HAEM5:Juvenile xanthogranuloma: Difference between revisions

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{{DISPLAYTITLE:Juvenile xanthogranuloma}}
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]
{{Under Construction}}
<span style="color:#0070C0">(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ HGVS-based nomenclature for variants], as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column to a table, click within the table and select the > symbol that appears to be given options. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see </span><u>[[Author_Instructions]]</u><span style="color:#0070C0"> and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>])</span>
==Primary Author(s)*==
==Primary Author(s)*==


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


<span style="color:#0070C0">Scott Turner, PhD </span>
<span style="color:#0070C0">Scott Turner, PhD </span>
Line 35: Line 28:
==Definition / Description of Disease==
==Definition / Description of Disease==


Juvenile Xanthogranuloma (JXG) is a clonal expansion of non–Langerhans cell histiocytes with dermal macrophage phenotype.<span style="color:#0070C0">(''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.'') </span>
Juvenile Xanthogranuloma (JXG) is a clonal expansion of non–Langerhans cell histiocytes with dermal macrophage phenotype.  


==Synonyms / Terminology==
==Synonyms / Terminology==


Juvenile Xanthogranuloma <span style="color:#0070C0">(''Instructions: Include currently used terms and major historical ones, adding “(historical)” after the latter.'') </span>
Juvenile Xanthogranuloma  


==Epidemiology / Prevalence==
==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.
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==
==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.   <span style="color:#0070C0">(''Instruction: Can include references in the table. Do not delete table.'') </span>
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"
{| class="wikitable"
|'''Signs and Symptoms'''
|'''Signs and Symptoms'''
|Asymptomatic in the beginning
|Initially asymptomatic
≥1 cutaneous papulonodular lesions
≥1 cutaneous papulonodular lesions


Rarely systemic involvement with abnormal labs, ophthalmologic exam findings, seizures, hydrocephalus, diabetes Insipidus
Rarely: systemic involvement with cytopenias, abnormal hepatic or metabolic function, ophthalmological involvement, or neurological involvement leading to seizures, hydrocephalus, or diabetes insipidus
|-
|-
|'''Laboratory Findings'''
|'''Laboratory Findings'''
|Abnormal blood count, liver enzymes, metabolic tests
|Abnormal liver enzymes and metabolic tests
Cytopenia if bone marrow involved
Cytopenia in cases with bone marrow involvement
|}
|}


==Sites of Involvement==
==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.   <span style="color:#0070C0">(''Instruction: Indicate physical sites; <span class="blue-text">EXAMPLE:</span> nodal, extranodal, bone marrow'') </span>
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==
==Morphologic Features==
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'''Histopathology:'''
'''Histopathology:'''


*Unencapsulated, circumscribed lesions composed of classic histiocytes, large xanthomatous histiocytes, foamy histiocytes and Touton giant cells..
*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.
*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.
*These histiocytes should not  show significant nuclear pleomorphism.
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*Mononuclear or multinucleated histiocytes with kidney shaped/oval nuclei, variable numbers of lymphocytes, neutrophils, and eosinophils.
*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.
*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==
==Immunophenotype==
Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table. Do not delete table.'') </span>


{| class="wikitable sortable"
{| class="wikitable sortable"
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==Chromosomal Rearrangements (Gene Fusions)==
==Chromosomal Rearrangements (Gene Fusions)==
Put your text here and fill in the table


{| class="wikitable sortable"
{| class="wikitable sortable"
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!Notes
!Notes
|-
|-
|NTRK1 fusions||TPM3::NTRK1 fusion
|''NTRK1'' fusions||''TPM3::NTRK1 fusion''
PRDX1–NTRK1
''PRDX1–NTRK1''
|Unknown||Unknown
|Unknown||Unknown
|Unknown
|Unknown
|Unknown
|Unknown
|Unknown
|Unknown
|Often associated with localized xanthogranuloma [3]
|Often associated with localized xanthogranuloma. [3]
|-
|-
|BRAF fusions
|''BRAF'' fusions
|FNBP1-BRAF  
|''FNBP1-BRAF''
RNF11-BRAF
''RNF11-BRAF''


''MS4A6A::BRAF'' ''BICD2::BRAF''
''MS4A6A::BRAF'' ''BICD2::BRAF''


GAB2-BRAF
''GAB2-BRAF''
|Unknown
|Unknown
|Unknown
|Unknown
|Unknown
|Unknown
|Unknown
|Unknown
|Disseminated JXG with ''GAB2::BRAF'' fusion showed favorable response to treatment with Trametinib (MEK1/2 inhibitor). [5].
|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]
|BRAF gene fusions are seen more often in adult and juvenile JXG compared to other histiocytic disorders. [10]
|-
|-
|RET fusions
|''RET'' fusions
|NCOA4–RET rearrangement
|''NCOA4–RET'' rearrangement
|Unknown
|Unknown
|Unknown
|Unknown
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|Disseminated cutaneous–xanthogranuloma [11]
|Disseminated cutaneous–xanthogranuloma [11]
|-
|-
|SYK fusions
|''SYK'' fusions
|CLTC::SYK fusions
|''CLTC::SYK'' fusions


-exon 5 or intron 5 of SYK that lead to fusion of CLTC exon 31 to SYK exon 6
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
ETV6::SYK fusion
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|May respond to  oral SYK inhibitors-fostamatinib and entospletinib [12]
|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]
|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]
Children between 2 months and 2 years of age with soft tissue involvement and no or limited cutaneous involvement. [12]
|-
|-
|ALK fusions/rearrangements
|''ALK'' fusions/rearrangements
|KIF5B–ALK
|''KIF5B::ALK''
TPM3–ALK
''TPM3::ALK''
|Unknown
|Unknown
|Unknown
|Unknown
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|Unknown
|Unknown
|A pediatric patient with systemic JXG, CNS lesions and  KIF5B-ALK fusion achieved clinical improvement with ALK-inhibitor Alectinib therapy. [7]
|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
|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
|''MRC1::PDGFRB'' fusion
|t(5;10)(q32; p12.33) translocation
|t(5;10)(q32; p12.33) translocation
|in-frame ''MRC1-PDGFRB'' gene fusion
|in-frame ''MRC1-PDGFRB'' gene fusion
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|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]
|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]
|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)
|''TBL1XR1::BOD1L1'' fusion (and reciprocal BOD1L1::ABHD10)
|Unknown
|Unknown
|Unknown
|Unknown
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==Individual Region Genomic Gain / Loss / LOH==
==Individual Region Genomic Gain / Loss / LOH==
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Includes aberrations not involving gene fusions. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable. Do not delete table.'') </span>


{| class="wikitable sortable"
{| class="wikitable sortable"
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!Therapeutic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
!Notes
|-
|<span class="blue-text">EXAMPLE:</span>
7
|<span class="blue-text">EXAMPLE:</span> Loss
|<span class="blue-text">EXAMPLE:</span>
chr7:1- 159,335,973 [hg38]
|<span class="blue-text">EXAMPLE:</span>
chr7
|Yes
|Yes
|No
|<span class="blue-text">EXAMPLE:</span>
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).
|-
|<span class="blue-text">EXAMPLE:</span>
8
|<span class="blue-text">EXAMPLE:</span> Gain
|<span class="blue-text">EXAMPLE:</span>
chr8:1-145,138,636 [hg38]
|<span class="blue-text">EXAMPLE:</span>
chr8
|No
|No
|No
|<span class="blue-text">EXAMPLE:</span>
Common recurrent secondary finding for t(8;21) (add reference).
|-
|-
|17
|17
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|}
|}
==Characteristic Chromosomal Patterns==
==Characteristic Chromosomal Patterns==
Put your text here <span style="color:#0070C0">(''EXAMPLE PATTERNS: hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis. Do not delete table.'')</span>


{| class="wikitable sortable"
{| class="wikitable sortable"
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!Therapeutic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
!Notes
|-
|<span class="blue-text">EXAMPLE:</span>
Co-deletion of 1p and 18q
|Yes
|No
|No
|<span class="blue-text">EXAMPLE:</span>
See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
|-
|-
|Gains on 1q and 11q
|Gains on 1q and 11q
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|}
|}
==Gene Mutations (SNV / INDEL)==
==Gene Mutations (SNV / INDEL)==
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent and common as well as either disease defining and/or clinically significant. Can include references in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable. Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Do not delete table.'') </span>


{| class="wikitable sortable"
{| class="wikitable sortable"
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!Notes
!Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span> TP53; Variable LOF mutations
|''MAP2K1''
 
<span class="blue-text">EXAMPLE:</span>
 
EGFR; Exon 20 mutations
 
<span class="blue-text">EXAMPLE:</span> BRAF; Activating mutations
|<span class="blue-text">EXAMPLE:</span> TSG
|<span class="blue-text">EXAMPLE:</span> 20% (COSMIC)
 
<span class="blue-text">EXAMPLE:</span> 30% (add Reference)
|<span class="blue-text">EXAMPLE:</span> IDH1 R123H
|<span class="blue-text">EXAMPLE:</span> EGFR amplification
|
|
|
|<span class="blue-text">EXAMPLE:</span>  Excludes hairy cell leukemia (HCL) (add reference).
<br />
|-
|MAP2K1
|p.T28I, p.L37P,p.E129Q, p.Y130C
|p.T28I, p.L37P,p.E129Q, p.Y130C
|Unknown
|Unknown
Line 327: Line 260:
|Unknown
|Unknown
|May respond to targeted treatment with (MEK) inhibitors. [5]
|May respond to targeted treatment with (MEK) inhibitors. [5]
|Systemic juvenile xanthogranuloma [4]
|Systemic juvenile xanthogranuloma. [4]<br />
<br />
|-
|-
|CSF1R mutations
|''CSF1R'' mutations
|Kinase driver mutations
|Kinase driver mutations
-Deletion in exon 12
Deletions in exon 12
 
-multiple missense mutations in exons 9 and 10


-large deletion of exons 21 and 22
Multiple missense mutations in exons 9 and 10


-Alternative CSF1R mutations in exons 9 and 10
Large deletions involving exons 21 and 22


-Missense mutations in exon 10
Alternative CSF1R mutations in exons 9 and 10


[12]
Missense mutations in exon 10 [12]
|Unknown
|Unknown
|Unknown
|Unknown
Line 349: Line 279:
|Unknown
|Unknown
|CSF-1R-specific small-molecule inhibitors Pexidartinib and BLZ945 is being studied. [11]
|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]
| 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]
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]
Children less than 2years of age with soft tissue involvement
[4] [12]
|-
|-
|PIK3CA mutations
|''PIK3CA'' mutations
|Unknown
|Unknown
|Unknown
|Unknown
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|[4]
|[4]
|-
|-
|NF1
|''NF1''
|Unknown
|Unknown
|Unknown
|Unknown
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|Unknown
|Unknown
|Unknown
|Unknown
|
|Neurofibromatosis is associated with JXG.
|-
|-
|KRAS
|''KRAS''
|p.G12D
|p.G12D
|Unknown
|Unknown
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|[4]
|[4]
|-
|-
|NRAS
|''NRAS''
|p.Q61R
|p.Q61R
|Unknown
|Unknown
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|[4]
|[4]
|-
|-
|ARAF
|''ARAF''
|p.N217K or p.F351L
|p.N217K or p.F351L
|Unknown
|Unknown
Line 411: Line 339:
|Unknown
|Unknown
|Unknown
|Unknown
|Yes,
|Yes, may indicate pediatric Erdheim–Chester disease.
Might represent pediatric Erdheim–Chester disease.
|Yes
|Yes
Aggressive course
Aggressive course
|Unknown.
|Unknown.
Targeted therapy with BRAF-inhibitor dabrafenib needs to be studied further .
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]
|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.
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.
Line 423: Line 350:
==Epigenomic Alterations==
==Epigenomic Alterations==


Put your text here
Not listed


==Genes and Main Pathways Involved==
==Genes and Main Pathways Involved==
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Can include references in the table. Do not delete table.'')</span>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
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|-
|-
|''NRAS'', ''KRAS'', ''ARAF'', ''MAP2K1'', and ''CSF1R, NTRK1 and BRAF gene fusions''
|''NRAS'', ''KRAS'', ''ARAF'', ''MAP2K1'', and ''CSF1R, NTRK1 and BRAF gene fusions''
|MAPK/ERK pathway alterations
|''MAPK/ERK'' pathway alterations
|Increased cell growth, proliferation, differentiation, apoptosis and stress responses
|Increased cell growth, proliferation, differentiation, apoptosis and stress responses
|-
|-
|''PIK3CD'' mutations
|''PIK3CD'' mutations
|PI3K pathway
|''PI3K'' pathway
|Unregulated cell survival, growth, and proliferation
|Unregulated cell survival, growth, and proliferation
|}
|}
==Genetic Diagnostic Testing Methods==
==Genetic Diagnostic Testing Methods==


Put your text here
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==
==Familial Forms==


Put your text here <span style="color:#0070C0">(''Instructions: Include associated hereditary conditions/syndromes that cause this entity or are caused by this entity.'') </span>
JXG may occur in patients with neurofibromatosis type 1 or Wiskott–Aldrich syndrome.  


==Additional Information==
==Additional Information==


Put your text here
Not listed


==Links==
==Links==


Put your text placeholder here (or anywhere appropriate on the page) and use the "Link" icon at the top of the page <span style="color:#0070C0">(''Instructions: Highlight text to which you want to add a link in this section or elsewhere, select the "Link" icon at the top of the page, and search the name of the internal page to which you want to link this text, or enter an external internet address by including the "<nowiki>http://www</nowiki>." portion.'')</span>
==References ==
<references />


==References==
<br />
(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking on where you want to insert the reference, selecting the “Cite” icon at the top of the page, and using the “Automatic” tab option to search such as by PMID to select the reference to insert. The reference list in this section will be automatically generated and sorted.''</span> <span style="color:#0070C0">''If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">) </span> <references />
 
'''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). <nowiki>https://publications.iarc.who.int/637</nowiki>.
#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>.

Latest revision as of 13:38, 3 February 2026

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

Links

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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