Compendium of Cancer Genome Aberrations

HAEM5:Juvenile xanthogranuloma: Difference between revisions

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{{DISPLAYTITLE:Juvenile xanthogranuloma}}
{{DISPLAYTITLE:Juvenile xanthogranuloma}}
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]


{{Under Construction}}
{{Under Construction}}


<span style="color:#0070C0">(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ <u>HGVS-based nomenclature for variants</u>], 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 in a table, click nearby within the table and select the > symbol that appears. 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>
<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)*==
Line 12: Line 11:


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


Line 43: Line 39:
==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 <span style="color:#0070C0">(''Instructions: Include currently used terms and major historical ones, adding “(historical)” after the latter.'') </span>


==Epidemiology / Prevalence==
==Epidemiology / Prevalence==
Line 72: Line 68:
'''Gross appearance:'''
'''Gross appearance:'''


Cutaneous JXGs: Early lesions are pink macules, later progress to form pale to tan, dome shaped lesions.
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.
Visceral JXGs: Nodules with variable size and appearance.
Line 78: Line 74:
'''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.


'''Cytology''':  
'''Cytology''':  


* 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.


==Immunophenotype==
==Immunophenotype==
Line 99: Line 95:
|Positive (subset)||S100 (light nuclear and cytoplasmic staining)
|Positive (subset)||S100 (light nuclear and cytoplasmic staining)
|-
|-
|Negative (universal)||CD1a and CD207 (langerin), ALK
|Negative (universal)||CD1a and CD207 (langerin), ALK
|-
|-
|Negative (subset)||N/A
|Negative (subset)||N/A
|}
|}


==WHO Essential and Desirable Genetic Diagnostic Criteria==
==Chromosomal Rearrangements (Gene Fusions)==
<span style="color:#0070C0">(''Instructions: The table will have the diagnostic criteria from the WHO book <u>autocompleted</u>; remove any <u>non</u>-genetics related criteria. If applicable, add text about other classification'' ''systems that define this entity and specify how the genetics-related criteria differ.'')</span>
{| class="wikitable"
|+
|WHO Essential Criteria (Genetics)*
|
|-
|WHO Desirable Criteria (Genetics)*
|
|-
|Other Classification
|
|}
<nowiki>*</nowiki>Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the [https://tumourclassification.iarc.who.int/home <u>WHO Classification of Tumours</u>].
==Related Terminology==
<span style="color:#0070C0">(''Instructions: The table will have the related terminology from the WHO <u>autocompleted</u>.)''</span>
{| class="wikitable"
|+
|Acceptable
|
|-
|Not Recommended
|
|}


==Gene Rearrangements==
Put your text here and fill in the table


Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.'')</span>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Driver Gene!!Fusion(s) and Common Partner Genes!!Molecular Pathogenesis!!Typical Chromosomal Alteration(s)
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
!Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!Diagnostic Significance (Yes, No or Unknown)
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!Prognostic Significance (Yes, No or Unknown)
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Therapeutic Significance (Yes, No or Unknown)
!Clinical Relevance Details/Other Notes
!Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''ABL1''||<span class="blue-text">EXAMPLE:</span> ''BCR::ABL1''||<span class="blue-text">EXAMPLE:</span> The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1.||<span class="blue-text">EXAMPLE:</span> t(9;22)(q34;q11.2)
|NTRK1 fusions||TPM3::NTRK1 fusion
|<span class="blue-text">EXAMPLE:</span> Common (CML)
PRDX1–NTRK1
|<span class="blue-text">EXAMPLE:</span> D, P, T
|Unknown||Unknown
|<span class="blue-text">EXAMPLE:</span> Yes (WHO, NCCN)
|Unknown
|<span class="blue-text">EXAMPLE:</span>
|Unknown
The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference). BCR::ABL1 is generally favorable in CML (add reference).
|Unknown
|Often associated with localized xanthogranuloma [3]
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''CIC''
|BRAF fusions
|<span class="blue-text">EXAMPLE:</span> ''CIC::DUX4''
|FNBP1-BRAF
|<span class="blue-text">EXAMPLE:</span> Typically, the last exon of ''CIC'' is fused to ''DUX4''. The fusion breakpoint in ''CIC'' is usually intra-exonic and removes an inhibitory sequence, upregulating ''PEA3'' genes downstream of ''CIC'' including ''ETV1'', ''ETV4'', and ''ETV5''.
RNF11-BRAF
|<span class="blue-text">EXAMPLE:</span> t(4;19)(q25;q13)
 
|<span class="blue-text">EXAMPLE:</span> Common (CIC-rearranged sarcoma)
''MS4A6A::BRAF'' ''BICD2::BRAF''
|<span class="blue-text">EXAMPLE:</span> D
|
|<span class="blue-text">EXAMPLE:</span>


''DUX4'' has many homologous genes; an alternate translocation in a minority of cases is t(10;19), but this is usually indistinguishable from t(4;19) by short-read sequencing (add references).
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]
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''ALK''
|RET fusions
|<span class="blue-text">EXAMPLE:</span> ''ELM4::ALK''
|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


Other fusion partners include ''KIF5B, NPM1, STRN, TFG, TPM3, CLTC, KLC1''
ETV6::SYK fusion
|<span class="blue-text">EXAMPLE:</span> Fusions result in constitutive activation of the ''ALK'' tyrosine kinase. The most common ''ALK'' fusion is ''EML4::ALK'', with breakpoints in intron 19 of ''ALK''. At the transcript level, a variable (5’) partner gene is fused to 3’ ''ALK'' at exon 20. Rarely, ''ALK'' fusions contain exon 19 due to breakpoints in intron 18.
|Unknown
|<span class="blue-text">EXAMPLE:</span> N/A
|Unknown
|<span class="blue-text">EXAMPLE:</span> Rare (Lung adenocarcinoma)
|Unknown
|<span class="blue-text">EXAMPLE:</span> T
|Unknown
|
|May respond to  oral SYK inhibitors-fostamatinib and entospletinib [12]
|<span class="blue-text">EXAMPLE:</span>
|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]
Both balanced and unbalanced forms are observed by FISH (add references).
|-
|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
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''ABL1''
|''MRC1-PDGFRB'' fusion
|<span class="blue-text">EXAMPLE:</span> N/A
|t(5;10)(q32; p12.33) translocation
|<span class="blue-text">EXAMPLE:</span> Intragenic deletion of exons 2–7 in ''EGFR'' removes the ligand-binding domain, resulting in a constitutively active tyrosine kinase with downstream activation of multiple oncogenic pathways.
|in-frame ''MRC1-PDGFRB'' gene fusion
|<span class="blue-text">EXAMPLE:</span> N/A
Can be seen with large deletion of exons 21 and 22 [12]
|<span class="blue-text">EXAMPLE:</span> Recurrent (IDH-wildtype Glioblastoma)
|Unknown
|<span class="blue-text">EXAMPLE:</span> D, P, T
|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==
==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>


Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Includes aberrations not involving gene rearrangements. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Can refer to CGC workgroup tables as linked on the homepage if applicable. Please include references throughout the table. Do not delete the table.'') </span>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Chr #!!'''Gain, Loss, Amp, LOH'''!!'''Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]'''!!'''Relevant Gene(s)'''
!Chr #!!Gain / Loss / Amp / LOH!!Minimal Region Genomic Coordinates [Genome Build]!!Minimal Region Cytoband
!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T'''
!Diagnostic Significance (Yes, No or Unknown)
!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
!Prognostic Significance (Yes, No or Unknown)
!'''Clinical Relevance Details/Other Notes'''
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|<span class="blue-text">EXAMPLE:</span>
7
7
|<span class="blue-text">EXAMPLE:</span> Loss
|<span class="blue-text">EXAMPLE:</span> Loss
|<span class="blue-text">EXAMPLE:</span>
|<span class="blue-text">EXAMPLE:</span>
chr7:1- 159,335,973 [hg38]
|<span class="blue-text">EXAMPLE:</span>
chr7
chr7
|Yes
|Yes
|No
|<span class="blue-text">EXAMPLE:</span>
|<span class="blue-text">EXAMPLE:</span>
Unknown
 
|<span class="blue-text">EXAMPLE:</span> D, P
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> 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 references).
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|<span class="blue-text">EXAMPLE:</span>
8
8
|<span class="blue-text">EXAMPLE:</span> Gain
|<span class="blue-text">EXAMPLE:</span> Gain
|<span class="blue-text">EXAMPLE:</span>
|<span class="blue-text">EXAMPLE:</span>
chr8:1-145,138,636 [hg38]
|<span class="blue-text">EXAMPLE:</span>
chr8
chr8
|No
|No
|No
|<span class="blue-text">EXAMPLE:</span>
|<span class="blue-text">EXAMPLE:</span>
Unknown
 
|<span class="blue-text">EXAMPLE:</span> D, P
Common recurrent secondary finding for t(8;21) (add reference).
|
|-
|<span class="blue-text">EXAMPLE:</span>
|17
Common recurrent secondary finding for t(8;21) (add references).
|Gain
|Unknown
|Unknown
|Unknown
|Unknown
|Unknown
|Diffuse cutaneous juvenile xanthogranuloma [2]
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|5
17
|Gain, Heterozygosity
|<span class="blue-text">EXAMPLE:</span> Amp
|Unknown
|<span class="blue-text">EXAMPLE:</span>
|Unknown
17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]
|Unknown
|<span class="blue-text">EXAMPLE:</span>
|Unknown
''ERBB2''
|Unknown
|<span class="blue-text">EXAMPLE:</span> D, P, T
|Trisomy 5 and 5q heterozygosity in diffuse cutaneous juvenile xanthogranuloma [2]
|
|<span class="blue-text">EXAMPLE:</span>
Amplification of ''ERBB2'' is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined.
|-
|-
|
|3
|
|Loss
|
|Unknown
|
|Unknown
|
|Unknown
|
|Unknown
|
|Unknown
|3p deletion in systemic juvenile xanthogranuloma [2]
|}
|}
==Characteristic Chromosomal or Other Global Mutational 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>


Put your text here and fill in the table <span style="color:#0070C0">(I''nstructions: Included in this category are alterations such as 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; microsatellite instability; homologous recombination deficiency; mutational signature pattern; etc. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.'')</span>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Chromosomal Pattern
!Chromosomal Pattern
!Molecular Pathogenesis
!Diagnostic Significance (Yes, No or Unknown)
!'''Prevalence -'''
!Prognostic Significance (Yes, No or Unknown)
'''Common >20%, Recurrent 5-20% or Rare <5% (Disease)'''
!Therapeutic Significance (Yes, No or Unknown)
!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T'''
!Notes
!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
!'''Clinical Relevance Details/Other Notes'''
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|<span class="blue-text">EXAMPLE:</span>
Co-deletion of 1p and 18q
Co-deletion of 1p and 18q
|<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).
|Yes
|<span class="blue-text">EXAMPLE:</span> Common (Oligodendroglioma)
|No
|<span class="blue-text">EXAMPLE:</span> D, P
|No
|
|
|-
|<span class="blue-text">EXAMPLE:</span>
|<span class="blue-text">EXAMPLE:</span>
Microsatellite instability - hypermutated
 
|
See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
|<span class="blue-text">EXAMPLE:</span> Common (Endometrial carcinoma)
|<span class="blue-text">EXAMPLE:</span> P, T
|
|
|-
|-
|
|Gains on 1q and 11q
|
|Unknown
|
|Unknown
|
|Unknown
|
|Gains on 1q and 11q in  systemic juvenile xanthogranuloma [2]
|
|}
|}
==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 or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries 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. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.'') </span>
 
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"
|-
|-
!Gene!!'''Genetic Alteration'''!!'''Tumor Suppressor Gene, Oncogene, Other'''!!'''Prevalence -'''
!Gene; Genetic Alteration!!Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)!!Prevalence (COSMIC /  TCGA / Other)!!Concomitant Mutations!!Mutually Exclusive Mutations
'''Common >20%, Recurrent 5-20% or Rare <5% (Disease)'''
!Diagnostic Significance (Yes, No or Unknown)
!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T  '''
!Prognostic Significance (Yes, No or Unknown)
!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
!Therapeutic Significance (Yes, No or Unknown)
!'''Clinical Relevance Details/Other Notes'''
!Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span>''EGFR''
|<span class="blue-text">EXAMPLE:</span> TP53; Variable LOF mutations
 
<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 />
<br />
|<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations
|<span class="blue-text">EXAMPLE:</span> Oncogene
|<span class="blue-text">EXAMPLE:</span> Common (lung cancer)
|<span class="blue-text">EXAMPLE:</span> T
|<span class="blue-text">EXAMPLE:</span> Yes (NCCN)
|<span class="blue-text">EXAMPLE:</span> Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references).
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''TP53''; Variable LOF mutations
|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 />
<br />
|<span class="blue-text">EXAMPLE:</span> Variable LOF mutations
|-
|<span class="blue-text">EXAMPLE:</span> Tumor Supressor Gene
|CSF1R mutations
|<span class="blue-text">EXAMPLE:</span> Common (breast cancer)
|Kinase driver mutations
|<span class="blue-text">EXAMPLE:</span> P
-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
|
|
|<span class="blue-text">EXAMPLE:</span> >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''BRAF''; Activating mutations
|KRAS
|<span class="blue-text">EXAMPLE:</span> Activating mutations
|p.G12D
|<span class="blue-text">EXAMPLE:</span> Oncogene
|Unknown
|<span class="blue-text">EXAMPLE:</span> Common (melanoma)
|Unknown
|<span class="blue-text">EXAMPLE:</span> T
|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.
|}Note: A more extensive list of mutations can be found in [https://www.cbioportal.org/ <u>cBioportal</u>], [https://cancer.sanger.ac.uk/cosmic <u>COSMIC</u>], and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
|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==
==Epigenomic Alterations==


Put your text here


Put your text here
==Genes and Main Pathways Involved==
==Genes and Main Pathways Involved==


Line 342: Line 434:
|''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
|<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation
|Increased cell growth, proliferation, differentiation, apoptosis and stress responses
|-
|-
|''PIK3CD'' mutations
|''PIK3CD'' mutations
|PI3K pathway
|PI3K pathway
|<span class="blue-text">EXAMPLE:</span> Unregulated cell division
|Unregulated cell survival, growth, and proliferation
|-
|NA
|NA
|NA
|}
|}
==Genetic Diagnostic Testing Methods==
==Genetic Diagnostic Testing Methods==


Put your text here


Put your text here <span style="color:#0070C0">(''Instructions: Include recommended testing type(s) to identify the clinically significant genetic alterations.'')</span>
==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>


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>
==Additional Information==
==Additional Information==


Line 366: Line 454:
==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>


Put a link here or anywhere appropriate in this page <span style="color:#0070C0">(''Instructions: Highlight the text to which you want to add a link in this section or elsewhere, select the "Link" icon at the top of the wiki 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==
(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking where you want to insert the reference, selecting the “Cite” icon at the top of the wiki page, and using the “Automatic” tab option to search by PMID to select the reference to insert. 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. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">)</span> <references />
(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'''
'''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>.
#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>.


==Notes==
==Notes==
<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the [[Leadership|''<u>Associate Editor</u>'']] or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.
<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.
 
Prior Author(s): 
 
       
<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>.
<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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[[Category:HAEM5]]
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[[Category:DISEASE]]
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[[Category:Diseases J]]
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