View source for HAEM5:Juvenile xanthogranuloma

==Primary Author(s)*==

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

<span style="color:#0070C0">Scott Turner, PhD </span>
==WHO Classification of Disease==

{| class="wikitable"
!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.  
{| class="wikitable"
|'''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.

{| class="wikitable"
|+'''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==

{| class="wikitable sortable"
|-
!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)==

{| class="wikitable sortable"
|-
!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==

{| class="wikitable sortable"
|-
!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==

{| class="wikitable sortable"
|-
!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)==

{| class="wikitable sortable"
|-
!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]<br />
|-
|''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==
{| class="wikitable sortable"
|-
!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 

==Links==

==References ==
<references />

<br />

#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). <nowiki>https://publications.iarc.who.int/637</nowiki>.
#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:<nowiki>https://doi.org/10.1038/modpathol.2017.50</nowiki>
#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, <nowiki>https://doi.org/10.1093/bjd/ljae328</nowiki>
#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, <nowiki>https://doi.org/10.1182/blood.2024025127</nowiki>.

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<nowiki>*</nowiki>''Citation of this Page'': “Juvenile xanthogranuloma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Juvenile_xanthogranuloma</nowiki>.
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