Juvenile Xanthogranuloma

Etiology

Juvenile xanthogranuloma is presumed arise in response to an unknown stimulus, possibly infectious or physical, triggering a granulomatous histiocytic reaction.[4] However, the true etiology of juvenile xanthogranuloma is currently unknown, and conservative management is generally advised.[6]

Juvenile xanthogranuloma has been associated with juvenile chronic myelogenous leukemia.[7] Juvenile myelomonocytic leukemia is also observed in patients with neurofibromatosis, with an estimated incidence of 1:2000 to 1:5000. Rarely, it is observed in patients with both juvenile xanthogranuloma and neurofibromatosis.[6] However, when this does occur, these children have a 20- to 32-fold increased risk of juvenile myelomonocytic leukemia when compared to patients with neurofibromatosis alone.[8] There have been many cases of neurofibromatosis type 1 (NF-1) presenting with juvenile xanthogranuloma, with possible correlation with lymphoproliferative diseases, and their prevalence is currently being studied.[9]

Other diseases associated with juvenile xanthogranuloma include urticaria pigmentosa, insulin-dependent diabetes mellitus, aquagenic pruritis, and cytomegalovirus infection.[7]

Epidemiology

Juvenile xanthogranuloma most commonly occurs in early childhood, with 15% to 20% of patients having lesions at birth. In approximately 75% of cases, lesions appear during the first year of life.[1] Approximately 10% of cases may appear in adulthood and are known as adult xanthogranuloma.[1] In children, the disease most often affects males; however, in adults, there is no sex prevalence.[4]

Histopathology

Juvenile xanthogranuloma most commonly occurs in the skin and has a characteristic morphology. Lesions show well-demarcated, dense infiltration of numerous histiocytes within the superficial dermis, often accompanied by blunting of the rete ridges and scattered lymphocytes, plasma cells, and eosinophils (see Image. Juvenile Xanthogranuloma).[1] Mononuclear cells may appear spindled or elongated.[7] Foam cells, foreign body giant cells, and Touton giant cells may be observed in the mature stage.[1] The characteristic multinucleated giant cell (Touton cell), observed in 85% of cases, exhibits a garland-like arrangement (see Image. Classic Multinucleated Giant (Touton) Cell of Juvenile Xanthogranuloma).[4][1] Late-stage lesions show increased fibroblasts and replacement of the infiltrate by fibrosis.[1] 

In ocular involvement, tumor cells typically have abundant cytoplasm and fewer Touton cells compared to cutaneous juvenile xanthogranuloma.[1]

Immunohistochemically, juvenile xanthogranuloma lesions classically stain positive for CD68 (Ki-M1P), factor XIIIa, vimentin, and CD4.[1]

History and Physical

Juvenile xanthogranuloma generally occurs in 2 forms. The first form consists of multiple dome-shaped papules measuring 2 to 5 mm that appear pink to reddish-brown and subsequently turn yellow.[10] The second form comprises 1 or more large nodules that measure 1 to 2 cm.[11] Other variants and presentations include giant juvenile xanthogranuloma, atrophic plaque, cutaneous horn, and subcutaneous mass.[11]

Serious complications can arise when systemic juvenile xanthogranuloma develops. Systemic juvenile xanthogranuloma develops in 4% of children, with an overall mortality of 5% to 10%.[8] Fatalities are typically due to progressive central nervous system (CNS) disease or liver failure.[8] Extracutaneous juvenile xanthogranuloma most commonly affects the eye, and ocular involvement has been observed in 0.3% to 10% of children with cutaneous juvenile xanthogranuloma.[1] Most patients with eye lesions are younger than 1 year.[4] The iris is most commonly involved, and complications can arise that lead to spontaneous intraocular hemorrhages, glaucoma, and blinding eye disease.[1] Notably, spontaneous hyphema, with or without an increase in intraocular pressure, is a common sign of juvenile iris xanthogranuloma.[12]

Other CNS complications include seizures, increased intracranial pressure, diabetes insipidus, and developmental delay.[8] These extracutaneous lesions may also be observed in the deeper soft tissues, spleen, and lung.[8]

Evaluation

Dermoscopy is a noninvasive technique used as an aid in the diagnosis of juvenile xanthogranuloma. This technique shows a characteristic setting sun appearance, characterized by a red-yellow center and a discrete erythematous halo.[13] Definitive diagnosis can be confirmed through complete surgical excision and histopathologic examination.[2]

Treatment / Management

Curative skin excisions may be performed at easily accessible sites; however, most lesions in childhood spontaneously involute and require no therapy.[8]

Management of non-cutaneous (internal) lesions is more difficult and may involve any combination of surgery, chemotherapy, radiotherapy, and immunosuppression.[4] In general, chemotherapy and radiotherapy are options for patients with symptomatic, unresectable, or incompletely resected extracutaneous disease.[6] (B3)

Patients with concurrent NF-1 should receive frequent follow-up with a complete blood count to monitor for juvenile chronic myelogenous leukemia.[8] 

Eye examination is recommended for high-risk patients. Topical, intralesional, and subconjunctival corticosteroids may be administered for ocular involvement. In cases of complications such as glaucoma or hyphema, surgery or systemic steroids may be required.[8]

Differential Diagnosis

The differential of juvenile xanthogranuloma includes both benign and malignant entities, depending on the clinical presentation and site of involvement.

Langerhans cell histiocytosis is a key differential diagnosis of juvenile xanthogranuloma, as both conditions may contain eosinophils. Distinguishing morphologic features of Langerhans cell histiocytosis include grooved, vesicular nuclei with a characteristic coffee bean appearance.[14] Additionally, immunohistochemistry shows that Langerhans cell histiocytosis cells are positive for CD1a and S-100, whereas juvenile xanthogranuloma cells are negative for these markers.[14] CD1a is a relatively specific marker for Langerhans cell histiocytosis and is not expressed in non-Langerhans cell histiocytosis diseases.[1]

Reticulohistiocytoma, another non-Langerhans cell histiocytosis histiocytic disorder, has a histologic appearance similar to juvenile xanthogranuloma.[14] This lesion demonstrates large, mono- or multinucleated histiocytes, a lymphocytic infiltrate, and dermal fibrosis.[14] Although reticulohistiocytoma is positive for CD68, it is negative for vimentin, unlike juvenile xanthogranuloma.[14]

Although juvenile xanthogranuloma may be found in uncommon locations, such as the vulva, it is important to remember that other entities, such as embryonal rhabdomyosarcoma, may have a similar histologic appearance and should be ruled out. [14] The morphologic appearance of monomorphic small round cells with a cambium layer and necrosis may help direct a malignant diagnosis in such cases.[14]

Other conditions to consider in the differential diagnosis include additional xanthomatous lesions, mastocytomas, dermatofibromas, and Spitz nevus.[6]

Prognosis

The prognosis of juvenile xanthogranuloma is generally excellent, with most lesions undergoing spontaneous involution over the course of 3 to 6 years. Lesions that are of cosmetic concern or pose a risk to vital functions can be treated.[8]

Complications

There are often minimal to no complications of juvenile xanthogranuloma due to its self-limiting nature. Occasionally, lesions are removed for cosmetic concerns. Ocular lesions often require intervention to avoid potential complications of blindness, glaucoma, or hyphema.