Juvenile Xanthogranuloma (JXG) is the most common disease among non-Langerhans cell histiocytoses (non-LCH). It was first reported by Adamson in 1905, and iris JXG was first described by Fry in 1948.
Epidemiologically, the average age of onset for cutaneous JXG is 3.3 years (median 1 year), while ocular JXG occurs slightly later at an average of 4.3 years (median 1.3 years). The incidence is approximately 1 per 1 million children, accounting for 0.5% of all pediatric tumors 9). 20–35% are diagnosed before 1 year of age as congenital JXG 9). There is a slight male predominance, with a male-to-female ratio of 1.1–1.4:1.
There have also been reports of adult onset. In a study that collected 32 cases of eyelid JXG, the median age at the authors’ institution was 9 years, and adult cases were included. However, onset in infancy is overwhelmingly more common.
Cutaneous JXG appears as painless yellow, red, or brown papules. Ocular JXG causes the following symptoms.
Ocular Lesions
Iris lesions: Account for 68% of intraocular JXG. They occur unilaterally and appear as yellow mass formation or diffuse infiltration. They can progress from spontaneous hyphema to secondary glaucoma.
Conjunctival lesions: Account for 19% of intraocular JXG. They appear as yellow nodules on the bulbar conjunctiva.
Eyelid lesions: 62.5% occur on the upper eyelid. Full-thickness type accounts for 75%, and chalazion-like subcutaneous type accounts for 25%. 1)
Extracutaneous lesions
Skin lesions: 75% of all cases. Papules measuring 1–20 mm, often regress spontaneously within 1–5 years.
Oral lesions: Rare, with 42 cases reported in the literature. Commonly found on the gingiva (29.8%) and tongue (27%). 4)
Deep/intramuscular lesions: 0.6% of all JXG cases, only 15 cases reported in the literature. May not recur even with positive resection margins. 7)
Systemic lesions: Occur in 0.75% of patients with cutaneous JXG. Hepatic infiltration is seen in 31.4% of cases. 8)
In spontaneous anterior chamber hemorrhage in children, JXG should be the top differential diagnosis. However, retinoblastoma, leukemia, and trauma are also important differential diagnoses, and JXG should be diagnosed after excluding these conditions.
The pathogenesis of JXG is thought to be a histiocytic xanthomatous reaction (reactive origin) to some stimulus. Although it is not considered a true neoplastic disease, recent molecular biological studies have revealed the involvement of genetic mutations.
In typical cases, diagnosis is possible based on clinical findings alone 2). When painless yellow-orange papules are observed in infants, clinical diagnosis may be made without biopsy.
For eyelid and conjunctival JXG, excisional biopsy provides a definitive diagnosis 1). In cases that do not respond to treatment, fine-needle aspiration biopsy (FNAB) is an option.
| Marker | JXG | LCH | Significance |
|---|---|---|---|
| CD68 | Positive | Positive | Histiocytic marker |
| CD163 | Positive | Negative to weakly positive | M2 macrophage marker |
| Factor XIIIa | Positive to negative | Negative | Dendritic cell marker |
| CD1a | Negative | Positive | Essential for differentiation from JXG |
| S100 | Negative | Positive | Essential for differentiation from JXG |
| CD207 (Langerin) | Negative | Positive | Essential for differentiation from JXG |
Typical histology shows infiltration of Touton giant cells and foamy histiocytes. However, deep JXG may lack Touton giant cells 7). Oral JXG has been reported to have a non-lipidized variant, with a relatively high Ki-67 positivity rate of about 25% 4). BRAF V600E mutation was negative in all 5 cases of oral JXG 4).
Treatment strategies vary significantly depending on the lesion site.
Skin Lesions
First-line treatment is observation. Most skin lesions regress spontaneously within 1 to 5 years. Surgical excision is reserved for cosmetic reasons or diagnostic purposes.
Outcomes after excision: no recurrence in 83%, recurrence in 10%, and new nearby lesions in 7%.
Eyelid and Conjunctival Lesions
Excisional biopsy is first-line. In a pooled study of 32 eyelid JXG cases, surgical excision was performed in 75%, with no recurrence observed during a median follow-up of 27 months. 1)
Iris JXG can lead to blindness from spontaneous hyphema, so prompt treatment is necessary.
For systemic JXG or severe cases with liver or central nervous system (CNS) involvement, the LCH treatment protocol (cytarabine + vincristine + prednisolone) is used 6). Cases with liver or CNS involvement have high mortality and require multidisciplinary management.
Most cutaneous JXG regress spontaneously within 1 to 5 years, so observation is the basic approach. However, ocular JXG does not regress spontaneously and can lead to blindness if left untreated. In infants with skin lesions, it is important to have an ophthalmologic examination to check for ocular involvement.
JXG is based on reactive histiocytic proliferation, but recent molecular analyses have revealed the presence of genetic abnormalities akin to neoplastic changes.
The histology of cutaneous JXG is characterized by a granulomatous infiltrate composed of foamy histiocytes (xanthoma cells) and Touton giant cells (multinucleated giant cells with a wreath-like arrangement of nuclei and surrounding foamy cytoplasm).
| Molecular Abnormality | Frequency | Notes |
|---|---|---|
| NTRK1 gene fusion | 28.6% (6/21 cases) | TPM3::NTRK1 most common (3 cases), IRF2BP2::NTRK1 (2 cases) 3) |
| MAP kinase pathway mutation | Some congenital JXG | MAP2K1, NRAS, KRAS, ARAF 9) |
| BRAF V600E | Rare (negative in 5 oral JXG cases) | Useful for differentiation from LCH4) |
| CSF-1R mutation | Some congenital JXG | Candidate for molecular targeted therapy9) |
LCH and JXG are closely related as histiocytic tumors. Cases of JXG developing after LCH treatment have been reported. In liver infiltration histology, LCH causes bile duct destruction, whereas JXG preserves bile ducts, a contrasting feature 8).
NTRK1 fusion and TRK inhibitors (Schloegl et al., 2025) 3)
In an analysis of 35 JXG cases, NTRK1 gene fusion was detected in 6 of 21 cases (28.6%). The most common was TPM3::NTRK1 (3 cases), followed by IRF2BP2::NTRK1 (2 cases). This finding suggests that TRK inhibitors such as larotrectinib and entrectinib may be molecular targeted therapy candidates for JXG. In one case of congenital JXG, improvement was achieved with dexamethasone 10 mg/m².
Treatment of JXG with topical rapamycin 1% (Effendi et al., 2022) 5)
In a 2-year-old boy with JXG, topical 1% rapamycin applied twice daily reduced the lesion from 25×10×3 mm to 10×8×1 mm at 12 weeks, and flattening of facial lesions was confirmed at 24 weeks. This is thought to be mediated by mTOR inhibition and is noted as a non-invasive treatment for cutaneous JXG.
Histological comparison of LCH vs JXG in the liver (Daeniker et al., 2025) 8)
Liver infiltration was observed in 31.4% of patients with systemic JXG. A contrasting pattern was shown: JXG liver tissue preserves bile ducts, whereas LCH causes bile duct destruction. BRAF inhibitors (vemurafenib) are also mentioned as a treatment option in cases with LCH.
Juvenile xanthogranuloma is a representative non-Langerhans cell histiocytosis that commonly occurs in infants and young children. Skin lesions regress spontaneously, but ocular and systemic lesions carry risks of blindness and death, requiring prompt evaluation and treatment. In cases associated with NF1, attention must be paid to an increased risk of JMML. Recent discovery of NTRK1 gene fusion has emerged as a new therapeutic target with TRK inhibitors, and future clinical application is expected.
Chen R, Liu S, Tang L, et al. On the knowledge of solitary juvenile xanthogranuloma of the eyelid: a case series and literature review. Graefes Arch Clin Exp Ophthalmol. 2022;260:2339-2345.
Santos R, Barros AM, Carvalho M. Juvenile Xanthogranuloma: A Visual Clinical Diagnosis. Cureus. 2025;17(12):e98625.
Schloegl E, Hoerner-Unterberger H, Simonitsch-Klupp I, et al. NTRK1 Gene Fusions Are Frequent in Juvenile Xanthogranuloma. Am J Surg Pathol. 2025;49:763-769.
Mota CP, Cunha JLS, Magalhaes MCSV, et al. Oral Juvenile Xanthogranuloma: A Clinicopathological, Immunohistochemical and BRAF V600E Study of Five New Cases, with Literature Review. Head Neck Pathol. 2022;16:407-415.
Effendi RMRA, Rizqandaru T, Yuliasari R, et al. Successful Treatment of Non-Langerhans Cell Histiocytosis With Topical Rapamycin in Two Pediatric Cases. Clin Cosmet Investig Dermatol. 2022;15:1575-1582.
Uehara Y, Wada YS, Iwasaki Y, et al. Neonatal systemic juvenile Xanthogranuloma with Hydrops diagnosed by Purpura skin biopsy: a case report and literature review. BMC Pediatr. 2021;21:161.
Maejima A, Okuno K, Miyaishi M, et al. Deep juvenile xanthogranuloma invading the left tensor fasciae latae muscle: a case report and a literature review. J Clin Exp Hematop. 2024;64:323-327.
Daeniker M, Baleydier F, Rock NM, et al. Bile Duct Targeting or Preservation: Contrasting Liver Histology in Langerhans Cell Histiocytosis and Disseminated Juvenile Xanthogranuloma. Pediatr Dev Pathol. 2026;29:38-50.
Maldonado A, Munoz R, Alarcon N, et al. Congenital Juvenile Xanthogranuloma in the Perioral Region: A Case Image. Head Neck Pathol. 2024;18:35.
