HAEM5:Juvenile xanthogranuloma

<2 yeHaematolymphoid Tumours (WHO Classification, 5th ed.)

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Primary Author(s)*

Mayuri Shende, MBBS, DCP, FCPS, DNB, ASCP-SH CM

Scott Turner, PhD

WHO Classification of Disease

Structure	Disease
Book	Haematolymphoid Tumours (5th ed.)
Category	Histiocytic/Dendritic cell neoplasms
Family	Histiocyte/macrophage neoplasms
Type	Histiocytic neoplasms
Subtype(s)	Juvenile xanthogranuloma

Definition / Description of Disease

Juvenile Xanthogranuloma (JXG) is a clonal expansion of non–Langerhans cell histiocytes with dermal macrophage phenotype.(Instructions: Brief description of approximately one paragraph - include disease context relative to other WHO classification categories, diagnostic criteria if applicable, and differential diagnosis if applicable. Other classifications can be referenced for comparison.)

Synonyms / Terminology

Juvenile X```````anthogranuloma (Instructions: Include currently used terms and major historical ones, adding “(historical)” after the latter.)

Epidemiology / Prevalence

Juvenile Xanthogranuloma is a rare histiocytic neoplasm comprising about 0.5% of all pediatric tumors, seldom seen in in adults. 20-35% cases are congenital, shows male predilection and mostly (>70% cases) arise during the first year of life.

Clinical Features

JXG are generally asymptomatic. Infants may present with ≥1 cutaneous, pale yellow-tan, dome-shaped papulonodular lesions, approximately5% patients show multiple lesions. These lesions begin as raised, pink to dark brown lesions that might get flatten later and heal/ scar within few months or years. A clinical subtype of JXG- benign cephalic histiocytosis occurs in head and neck of young children, asymptomatic, self-healing papular lesions. The lesions are often large, solitary and persistent in adults which needs exclusion of Erdheim–Chester disease. JXG may occur in patients with neurofibromatosis type 1, also reported in Wiskott–Aldrich syndrome. (Instruction: Can include references in the table. Do not delete table.)

Signs and Symptoms	Asymptomatic in the beginning ≥1 cutaneous papulonodular lesions Rarely systemic involvement with abnormal labs, ophthalmologic exam findings, seizures, hydrocephalus, diabetes Insipidus
Laboratory Findings	Abnormal blood count, liver enzymes, metabolic tests Cytopenia if bone marrow involved

Sites of Involvement

JXG involves and is generally confined to skin, head and neck, upper trunk and proximal extremities. Rarely ocular involvement, solitary lesion noted. Other extracutaneous sites of involvement- visceral, spinal, or intracranial area also reported rarely. (Instruction: Indicate physical sites; EXAMPLE: nodal, extranodal, bone marrow)

Morphologic Features

Gross appearance:

Cutaneous JXGs: Early lesions are orange-red papules/macules, later progress to form pale to tan, dome shaped lesions.

Visceral JXGs: Nodules with variable size and appearance.

Histopathology:

• Unencapsulated, circumscribed lesions composed of classic histiocytes, large xanthomatous histiocytes, foamy histiocytes and Touton giant cells..
• Variable numbers of lymphocytes, eosinophils, plasma cells, neutrophils, and mast cells are often intermixed along with epithelioid cells, spindle cells and oncocytic histiocytes.
• These histiocytes should not show significant nuclear pleomorphism.

Cytology:

• Mononuclear or multinucleated histiocytes with kidney shaped/oval nuclei, variable numbers of lymphocytes, neutrophils, and eosinophils.
• Touton giant cells or foreign body giant cells may be present.

Immunophenotype

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Finding	Marker
Positive (universal)	CD68, CD163, CD4, CD14, factor XIIIa, and fascin
Positive (subset)	S100 (light nuclear and cytoplasmic staining)
Negative (universal)	CD1a and CD207 (langerin), ALK
Negative (subset)	N/A

Chromosomal Rearrangements (Gene Fusions)

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Chromosomal Rearrangement	Genes in Fusion (5’ or 3’ Segments)	Pathogenic Derivative	Prevalence	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
NTRK1 fusions	TPM3::NTRK1 fusion PRDX1–NTRK1	Unknown	Unknown	Unknown	Unknown	Unknown	Often associated with localized xanthogranuloma [3]
BRAF fusions	FNBP1-BRAF RNF11-BRAF MS4A6A::BRAF BICD2::BRAF GAB2-BRAF	Unknown	Unknown	Unknown	Unknown	Unknown	Disseminated JXG with GAB2::BRAF fusion, showed favorable response to treatment with trametinib (kinase inhibitor). [5]
RET fusions
CLTC::SYK fusions							Children less than 2 years of age with soft tissue involvement
ALK fusions/rearrangements	KIF5B–ALK TPM3–ALK						A unique group of infants with an aggressive form of JXG with spleen, liver, and bone marrow showed infiltration with histiocytes with activating ALK fusions
PTPN11 E76K

Individual Region Genomic Gain / Loss / LOH

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Chr #	Gain / Loss / Amp / LOH	Minimal Region Genomic Coordinates [Genome Build]	Minimal Region Cytoband	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: 7	EXAMPLE: Loss	EXAMPLE: chr7:1- 159,335,973 [hg38]	EXAMPLE: chr7	Yes	Yes	No	EXAMPLE: Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference).
EXAMPLE: 8	EXAMPLE: Gain	EXAMPLE: chr8:1-145,138,636 [hg38]	EXAMPLE: chr8	No	No	No	EXAMPLE: Common recurrent secondary finding for t(8;21) (add reference).
Trisomy 5 and 17	Unknown	Unknown	Unknown	Unknown	Unknown	Unknown	Diffuse cutaneous juvenile xanthogranuloma [2]
Heterozygosity in 5q	Unknown	Unknown	Unknown	Unknown	Unknown	Unknown	Diffuse cutaneous juvenile xanthogranuloma [2]
Gains on 1q and 11q	Unknown	Unknown	Unknown	Unknown	Unknown	Unknown	Systemic juvenile xanthogranuloma [2]
Loss in 3p	Unknown	Unknown	Unknown	Unknown	Unknown	Unknown	Systemic juvenile xanthogranuloma [2]

Characteristic Chromosomal Patterns

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Chromosomal Pattern	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: Co-deletion of 1p and 18q	Yes	No	No	EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).

Gene Mutations (SNV / INDEL)

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Gene; Genetic Alteration	Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)	Prevalence (COSMIC / TCGA / Other)	Concomitant Mutations	Mutually Exclusive Mutations	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: TP53; Variable LOF mutations EXAMPLE: EGFR; Exon 20 mutations EXAMPLE: BRAF; Activating mutations	EXAMPLE: TSG	EXAMPLE: 20% (COSMIC) EXAMPLE: 30% (add Reference)	EXAMPLE: IDH1 R123H	EXAMPLE: EGFR amplification				EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).
MAP2K1	p.T28I, p.L37P,p.E129Q, p.Y130C							Systemic juvenile xanthogranuloma [4] (MEK) inhibitors [5]
CSF1R mutations	Kinase driver mutations							Children less than 2years of age with soft tissue involvement [4]
PIK3CA mutations								[4]
NF1
KRAS	p.G12D							[4]
NRAS	p.Q61R							[4]
ARAF	p.N217K or p.F351L							[4]
BRAF V600E mutation	Proto-oncogene				Yes, Might represent pediatric Erdheim–Chester disease.	Yes Aggressive course	Unknown. Targeted therapy with BRAF-inhibitor dabrafenib needs to be studied further .	Pediatric cases with systemic JXG with CNS involvement and BRAF V600E mutations show male preponderance and are associated with aggressive disease at presentation. These cases needs to be followed up, they probably represent Erdheim–Chester disease.[6]

Note: A more extensive list of mutations can be found in Bioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

Epigenomic Alterations

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Genes and Main Pathways Involved

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Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
NRAS, KRAS, ARAF, MAP2K1, and CSF1R, NTRK1 and BRAF gene fusions	MAPK/ERK pathway alterations	EXAMPLE: Increased cell growth and proliferation
PIK3CD mutations	PI3K pathway	EXAMPLE: Unregulated cell division
NA	NA	NA

Genetic Diagnostic Testing Methods

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Familial Forms

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Additional Information

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Links

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References

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EXAMPLE Book

1. John  Chan et al., Juvenile xanthogranuloma, in: WHO Classification of Tumours Editorial Board. Haematolymphoid tumours. Lyon (France): International Agency for Research on Cancer; 2024. . (WHO classification of tumours series, 5th ed.; vol. 11). https://publications.iarc.who.int/637.
2. Paxton, C. N., O'malley, D.,P., Bellizzi, A. M., Alkapalan, D., Fedoriw, Y., Hornick, J. L., Andersen, E. F. (2017). Genetic evaluation of juvenile xanthogranuloma: Genomic abnormalities are uncommon in solitary lesions, advanced cases may show more complexity. Modern Pathology, 30(9), 1234-1240. doi:https://doi.org/10.1038/modpathol.2017.50
3. Umphress B, Kuhar M, Kowal R, et al. NTRK expression is common in xanthogranuloma and is associated with the solitary variant. J Cutan Pathol. 2023; 50(11): 991-1000. doi:10.1111/cup.14510
4. Seidel MG, Brcic L, Hoefler G, et al. Concurrence of a kinase‐dead BRAF and an oncogenic KRAS gain‐of‐function mutation in juvenile xanthogranuloma. Pediatric blood & cancer. 2023;70(4):e30060-n/a. doi:10.1002/pbc.30060
5. Kai-ni Shen, He Lin, Long Chang, Xin-xin Cao, Disseminated juvenile xanthogranuloma harbouring a GAB2::BRAF fusion successfully treated with trametinib: a case report, British Journal of Dermatology, Volume 192, Issue 1, January 2025, Pages 169–171, https://doi.org/10.1093/bjd/ljae328
6. Picarsic J, Pysher T, Zhou H, Fluchel M, Pettit T, Whitehead M, Surrey LF, Harding B, Goldstein G, Fellig Y, Weintraub M, Mobley BC, Sharples PM, Sulis ML, Diamond EL, Jaffe R, Shekdar K, Santi M. BRAF V600E mutation in Juvenile Xanthogranuloma family neoplasms of the central nervous system (CNS-JXG): a revised diagnostic algorithm to include pediatric Erdheim-Chester disease. Acta Neuropathol Commun. 2019 Nov 4;7(1):168. doi: 10.1186/s40478-019-0811-6. PMID: 31685033; PMCID: PMC6827236.
7. McClain KL, Bigenwald C, Collin M, et al. Histiocytic disorders. Nature reviews Disease primers. 2021;7(1):73-73. doi:10.1038/s41572-021-00307-9

Notes

*Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome. *Citation of this Page: “Juvenile xanthogranuloma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 03/27/2025, https://ccga.io/index.php/HAEM5:Juvenile_xanthogranuloma.