Juvenile xanthogranuloma (JXG) is a rare benign histiocytic proliferation that develops in infants and young children. JXG is the most common form of non-Langerhans’ cell histiocytoses. It is characterized by the presence of Touton giant cells.
While the majority of cases present as a solitary cutaneous nodular lesion, the eye is the most frequent extracutaneous site of JXG. Among ocular tissues, the iris is most commonly affected, although eyelid, orbital, conjunctival, retinal, choroid and optic disc involvement has been reported. Skin lesions are present in 75% of patients as the sole manifestation of disease and can be found throughout the body including eyelids, other parts of the head and neck, trunk, and extremities. These lesions usually appear as discrete, round and firm papules that may be brown, red or yellow (see Figure 1). The size of a single papule has been reported to vary from 1 to 20mm, with a wide range in the number of lesions. They typically stabilize or regress spontaneously in one to five years. Regressed skin lesions often are flat and wrinkled in appearance and may leave atrophic hypopigmented scars.
Iris lesions are the most common intraocular manifestation of the disease (68%) and virtually always unilateral. Iris lesions may be localized, yellowish, vascularized elevated masses or appear as a diffuse thin layer on the iris surface, causing heterochromia (Figure 2). Spontaneous hyphema can occur from these lesions and may lead to secondary glaucoma. 0.3-10% of patients with cutaneous JXG were found to have ocular involvement. In patients with ocular JXG, the conjunctiva (19%) was the second most common site. Conjunctival lesions present as a localized yellow nodule on the bulbar conjunctiva (Figure 3). Other less frequently involved extracutaneous sites include the pericardium, lungs, viscera, bones, kidneys, central nervous system, ovaries, testes and salivary glands.
The pathogenesis of JXG is thought to be of reactive origin, namely local tissue injury that evoked a histioxanthomatous reaction. Histologically, the cutaneous infiltrate includes a mixture of foamy histiocytes, lymphocytes, fibroblasts and multinucleated giant cells, including Touton-type giant cells, with a moderate amount of collagen deposition (Figures 4-5). A Touton giant cell is a multinucleated cell that contains a wreath of nuclei surrounding homogeneous cytoplasm, with a rim of foamy cytoplasm peripheral to the nuclei. Other inflammatory cells may be present to varying degrees. JXG cells stain positive for CD68, have variable reactivity for factor XIIIa and stain negative for CD1a, S100, CD20716. JXG does not carry BRAF V600E mutation, except in patients with both Langerhans’ cells histiocytosis (LCH) and JXG (non-Langerhan cells histiocytosis) diseases and in the aggressive forms of JXG. Development of JXG after chemotherapy for LCH has been reported in 11 patients. One theory proposed the coexistence of LCH and JXG could be the result of chemotherapy-induced maturation of Langerhans’ cells into macrophages, in particular foamy cells. Another theory hypothesized that JXG may be triggered by LCH lesions through the production of a ‘cytokine storm.
JXG has been associated with neurofibromatosis 1, Niemann- pick disease and urticaria pigmentosa. Patents with neurofibromatosis 1 and JXG have a 20- to 32- fold higher risk of juvenile myelomonocytic leukemia (JMML) than patients with NF1 without JXG. Due to this association, it has been suggested that patients with JXG and NF1 should be screened for the development of JMML. Common signs of JMML include anemia, thrombocytopenia, leukocytosis, lymphadenopathy and hepatosplenomegaly.
JXG most commonly develops in infants younger than 2 years of age but has been found in older children. In a cohort of 174 JXG patients with cutaneous lesions, the mean age was 3.3 years (median 1 year). In a cohort of 30 patients with ocular JXG, the mean age at diagnosis was 4.3 years (median 1.3 years)2. 0.3%-10% of patients with cutaneous JXG were reported to have ocular involvement with children under 2 years being at increased risk. JXG has been reported to be more common in boys than in girls, with a male/female ratio ranging from 1.1:1 to 1.4:1. However, in a cohort of 30 patients with ocular JXG, no gender predilection was shown. A large literature review found a 0.75% rate of systemic manifestations in patients with cutaneous JXG.
A diagnosis of JXG is suspected in patients with characteristic yellowish cutaneous lesions. Excisional biopsy can be performed to confirm the diagnosis in cutaneous eyelid or conjunctival lesions. All patients with cutaneous JXG are advised to have a complete ophthalmic examination. In cases of iris JXG, anterior segment optical coherence tomography can help confirm the diagnosis by demonstrating a thin, epi-iridic, flat mass. Fine needle aspiration biopsy may be considered in cases that do not respond to corticosteroids or show an atypical presentations concerning for malignancy.
The classic histopathologic findings include multinucleated Touton giant cells in addition to epitheloid histiocytes, lymphocytes and eosinophils (Figures 4-5). However, Touton giant cells are not mandatory for the diagnosis of JXG. In early JXG, small- to intermediate-sized mononuclear histiocytes display a compact sheet-like infiltrate; the lipidization of histiocytes is not detectable and Touton giant cells are rarely found. The pale eosinophilic cytoplasm is sparse to moderate and does often not contain any lipid vacuoles or only fine vacuoles.
Adamson first described JXG in 1905 in an infant with multiple cutaneous nodules, which he defined as congenital xanthoma multiplex. JXG and its distinct histopathological appearance became more widely recognized in 1954. In 1948, Fry first presented a case of JXG with iris involvement at the Ophthalmic Pathology Club meeting in Washington DC and the case was subsequently published by Blank et al. one year later.
Eyelid JXG typically presents as a cutaneous yellowish nodule. The differential diagnosis for non-pigmented elevated eyelid lesions in children and young adults is wide and includes amelanotic nevus, syringoma, eccrine hidrocystoma, apocrine hidrocystoma, squamous papilloma, lipoma, molluscum and sarcoidosis. Conjunctival JXG must be differentiated from epibulbar dermoid or lipodermoid. Spontaneous hyphema is a common presenting sign of iris JXG. The differential diagnosis of hyphema in childhood includes neoplasm (retinoblastoma, medulloepithelioma, and leukemia), trauma, retinopathy of prematurity, and blood dyscrasias.
For eyelid JXG, excisional biopsy is commonly performed and is both diagnostic and therapeutic. Alternatively, topical and intralesional corticosteroids have been used to treat eyelid lesions. Topical corticosteroids have also shown success in the treatment of limbal JXG. Observation alone is a reasonable option for characteristic lesions, as most cutaneous lesions stabilize or regress in one to five years. In a case report of a newborn with extensive JXG involving the orbit, sinuses, brain and subtemporal fossa, management was limited to conservative observation. For iris JXG, prompt treatment is recommended to prevent vision loss from recurrent hyphema, secondary glaucoma, and complications related to neovascularization. Corticosteroids are the mainstay for treatment of iris JXG. Samara et al. reported the use of topical high-dose corticosteroids with a slow taper lasting 3 to 4 months. Periocular corticosteroid injection was considered when response to topical administration was poor or in case of concerns with compliance. Systemic corticosteroid or low-dose ocular radiotherapy can be considered in recalcitrant cases. Multimodal chemotherapy has been used in rare cases of extensive, systemic JXG.
The prognosis for patients with JXG is generally good. The skin lesions usually regress (or at least stabilize) with time, and even large, deeply located tumors pursue a favorable course. Eyelid and conjunctiva JXG have a more benign course compared with JXG of the iris. Iris JXG can lead to vision loss due to recurrent hyphema, secondary glaucoma and neovascularization-related complications. Analysis of the clinical course of 129 patients who had undergone excisional biopsy showed that 83% of JXG patients did not have any recurrence, 10% experienced recurrence of the excised lesion, and 7% developed additional lesion(s) in the vicinity of the original tumor following excision. Death has been reported in rare systemic JXG cases. Dehner documented two deaths among eight patients with systemic disease. Unlike in LCH, parenchymal and systemic manifestations are rare in JXG, which explains the favorable overall prognosis.
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