HAEM5:Juvenile xanthogranuloma

Primary Author(s)*

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

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.

Synonyms / Terminology

Juvenile Xanthogranuloma

Epidemiology / Prevalence

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

Clinical Features

JXG lesions are generally asymptomatic; their appearance is typically different in adult and pediatric settings. Infants may present with ≥1 cutaneous, pale yellow-tan, dome-shaped papulonodular lesions. Approximately 5% of patients present with multiple lesions. Typically lesions begin as raised, pink to dark-brown lesions that may become less elevated over time. Spontaneous resolution of some lesions, leaving residual scarring or wrinkling, may occur after months or years. A clinical subtype of JXG called benign cephalic histiocytosis presents with asymptomatic self-healing papular lesions involving the head and neck of young children.

In adult JXG, lesions are often large, solitary and persistent; in this context Erdheim–Chester disease is an important differential diagnosis.

JXG may occur in patients with neurofibromatosis type 1 and is also reported in Wiskott–Aldrich syndrome.

Signs and Symptoms	Initially asymptomatic ≥1 cutaneous papulonodular lesions Rarely: systemic involvement with cytopenias, abnormal hepatic or metabolic function, ophthalmological involvement, or neurological involvement leading to seizures, hydrocephalus, or diabetes insipidus
Laboratory Findings	Abnormal liver enzymes and metabolic tests Cytopenia in cases with bone marrow involvement

Sites of Involvement

JXG commonly involves, and is generally confined to, the skin of the head and neck, upper trunk and proximal extremities. Solitary ocular lesions occur but are rare. Other rare extracutaneous sites of involvement include viscera, and paraspinal or intracranial regions.

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.

WHO Diagnostic criteria

Essential	A circumscribed lesion comprising histiocytes (commonly foamy) lacking significant nuclear pleomorphism; dermal macrophage immunophenotype (CD68, CD163, and factor XIIIa); negativity for CD1a, CD207 (langerin), and ALK
Desirable	Touton giant cells; clinical exclusion of Erdheim–Chester disease.

Immunophenotype

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)

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 seen more often in adult and juvenile JXG compared to 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 Breakpoints in exon 5 or intron 5 of SYK (resulting in alternative splicing through exon skipping) lead to the fusion of SYK exon 6 to CLTC exon 31 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 2 months 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]
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]	A 3 month old female with a large JXG intra-abdominal tumor involving the greater omentum, intestinal walls and hepatic hilum achieved complete remission without relapse during 24 years of follow up. Testing showed a large deletion of exons 21 and 22 of CSF1R in parallel with MRC1::PDGFRB fusion. [12] IHC staining showed diffuse expression of cyclin D1 in tumor cells.[9] A child with chemotherapy-refractory left chest wall JXG, MRC1::PDGFRB fusion was treated with dasatinib and demonstrated clinical and radiological reduction in size and metabolic activity of the tumor mass. [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

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
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

Chromosomal Pattern	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
Gains on 1q and 11q	Unknown	Unknown	Unknown	Gains on 1q and 11q in systemic juvenile xanthogranuloma [2]

Gene Mutations (SNV / INDEL)

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
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 Deletions in exon 12 Multiple missense mutations in exons 9 and 10 Large deletions involving 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 2 years 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	Neurofibromatosis is associated with JXG.
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, may indicate pediatric Erdheim–Chester disease.	Yes Aggressive course	Unknown. Targeted therapy with BRAF-inhibitor dabrafenib needs to be studied further .	Cases of systemic pediatric JXG with CNS involvement and BRAF V600E mutations show male preponderance and are associated with aggressive disease at presentation. Erdheim–Chester disease is an important differential diagnosis. [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

Not listed

Genes and Main Pathways Involved

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

Sequencing is not relevant to establishing the diagnosis, given there are no recognized molecular diagnostic features, but whole exome sequencing, whole transcriptome sequencing, and targeted DNA and/or RNA sequencing may identify BRAF, ALK, RET, and NTRK1 gene rearrangements or other variants that disrupt the RAS/RAF/MAPK/ERK and PI3K/AKT pathways.

Familial Forms

JXG may occur in patients with neurofibromatosis type 1 or Wiskott–Aldrich syndrome.

Additional Information

Not listed

References

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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