HAEM5:Juvenile xanthogranuloma

Haematolymphoid 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 Xanthogranuloma (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	Disseminated JXG with GAB2::BRAF fusion showed favorable response to treatment with Trametinib (MEK1/2 inhibitor). [5].	BRAF gene fusions are more often seen in adult and Juvenile JXG as compared with other histiocytic disorders. [10]
RET fusions	NCOA4–RET rearrangement	Unknown	Unknown	Unknown	Unknown	Treatment with RET inhibitor Selpercatinib showed dramatic resolution of disfiguring skin lesions. [11]	Disseminated cutaneous–xanthogranuloma [11]
SYK fusions	CLTC::SYK fusions -exon 5 or intron 5 of SYK that lead to fusion of CLTC exon 31 to SYK exon 6 ETV6::SYK fusion	Unknown	Unknown	Unknown	Unknown	May respond to oral SYK inhibitors-fostamatinib and entospletinib [12]	Lacks or shows rare touton giant cells [12] IHC staining shows strong positivity for p-SYK, positive for cyclin D1 and p-S6. p-Akt negative. [12] Children between 2months and 2 years of age with soft tissue involvement and no or limited cutaneous involvement. [12]
ALK fusions/rearrangements	KIF5B–ALK TPM3–ALK	Unknown	Unknown	Unknown	Unknown	A pediatric patient with systemic JXG, CNS lesions and KIF5B-ALK fusion achieved clinical improvement with ALK-inhibitor Alectinib therapy. [7]	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. [8] KIF5B–ALK seen in systemic JXG with CNS involvement. [7] child with JXG of soft tissue
MRC1-PDGFRB fusion	t(5;10)(q32; p12.33) translocation	in-frame MRC1-PDGFRB gene fusion Can be seen with large deletion of exons 21 and 22 [12]	Unknown	Unknown	Unknown	Targeted therapy of treatment resistant systemic JXG with Dasatinib showed a steady and dramatic clinical response with a reduction in the size of the primary tumor. [9]	JXG case showing large deletion of CSF1R exons 21 and 22 and MRC1::PDGFRB fusion was a 3 month old female with large intra-abdominal tumor involving greater omentum, intestinal walls and liver hilum. Achieved complete remission without relapse during 24 years of follow up. [12] IHC staining showed diffuse expression of cyclin D1 in tumor cells.[9] . Child with chemotherapy-refractory left chest wall JXG, MRC1::PDGFRB fusion was treated with dasatinib. [12]
TBL1XR1::BOD1L1 fusion (and reciprocal BOD1L1::ABHD10)	Unknown	Unknown	Unknown	Unknown	Unknown	Unknown	Unifocal soft tissue JXG in the nasopharynx [12]

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).
17	Gain	Unknown	Unknown	Unknown	Unknown	Unknown	Diffuse cutaneous juvenile xanthogranuloma [2]
5	Gain, Heterozygosity	Unknown	Unknown	Unknown	Unknown	Unknown	Trisomy 5 and 5q heterozygosity in diffuse cutaneous juvenile xanthogranuloma [2]
3	Loss	Unknown	Unknown	Unknown	Unknown	Unknown	3p deletion in 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).
Gains on 1q and 11q	Unknown	Unknown	Unknown	Gains on 1q and 11q in systemic juvenile xanthogranuloma [2]

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	Unknown	Unknown	Unknown	Unknown	Unknown	May respond to targeted treatment with (MEK) inhibitors. [5]	Systemic juvenile xanthogranuloma [4]
CSF1R mutations	Kinase driver mutations -Deletion in exon 12 -multiple missense mutations in exons 9 and 10 -large deletion of exons 21 and 22 -Alternative CSF1R mutations in exons 9 and 10 -Missense mutations in exon 10 [12]	Unknown	Unknown	Unknown	Unknown	Unknown	CSF-1R-specific small-molecule inhibitors Pexidartinib and BLZ945 is being studied. [11]	-Exon 10 mutations affect the extracellular region of CSF-1R and might enhance receptor dimerization. [12] -Large deletion of CSF1R exons 21 and 22 affects the intracellular c-CBL binding domain leading to defective receptor ubiquitination, and degradation [12] Children less than 2years of age with soft tissue involvement [4] [12]
PIK3CA mutations	Unknown	Unknown	Unknown	Unknown	Unknown	Unknown	Unknown	[4]
NF1	Unknown	Unknown	Unknown	Unknown	Unknown	Unknown	Unknown
KRAS	p.G12D	Unknown	Unknown	Unknown	Unknown	Unknown	Unknown	[4]
NRAS	p.Q61R	Unknown	Unknown	Unknown	Unknown	Unknown	Unknown	[4]
ARAF	p.N217K or p.F351L	Unknown	Unknown	Unknown	Unknown	Unknown	Unknown	[4]
BRAF V600E mutation	Proto-oncogene	Unknown	Unknown	Unknown	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	Increased cell growth, proliferation, differentiation, apoptosis and stress responses
PIK3CD mutations	PI3K pathway	Unregulated cell survival, growth, and proliferation

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. Sugiyama M, Hirabayashi S, Ishi Y, et al. Notable therapeutic response in a patient with systemic juvenile xanthogranuloma with KIF5B‐ALK fusion. Pediatric blood & cancer. 2021;68(11):e29227-n/a. doi:10.1002/pbc.29227
8. 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
9. Eissa SS, Clay MR, Santiago T, Wu G, Wang L, Shulkin BL, Picarsic J, Nichols KE, Campbell PK. Dasatinib induces a dramatic response in a child with refractory juvenile xanthogranuloma with a novel MRC1-PDGFRB fusion. Blood Adv. 2020 Jul 14;4(13):2991-2995. doi: 10.1182/bloodadvances.2020001890. PMID: 32609843; PMCID: PMC7362356.
10. Zanwar S, Abeykoon JP, Acosta-Medina AA, et al. BRAF Fusions in Histiocytic Disorders: Frequency and Clinical Characteristics. Blood. 2021;138(Supplement 1):2582-2582. doi:10.1182/blood-2021-149802
11. Durham BH, Lopez Rodrigo E, Picarsic J, et al. Activating mutations in CSF1R and additional receptor tyrosine kinases in histiocytic neoplasms. Nature medicine. 2019;25(12):1839-1842. doi:10.1038/s41591-019-0653-6
12. Paul G. Kemps, Hans J. Baelde, Ruben H. P. Vorderman, Ellen Stelloo, Joost F. Swennenhuis, Karoly Szuhai, Meindert H. Lamers, Boyd Kenkhuis, Maysa Al-Hussaini, Inge H. Briaire-de Bruijn, Suk Wai Lam, Judith V. M. G. Bovée, Arjen H. G. Cleven, Robert M. Verdijk, Carel J. M. van Noesel, Marijke R. van Dijk, Marijn A. Scheijde-Vermeulen, Annette H. Bruggink, Jan A. M. van Laar, Andrica C. H. de Vries, Wim J. E. Tissing, Cor van den Bos, Andreas von Deimling, Tom van Wezel, Astrid G. S. van Halteren, Pancras C. W. Hogendoorn, Recurrent CLTC::SYK fusions and CSF1R mutations in juvenile xanthogranuloma of soft tissue, Blood, Volume 144, Issue 23, 2024, Pages 2439-2455, ISSN 0006-4971, https://doi.org/10.1182/blood.2024025127.

Notes

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