells are named after Karl Touton, who first described them in 1885. Touton giant cells are seen in xanthoma, juvenile and adult xanthogranulomas, dermatofibroma, and fat necrosis.

Immunohistochemistry shows the lesions to be positive for factor XIIIa, CD68, CD163, fascin, and CD14 but negative for S100 and CD1. This can be used to differentiate these lesions from Langerhans cell histiocytoses.

A prominent vascular network is often present. Evidence of tissue inflammation is seen in the swelling and degeneration of epithelial cells and redundant capillary basement membranes with perivascular edema.

Factor XIIIa is a fibrohistiocytic marker that is positive in juvenile xanthogranuloma, benign fibrous histiocytoma, malignant fibrous histiocytoma, calcifying fibrous tumors, verruciform xanthomas, fibroxanthoma, hemangiopericytoma, Erdheim-Chester disease, and other rarer diseases such as myofibroblastoma, pleomorphic hyalinizing angiectatic tumor, and storiform collagenoma.

CD68 is also called KP1 or macrosialin. It is a marker of histiocytes and is positive in a large number of histiocytic diseases besides juvenile xanthogranuloma.

CD163 stains monocytes and macrophages and is positive in juvenile xanthogranuloma and histiocytic sarcoma.

Fascin is a protein that stains in carcinoma of the colon, lung, and ovary and is positive in Hodgkin lymphoma, Langerhans cell histiocytosis, and juvenile xanthogranuloma.

CD14 is used to identify monocytes and macrophages. It is positive in histiocytic sarcoma, myelomonocytic leukemia, and juvenile xanthogranuloma.

S100 an acidic protein used as a marker for melanoma and neural lesions.

CD1a, CD1b, and CD1d are found in humans. CD1a is used to diagnose Langerhans cell histiocytosis.

Management of iris juvenile xanthogranuloma (JXG) should be prompt to avoid the development of iritis with photophobia, advanced hyphema, secondary glaucoma, neovascularization-related complications, loss of vision, and, even, loss of the eye.

Pharmacotherapy: Topical, subconjunctival, intralesional, and systemic corticosteroids are used for intraocular and orbital juvenile xanthogranuloma (JXG). Orbital lesions may respond to intralesional steroid injections. Iris lesions are treated with topical prednisolone or subconjunctival steroids. These are followed by sub-Tenon steroids if no improvement occurs in several weeks.

The first-line treatment of iris JXG is high-dose corticosteroids applied topically (every two hours during waking hours and ointment at night) with a slow taper. If there is difficulty administering topical medication, periocular steroids can be considered, although the effects of the steroids may last for 3-4 months.

Systemic steroids are considered only if the topical steroids do not yield an adequate response.

Radiotherapy: Low-dose radiation may be the treatment of choice for diffuse uveal lesions, especially if glaucoma is present, or if there is poor response to steroid treatment. Typically, 100-200 cGy is administered per dose over a 2- to 3-week period. The total is usually kept under 500 cGy, but higher doses are used for poorly responsive tumors.

Antimetabolites are sometimes used as adjuvants to radiotherapy.

Appropriate glaucoma medications should be used in the setting of hyphema and increased intraocular pressure.

Occasionally, surgery is indicated for localized iris lesions involving less than one quadrant. However, the risks to normal ocular structures may outweigh the benefits.

The surgeon should be prepared to deal with massive amounts of bleeding, which can occur with iridectomy in this setting.

Conjunctival, eyelid, and orbital JXG may be resected or treated with steroids. Topical corticosteroids may be used for limbal JXG and intralesional steroids for eyelid JXG, although surgical resections are also reasonable. Similarly, solitary orbital JXG can be surgically resected. Kontos et al have shown that spontaneous regression of corneoscleral limbus xanthogranulomas is unlikely and recommend prompt surgical intervention.[12]

Discussion with a pediatric dermatologist or radiation oncologist may be helpful to document the extent of the disease and plan treatment.

No dietary restrictions are indicated for this disorder.

Standard activity restrictions should be put in place for patients who develop spontaneous hyphema. These restrictions generally include bed rest with bathroom privileges and elevation of the head of the bed 30° from the horizontal.

Small children should have a protective shield over the eye at all times to prevent rubbing.

Eye protection, especially during sports, should be prescribed for older children who have known ocular tumors.

Patients with juvenile xanthogranuloma (JXG) who have known cutaneous lesions should be seen regularly and screened for the development of ocular or other noncutaneous lesions.

Patients with iris tumors should undergo prompt treatment.

Patients presenting with hyphema should be monitored closely after acute management for ocular sequelae and management of amblyopia when appropriate.

Patients with JXG rarely are admitted, except for management of acute hyphema or extensive visceral involvement. Follow-up care is dictated by the clinical situation.

Patients prescribed topical or oral steroids, as well as those receiving steroid injection, should be observed for development of cataract and glaucoma, as well as tumor response.

Topical, oral, or intralesional corticosteroids are used in the treatment of ocular juvenile xanthogranuloma (JXG). Because of risk of spontaneous hemorrhage, all ocular tumors probably should be treated.[13] Specific medications used include the treatments described below.

Class Summary

Minimize the activity of inflammatory cells and formation of granulomas. Used in symptomatic patients and commonly provides symptomatic improvement.

Prednisolone acetate 1% (Pred Forte)

Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability. DOC for lesions involving the anterior segment.

Prednisolone ophthalmic (Delta-Cortef, Econopred)

Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability. For ocular lesions not responsive to topical steroids.

Dexamethasone ophthalmic (Maxidex)