Juvenile xanthogranuloma (JXG)

INTRODUCTION — Juvenile xanthogranuloma (JXG) is a benign, proliferative disorder belonging to the broad group of non-Langerhans cell histiocytoses and is typically a disorder of early childhood [1]. JXG presents in the first two years of life as a solitary, reddish or yellowish skin papule or nodule (picture 1D), most often on the head, neck, or upper trunk. Extracutaneous or systemic forms are exceedingly rare and can be associated with considerable morbidity.

An overview of JXG will be presented here. Langerhans cell histiocytosis is discussed separately. (See "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis".)

EPIDEMIOLOGY — JXG is the most common of the non-Langerhans cell histiocytoses [2]. The incidence is unknown. In a large tumor registry spanning 35 years, JXG accounted for 129 of 24,600 pediatric tumors (0.5 percent) [3]. However, this figure may be an underestimate of the relative frequency of JXG since many cases are diagnosed on clinical grounds without histologic confirmation. In a survey of 122 dermatologists with an average of 12 years of practice, 2371 cases of JXG were reported (an average of less than two cases per dermatologist per year), and only seven cases had ocular involvement [4].

The median ages of onset in two large case series were 5 months (range 0 to 244 months) and 1 year (range 0 to 20 years) [3,5]. The male-to-female ratio was approximately 1.4:1.

PATHOGENESIS — The cause of JXG is unknown. All histiocytoses arise from CD34⁺ stem cells that develop, based on the cytokine milieu, into CD14⁺ or CD14^- cells. Langerhans cells and Langerhans cell histiocytoses derive from CD14^- cells. CD14⁺ cells may become monocyte/macrophage lineage or dermal/interstitial dendrocytes, the latter considered to be the precursor cell of non-Langerhans cell histiocytoses [2,6].

A genomic analysis with molecular inversion probe array searching for copy number variation or loss of heterozygosity in 21 cases of JXG found that most solitary, cutaneous JXGs (19 of 21) lacked identifiable genetic changes [7]. Genomic alterations appear more common in the setting of systemic JXG. A retrospective study showed that 35 percent of systemic JXGs had ALK translocations and 17 percent had BRAF V600E mutations (these two molecular alterations were mutually exclusive) [8]. In a series of 12 JXG cases with systemic involvement, seven had mutations in several MAPK pathway genes, including ARAF, KRAS, MAP2K1, and NRAS [9].

PATHOLOGY — Classic histology of JXG shows a mixed dermal infiltrate of mononuclear cells, multinucleated giant cells with or without the features of Touton giant cells (characterized by a ring or wreath of nuclei surrounded by a foamy cytoplasm), and spindle cells. Lymphocytes, eosinophils, neutrophils, and mast cells can be seen. The lesion is nonencapsulated but well demarcated, with dense sheets of cells infiltrating the dermis and the upper portion of the subcutaneous fat. The epidermis and adnexae are spared, though the epidermis can be thinned and, rarely, ulcerated.

The microscopic appearance depends upon the age of the lesion. Early JXG shows only histiocytes or spindle-shaped fibrohistiocytic cells minimally lipidized. More mature JXG shows foamy, lipid-laden, vacuolated mononuclear cells and Touton giant cells. Regressing lesions show progressive replacement by fibrous tissue [10].

Immunostaining is important in establishing the diagnosis. JXG stains positively for factor XIIIa, a marker of interstitial dendrocytes, CD68, CD163, CD14, and fascin. A retrospective study of 77 JXGs showed positive staining for CD11c (a marker for macrophages, with expression limited to hematopoietic cells) in 97 percent of cases and positive staining for CD4 (which is expressed in a subset of monocyte and macrophage cells) in 100 percent of cases [11]. Stains for S100 and CD1a, the latter of which is specific for Langerhans cells, are negative.

CLINICAL MANIFESTATIONS

Age of onset and lesion distribution — Between 40 and 70 percent of JXGs arise in the first year of life [10]. In a series of 147 children, the median age of onset was 15.5 months, with 69 percent occurring before the age of two years [12]. Rarely, JXG may be present at birth [13]. In a retrospective study of 44 patients with JXG, only one (2.3 percent) was congenital [14]. In a review of 47 cases of congenital JXG, 66 percent presented with isolated cutaneous involvement, and 34 percent presented with systemic involvement [15].

In large case series, the lesion distribution was as follows [3-5,12,16]:

●Solitary skin lesion – 67 to 76 percent

●Multiple skin lesions – 7 to 10 percent

●Superficial or deep soft tissue lesions – 15 to 16 percent

●Systemic involvement (with or without skin lesions) – 4 to 5 percent

●Eye involvement (with or without skin lesions) – 0 to 0.3 percent

Cutaneous lesions — JXG typically presents as a reddish, yellowish, or brown papule, plaque, or nodule (picture 1D). The lesions are usually solitary (picture 1A-D and picture 2), but multiple lesions (picture 3A-B) can occur.

A size of 0.5 to 2 cm is typical. Lesions >2 cm (giant JXG) are rare. The lesions can occur in any location and are most common on the head, neck, and upper trunk.

Early lesions tend to be more reddish and raised, but as they mature and become progressively more lipidized, they appear more yellow and will often flatten. Fine telangiectasias occasionally can be seen overlying the lesion, and extracutaneous and systemic involvement may occur. All organs and systems can be affected. (See 'Extracutaneous and systemic involvement' below.)

Extracutaneous and systemic involvement — The most common extracutaneous presentation of JXG is a solitary nodule or mass in the subcutaneous or deep soft tissues [5].

Systemic involvement is rare and tends to occur in very young children, with a median age of onset of nine months [17]. In a review of nearly 3000 published cases, systemic involvement occurred in 0.75 percent of patients [16]. In another study of 456 cases of biopsy-confirmed JXG, systemic involvement was observed in 23 patients (5 percent), of which 15 had cutaneous lesions as well [8]. Compared with those with cutaneous involvement only, those with systemic involvement often had multiple skin papules or nodules with ≥2 locations or giant cutaneous masses [8].

In a systematic review that included 159 patients with systemic JXG, the most commonly involved site was the central nervous system (41 percent), followed by the liver (31 percent), the lung (19 percent), and the eye (18 percent) [17] (see 'Ocular juvenile xanthogranuloma' below). Lesions may also occur in the spleen, lymph nodes, bones, kidneys, and gastrointestinal tract and may or may not be associated with cutaneous lesions [1,5,18].

Ocular juvenile xanthogranuloma — Eye involvement is rare. In a series of 2949 cases, the prevalence of ocular JXG was 0.2 percent [16]. Ocular JXG typically occurs in young children (<2 years) and is associated with coexistent cutaneous lesions in approximately one-third of the cases [1].

The iris (picture 4B) is the most frequent site of ocular involvement, but the lid (picture 4A), orbit, ciliary body, cornea, and episclera may also be affected. Red eye and hyphema (bleeding into the anterior chamber of the eye) are the most common presenting complaints. Uveitis, heterochromia iridis, or iris masses (picture 4B) can also occur [19].

Secondary unilateral glaucoma can occur as a result of an acute rise in intraocular pressure from mass effect of blood or the JXG itself and can cause blindness (see "Overview of glaucoma in infants and children", section on 'Secondary glaucoma'). Posterior segment involvement is rare [20,21].

CLINICAL COURSE — JXG generally follows a benign course. Spontaneous regression is the rule for skin lesions and occurs in approximately one to five years [13], sometimes leaving an atrophic or hyperpigmented scar. Extracutaneous and systemic JXGs also spontaneously regress in most cases.

Congenital JXG with multisystem or extensive visceral involvement may require aggressive treatment, as fatalities may occur in up to 20 percent of cases [3,5,8]. (See 'Management' below.)

ASSOCIATED CONDITIONS — JXG has been reported in approximately 3 to 10 percent of patients with neurofibromatosis type 1 (NF1) and in approximately 30 percent of NF1 patients younger than two years [22-24]. In young children, the presence of multiple café-au-lait macules and JXG may be a marker of NF1 even in the absence of other reliable diagnostic signs of NF1 [25]. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis".)

An association between JXG, NF1, and juvenile myelomonocytic leukemia (a rare form of childhood leukemia) has been described in a few single case reports [25-32]. However, the clinical implications of this triple association are unclear [22,33]. In a large, retrospective, case-control study of 739 patients with NF1, those who had JXGs were not found to have an increased risk of any malignancies compared with those without JXGs (odds ratio 1.5, 95% CI 0.35-6.6, p = 0.56) [34]. (See "Clinical manifestations and diagnosis of chronic myeloid leukemia", section on 'Juvenile myelomonocytic leukemia'.)

DIAGNOSIS — Diagnosis of JXG is in most cases made clinically, based on the typical appearance of lesions on physical examination. Biopsy is infrequently performed because the clinical picture is usually so typical and because of the self-healing nature of the disease. When the diagnosis is in doubt, skin biopsy for histology and immunostaining is necessary. (See 'Pathology' above.)

Dermoscopy has been suggested as a potentially useful tool for the diagnosis of JXG. The most characteristic dermoscopic finding in early to fully developed JXG is the so-called "setting sun" sign, which consists of a yellow-orange, central area surrounded by a peripheral, pink border with fine, branched, linear telangiectasias. In older lesions that contain more lipidized cells, dermoscopy shows white and yellow globules [35,36]. Other dermoscopic features may include shiny, white streaks and irregularly distributed, heterogenous, vascular structures [37].

DIFFERENTIAL DIAGNOSIS — The clinical differential diagnosis of JXG in children includes Langerhans cell histiocytosis, other xanthomatous lesions, mastocytoma, Spitz nevus, and dermatofibroma. In most cases, the histologic features and immunohistochemistry staining are diagnostic (table 1):

●Langerhans cell histiocytosis – Langerhans cell histiocytosis typically presents in infancy as a refractory seborrheic dermatitis, a recalcitrant diaper dermatitis with ulcerations and erosions, or an eruption of cutaneous papules and nodules (picture 5). Arginine vasopressin deficiency (central diabetes insipidus), hepatosplenomegaly, lymphadenopathy, and bone marrow involvement can occur. Individual lesions are typically smaller than those of JXG. On immunostaining of biopsied tissue, Langerhans cell histiocytosis is S100 and CD1a positive, but JXG is S100 and CD1a negative. (See "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis", section on 'Skin and oral mucosa'.)

●Other xanthomatous lesions:

•Xanthoma disseminatum – Xanthoma disseminatum is a rare, nonfamilial form of non-Langerhans cell histiocytosis occurring in young adults, with frequent involvement of mucocutaneous sites [38,39]. It is often associated with arginine vasopressin deficiency (central diabetes insipidus). Numerous erythematous, yellow-brown papules and nodules are symmetrically distributed on the trunk, face, and upper extremities (picture 6). Lesions may become confluent in flexural areas [40]. The histologic and immunohistochemical characteristics are the same as JXG.

•Papular xanthoma – Papular xanthoma (picture 7) is a very uncommon disease that occurs mainly in normolipidemic adults and presents as multiple yellow or red papules or nodules on the trunk and, less frequently, on the head and extremities. Rare pediatric cases have been reported [41-44]. The histologic and immunohistochemical differentiation from JXG is difficult. Papular xanthoma presents with a dense infiltrate of foam cells, with fewer Touton cells and inflammatory cells than JXG. Immunostaining for factor XIIIa was negative in a series of 10 cases [41].

•Eruptive xanthomas – Eruptive xanthomas occur in adults in the setting of hypertriglyceridemia, as crops of tiny, yellowish-red papules on a background of erythema (picture 8). Sites of predilection include the buttocks, shoulders, and extensor extremities. Facial and oral involvement can occur. Histologically, eruptive xanthoma consists of a dermal infiltrate of histiocytes, lymphocytes, neutrophils, and, in mature lesions, small foam cells. (See "Cutaneous xanthomas", section on 'Eruptive xanthomas'.)

•Tuberous xanthoma – Tuberous xanthomas occur most often in areas of pressure, such as the buttocks, knees (picture 9), and elbows (picture 10A-B). They are firm, asymptomatic, reddish-yellow nodules, seen in patients with hypercholesterolemia and high low-density lipoprotein. Histologically, tuberous xanthoma consists of dermal aggregates of foam cells, with absence of Touton cells or other inflammatory cells. (See "Cutaneous xanthomas", section on 'Tuberous xanthomas'.)

●Spitz nevus – Spitz nevi present as a single, dome-shaped, pink to red or dark-brown papule on the face or extremities of children. Histologically, classic Spitz nevi show a symmetrical proliferation of spindle and epithelioid cells, often in nests. Immunostaining confirms the melanocytic origin (S100, Melan-A [Mart-1], and tyrosinase positive) [45]. (See "Spitz nevus and atypical Spitz tumors".)

●Mastocytoma – Mastocytomas are benign collections of mast cells within the dermis that demonstrate urtication (wheal formation) with stroking (Darier sign). They are relatively common in children and appear as reddish to golden brown papules or plaques, which can sometimes have a rubbery feel (picture 11A-B). They are generally asymptomatic but can be mildly pruritic with urtication. Pathology shows mast cells in the papillary dermis highlighted by Giemsa stain. (See "Mastocytosis (cutaneous and systemic) in children: Epidemiology, clinical manifestations, evaluation, and diagnosis", section on 'Skin'.)

●Dermatofibroma – Dermatofibromas are benign, generally asymptomatic, tan to reddish-brown papules seen frequently on the extremities. They often arise after minor inflammation or trauma (eg, folliculitis or insect bite). They are seen more commonly in older children and adults than in infants. Histologically, an acanthotic epidermis with an underlying zone of normal papillary dermis is seen. The lesion is unencapsulated, and collagen trapping (spindle cells encasing normal collagen) occurs at the periphery. Spindle cells overlap in fascicles and whorls. (See "Overview of benign lesions of the skin", section on 'Dermatofibroma'.)

MANAGEMENT — The management of JXG depends on the site(s) of involvement.

Cutaneous juvenile xanthogranuloma — No treatment is needed for cutaneous JXG. Reassurance to patients and the parents/caregivers of affected children about the benign course and spontaneous regression of the disease is usually all that is necessary. Involution usually occurs one to five years after onset [46]. Most resolve without scarring, though atrophic scarring is possible and likely more common in larger lesions.

Routine referral of all patients with cutaneous JXG for ophthalmologic evaluation is not recommended [4]. Most patients with ocular involvement present with acute ocular complaints; asymptomatic eye involvement is rare.

However, it is reasonable to consider referral to ophthalmology for patients under age 2 presenting with multiple micronodular (<10 mm) JXGs, as they may have a higher risk of ocular involvement [4], though yield of routine eye examination is low in the absence of ocular complaints or signs [16].

Subcutaneous and soft tissue juvenile xanthogranuloma — Subcutaneous and soft tissue lesions also resolve spontaneously and do not require treatment.

Ocular juvenile xanthogranuloma — Children with ocular and periocular lesions should be referred to an ophthalmologist for diagnosis confirmation and management. The treatment depends on the type of ocular involvement and complications [19].

Symptomatic systemic juvenile xanthogranuloma — Systemic lesions that are associated with symptoms (eg, mass effect) may require treatment if they do not spontaneously regress [18]. Treatment decisions for patients with symptomatic systemic JXG should be made on a case-by-case basis. Referral to an oncologist may be warranted. Treatment may involve excision, radiotherapy, and/or systemic chemotherapy [47-51].

There is no standard chemotherapeutic regimen for systemic JXG. A variety of regimens have been tried with variable results [47]. Most of these regimens included agents that are used in the treatment of Langerhans cell histiocytosis (eg, vinblastine, prednisone, methotrexate, and mercaptopurine). (See "Treatment of non-pulmonary Langerhans cell histiocytosis".)

Central nervous system involvement has been successfully treated with cladribine (2-chlorodeoxyadenosine) [52-54]. In one patient, extracutaneous JXG was successfully treated with thalidomide after failure of other chemotherapeutic regimens [55].

PROGNOSIS — Prognosis of cutaneous JXG is uniformly good; spontaneous regression of skin lesions over a few years is the rule. Patients may have residual hyperpigmentation, minimal atrophy, or anetoderma (loss of elastic fibers in the dermis) following regression [10].

Extracutaneous JXGs most often regress spontaneously as well, although treatment may be needed to relieve symptoms due to mass effect. Long-term sequelae are rarely reported. Fatalities can occur, typically in infants with central nervous system or massive hepatic involvement and liver failure [3,5,18,56-58].

SUMMARY AND RECOMMENDATIONS

●Definition – Juvenile xanthogranuloma (JXG) is a rare, benign, proliferative, histiocytic disorder of dermal dendrocyte origin and is the most common of the non-Langerhans cell histiocytoses. It occurs predominantly in young children. (See 'Epidemiology' above.)

●Clinical manifestations – In most cases, JXG arises in the first year of life. Infrequently, JXG may be present at birth (see 'Age of onset and lesion distribution' above):

•Cutaneous lesions – Typical skin lesions appear as reddish to yellow papules, plaques, or nodules 0.5 to 2 cm in size, most often located on the head, neck, and upper trunk (picture 1D). (See 'Cutaneous lesions' above.)

•Extracutaneous/systemic juvenile xanthogranuloma – Extracutaneous or systemic JXG is rare, occurring in up to 4 percent of all cases, and may involve every organ or system (including the eye). Ocular JXG may occur in the absence of skin lesions and usually presents with ocular manifestations (hyphema, uveitis, iris or corneal lesions) (picture 4A-B). (See 'Extracutaneous and systemic involvement' above and 'Ocular juvenile xanthogranuloma' above.)

●Diagnosis – The diagnosis is clinical in most cases. In difficult cases, histology and immunohistochemistry are diagnostic. (See 'Diagnosis' above.)

●Management – Cutaneous JXG generally regresses spontaneously. Reassurance about the benign course is usually all that is necessary. Patients with ocular JXG should be referred to an ophthalmologist. Systemic JXG may require treatment (excision, radiotherapy, and/or chemotherapy) if it causes symptoms. (See 'Management' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Kate B Püttgen, MD, FAAD, who contributed to earlier versions of this topic review.