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]
|
| 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
- 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.
- 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
- 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
- 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
- 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
- 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.
- 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
- 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
- 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.
- 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
- 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
- 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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