Compendium of Cancer Genome Aberrations

Difference between revisions of "HAEM5:Juvenile xanthogranuloma"

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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.)]]
  
Line 8: Line 9:
 
==Primary Author(s)*==
 
==Primary Author(s)*==
  
−
Put your text here<span style="color:#0070C0"> (''<span class="blue-text">EXAMPLE:</span>'' Jane Smith, PhD) </span>
+
Mayuri Shende, MBBS, DCP, FCPS, DNB, ASCP-SH CM
 +
 
 +
<span style="color:#0070C0">Scott Turner, PhD </span>
  
 
__TOC__
 
__TOC__
Line 36: Line 39:
 
==Definition / Description of Disease==
 
==Definition / Description of Disease==
  
−
Put your text here <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.<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>
  
 
==Synonyms / Terminology==
 
==Synonyms / Terminology==
  
−
Put your text here <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==
  
−
Put your text here
+
Juvenile Xanthogranuloma is a rare histiocytic neoplasm comprising about 0.5% of all pediatric tumors, seldom seen in in adults. 20-35% cases are congenital, shows male predilection and mostly (>70% cases) arise during the first year of life.
  
 
==Clinical Features==
 
==Clinical Features==
  
−
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>
+
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>
 
{| class="wikitable"
 
{| class="wikitable"
 
|'''Signs and Symptoms'''
 
|'''Signs and Symptoms'''
−
|<span class="blue-text">EXAMPLE:</span> Asymptomatic (incidental finding on complete blood counts)
+
|Asymptomatic in the beginning
 +
≥1 cutaneous papulonodular lesions
  
−
<span class="blue-text">EXAMPLE:</span> B-symptoms (weight loss, fever, night sweats)
+
Rarely systemic involvement with abnormal labs, ophthalmologic exam findings, seizures, hydrocephalus, diabetes Insipidus
−
 
 
−
<span class="blue-text">EXAMPLE:</span> Fatigue
 
−
 
 
−
<span class="blue-text">EXAMPLE:</span> Lymphadenopathy (uncommon)
 
 
|-
 
|-
 
|'''Laboratory Findings'''
 
|'''Laboratory Findings'''
−
|<span class="blue-text">EXAMPLE:</span> Cytopenias
+
|Abnormal blood count, liver enzymes, metabolic tests
−
 
+
Cytopenia if bone marrow involved
−
<span class="blue-text">EXAMPLE:</span> Lymphocytosis (low level)
 
 
|}
 
|}
  
 
==Sites of Involvement==
 
==Sites of Involvement==
  
−
Put your text here <span style="color:#0070C0">(''Instruction: Indicate physical sites; <span class="blue-text">EXAMPLE:</span> nodal, extranodal, bone marrow'') </span>
+
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>
  
 
==Morphologic Features==
 
==Morphologic Features==
  
−
Put your text here
+
'''Gross appearance:'''
 +
 
 +
Cutaneous JXGs: Early lesions are orange-red papules/macules, later progress to form pale to tan, dome shaped lesions.
 +
 
 +
Visceral JXGs: Nodules with variable size and appearance.
 +
 
 +
'''Histopathology:'''
 +
 
 +
*Unencapsulated, circumscribed lesions composed of classic histiocytes, large xanthomatous histiocytes, foamy histiocytes and Touton giant cells..
 +
*Variable numbers of lymphocytes, eosinophils, plasma cells, neutrophils, and mast cells are often intermixed along with epithelioid cells, spindle cells and oncocytic histiocytes.
 +
*These histiocytes should not  show significant nuclear pleomorphism.
 +
 
 +
'''Cytology''':
 +
 
 +
*Mononuclear or multinucleated histiocytes with kidney shaped/oval nuclei, variable numbers of lymphocytes, neutrophils, and eosinophils.
 +
*Touton giant cells or foreign body giant cells may be present.
  
 
==Immunophenotype==
 
==Immunophenotype==
Line 81: Line 95:
 
!Finding!!Marker
 
!Finding!!Marker
 
|-
 
|-
−
|Positive (universal)||<span class="blue-text">EXAMPLE:</span> CD1
+
|Positive (universal)||CD68, CD163, CD4, CD14, factor XIIIa, and fascin
 
|-
 
|-
−
|Positive (subset)||<span class="blue-text">EXAMPLE:</span> CD2
+
|Positive (subset)||S100 (light nuclear and cytoplasmic staining)
 
|-
 
|-
−
|Negative (universal)||<span class="blue-text">EXAMPLE:</span> CD3
+
|Negative (universal)||CD1a and CD207 (langerin), ALK
 
|-
 
|-
−
|Negative (subset)||<span class="blue-text">EXAMPLE:</span> CD4
+
|Negative (subset)||N/A
 
|}
 
|}
  
Line 102: Line 116:
 
!Notes
 
!Notes
 
|-
 
|-
−
|<span class="blue-text">EXAMPLE:</span> t(9;22)(q34;q11.2)||<span class="blue-text">EXAMPLE:</span> 3'ABL1 / 5'BCR||<span class="blue-text">EXAMPLE:</span> der(22)||<span class="blue-text">EXAMPLE:</span> 20% (COSMIC)
+
|NTRK1 fusions||TPM3::NTRK1 fusion
−
<span class="blue-text">EXAMPLE:</span> 30% (add reference)
+
PRDX1–NTRK1
−
|Yes
+
|Unknown||Unknown
−
|No
+
|Unknown
−
|Yes
+
|Unknown
−
|<span class="blue-text">EXAMPLE:</span>
+
|Unknown
 +
|Often associated with localized xanthogranuloma [3]
 +
|-
 +
|BRAF fusions
 +
|FNBP1-BRAF
 +
RNF11-BRAF
 +
 
 +
''MS4A6A::BRAF'' ''BICD2::BRAF''
 +
 
 +
GAB2-BRAF
 +
|Unknown
 +
|Unknown
 +
|Unknown
 +
|Unknown
 +
|Disseminated JXG with ''GAB2::BRAF'' fusion showed favorable response to treatment with Trametinib (MEK1/2 inhibitor). [5].
 +
|BRAF gene fusions are more often seen in adult and Juvenile JXG as compared with other histiocytic disorders. [10]
 +
|-
 +
|RET fusions
 +
|NCOA4–RET rearrangement
 +
|Unknown
 +
|Unknown
 +
|Unknown
 +
|Unknown
 +
|Treatment with RET inhibitor Selpercatinib showed dramatic resolution of disfiguring skin lesions. [11]
 +
|Disseminated cutaneous–xanthogranuloma [11]
 +
|-
 +
|SYK fusions
 +
|CLTC::SYK fusions
 +
 
 +
-exon 5 or intron 5 of SYK that lead to fusion of CLTC exon 31 to SYK exon 6
  
−
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).
+
ETV6::SYK fusion
 +
|Unknown
 +
|Unknown
 +
|Unknown
 +
|Unknown
 +
|May respond to  oral SYK inhibitors-fostamatinib and entospletinib [12]
 +
|Lacks or shows rare touton giant cells [12]  IHC staining shows strong positivity for p-SYK, positive for cyclin D1 and p-S6. p-Akt negative. [12]
 +
Children between 2months and 2 years of age with soft tissue involvement and no or limited cutaneous involvement. [12]
 +
|-
 +
|ALK fusions/rearrangements
 +
|KIF5B–ALK
 +
TPM3–ALK
 +
|Unknown
 +
|Unknown
 +
|Unknown
 +
|Unknown
 +
|A pediatric patient with systemic JXG, CNS lesions and  KIF5B-ALK fusion achieved clinical improvement with ALK-inhibitor Alectinib therapy. [7]
 +
|A unique group of infants with an aggressive form of JXG with spleen, liver, and bone marrow showed infiltration with histiocytes with activating ALK fusions. [8] KIF5B–ALK seen in systemic JXG with CNS involvement. [7] child with JXG of soft tissue
 +
|-
 +
|''MRC1-PDGFRB'' fusion
 +
|t(5;10)(q32; p12.33) translocation
 +
|in-frame ''MRC1-PDGFRB'' gene fusion
 +
Can be seen with large deletion of exons 21 and 22 [12]
 +
|Unknown
 +
|Unknown
 +
|Unknown
 +
|Targeted therapy of treatment resistant systemic JXG with Dasatinib showed a steady and dramatic clinical response with a reduction in the size of the primary tumor. [9]
 +
|JXG case showing large deletion of CSF1R exons 21 and 22 and  MRC1::PDGFRB fusion was a 3 month old female with large intra-abdominal tumor involving greater omentum, intestinal walls and liver hilum. Achieved complete remission without relapse during 24 years of follow up. [12] IHC staining showed diffuse expression of cyclin D1 in tumor cells.[9] . Child with  chemotherapy-refractory left chest wall JXG, MRC1::PDGFRB fusion was treated with dasatinib. [12]
 +
|-
 +
|TBL1XR1::BOD1L1 fusion (and reciprocal BOD1L1::ABHD10)
 +
|Unknown
 +
|Unknown
 +
|Unknown
 +
|Unknown
 +
|Unknown
 +
|Unknown
 +
|Unifocal soft tissue JXG in the nasopharynx [12]
 
|}
 
|}
 
 
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Common recurrent secondary finding for t(8;21) (add reference).
 
Common recurrent secondary finding for t(8;21) (add reference).
 +
|-
 +
|17
 +
|Gain
 +
|Unknown
 +
|Unknown
 +
|Unknown
 +
|Unknown
 +
|Unknown
 +
|Diffuse cutaneous juvenile xanthogranuloma [2]
 +
|-
 +
|5
 +
|Gain, Heterozygosity
 +
|Unknown
 +
|Unknown
 +
|Unknown
 +
|Unknown
 +
|Unknown
 +
|Trisomy 5 and 5q heterozygosity in diffuse cutaneous juvenile xanthogranuloma [2]
 +
|-
 +
|3
 +
|Loss
 +
|Unknown
 +
|Unknown
 +
|Unknown
 +
|Unknown
 +
|Unknown
 +
|3p deletion in systemic juvenile xanthogranuloma [2]
 
|}
 
|}
 
==Characteristic Chromosomal Patterns==
 
==Characteristic Chromosomal Patterns==
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See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
 
See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
 +
|-
 +
|Gains on 1q and 11q
 +
|Unknown
 +
|Unknown
 +
|Unknown
 +
|Gains on 1q and 11q in  systemic juvenile xanthogranuloma [2]
 
|}
 
|}
 
==Gene Mutations (SNV / INDEL)==
 
==Gene Mutations (SNV / INDEL)==
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|<span class="blue-text">EXAMPLE:</span>  Excludes hairy cell leukemia (HCL) (add reference).
 
|<span class="blue-text">EXAMPLE:</span>  Excludes hairy cell leukemia (HCL) (add reference).
 
<br />
 
<br />
 +
|-
 +
|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
 +
-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
 +
|
 +
|-
 +
|KRAS
 +
|p.G12D
 +
|Unknown
 +
|Unknown
 +
|Unknown
 +
|Unknown
 +
|Unknown
 +
|Unknown
 +
|[4]
 +
|-
 +
|NRAS
 +
|p.Q61R
 +
|Unknown
 +
|Unknown
 +
|Unknown
 +
|Unknown
 +
|Unknown
 +
|Unknown
 +
|[4]
 +
|-
 +
|ARAF
 +
|p.N217K or p.F351L
 +
|Unknown
 +
|Unknown
 +
|Unknown
 +
|Unknown
 +
|Unknown
 +
|Unknown
 +
|[4]
 +
|-
 +
|''BRAF'' V600E mutation
 +
|Proto-oncogene
 +
|Unknown
 +
|Unknown
 +
|Unknown
 +
|Yes,
 +
Might represent pediatric Erdheim–Chester disease.
 +
|Yes
 +
Aggressive course
 +
|Unknown.
 +
Targeted therapy with BRAF-inhibitor dabrafenib needs to be studied further .
 +
|Pediatric cases with systemic JXG with CNS involvement and ''BRAF'' V600E mutations show male preponderance and are associated with aggressive disease at presentation. These cases needs to be  followed up, they probably represent Erdheim–Chester disease.[6]
 
|}
 
|}
−
Note: A more extensive list of mutations can be found in cBioportal (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.
  
 
==Epigenomic Alterations==
 
==Epigenomic Alterations==
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!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
 
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
 
|-
 
|-
−
|<span class="blue-text">EXAMPLE:</span> BRAF and MAP2K1; Activating mutations
+
|''NRAS'', ''KRAS'', ''ARAF'', ''MAP2K1'', and ''CSF1R, NTRK1 and BRAF gene fusions''
−
|<span class="blue-text">EXAMPLE:</span> MAPK signaling
+
|MAPK/ERK pathway alterations
−
|<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation
+
|Increased cell growth, proliferation, differentiation, apoptosis and stress responses
−
|-
 
−
|<span class="blue-text">EXAMPLE:</span> CDKN2A; Inactivating mutations
 
−
|<span class="blue-text">EXAMPLE:</span> Cell cycle regulation
 
−
|<span class="blue-text">EXAMPLE:</span> Unregulated cell division
 
 
|-
 
|-
−
|<span class="blue-text">EXAMPLE:</span>  KMT2C and ARID1A; Inactivating mutations
+
|''PIK3CD'' mutations
−
|<span class="blue-text">EXAMPLE:</span>  Histone modification, chromatin remodeling
+
|PI3K pathway
−
|<span class="blue-text">EXAMPLE:</span>  Abnormal gene expression program
+
|Unregulated cell survival, growth, and proliferation
 
|}
 
|}
 
==Genetic Diagnostic Testing Methods==
 
==Genetic Diagnostic Testing Methods==
Line 257: Line 465:
 
'''EXAMPLE Book'''
 
'''EXAMPLE Book'''
  
−
#Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p129-171.
+
#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 CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.
 
<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.
 
<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>.
−
[[Category:HAEM5]][[Category:DISEASE]][[Category:Diseases J]]
+
[[Category:HAEM5]]
 +
[[Category:DISEASE]]
 +
[[Category:Diseases J]]

Latest revision as of 13:29, 28 March 2025


Haematolymphoid Tumours (WHO Classification, 5th ed.)

(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use HUGO-approved gene names and symbols (italicized when appropriate), 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 Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support)

Primary Author(s)*

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

Scott Turner, PhD

WHO Classification of Disease

Structure Disease
Book Haematolymphoid Tumours (5th ed.)
Category Histiocytic/Dendritic cell neoplasms
Family Histiocyte/macrophage neoplasms
Type Histiocytic neoplasms
Subtype(s) Juvenile xanthogranuloma

Definition / Description of Disease

Juvenile Xanthogranuloma (JXG) is a clonal expansion of non–Langerhans cell histiocytes with dermal macrophage phenotype.(Instructions: Brief description of approximately one paragraph - include disease context relative to other WHO classification categories, diagnostic criteria if applicable, and differential diagnosis if applicable. Other classifications can be referenced for comparison.)

Synonyms / Terminology

Juvenile Xanthogranuloma (Instructions: Include currently used terms and major historical ones, adding “(historical)” after the latter.)

Epidemiology / Prevalence

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

Clinical Features

JXG are generally asymptomatic. Infants may present with ≥1 cutaneous, pale yellow-tan, dome-shaped papulonodular lesions, approximately5% patients show multiple lesions. These lesions begin as raised, pink to dark brown lesions that might get flatten later and heal/ scar within few months or years. A clinical subtype of JXG- benign cephalic histiocytosis occurs in head and neck of young children, asymptomatic, self-healing papular lesions. The lesions are often large, solitary and persistent in adults which needs exclusion of Erdheim–Chester disease. JXG may occur in patients with neurofibromatosis type 1, also reported in Wiskott–Aldrich syndrome. (Instruction: Can include references in the table. Do not delete table.)

Signs and Symptoms Asymptomatic in the beginning

≥1 cutaneous papulonodular lesions

Rarely systemic involvement with abnormal labs, ophthalmologic exam findings, seizures, hydrocephalus, diabetes Insipidus

Laboratory Findings Abnormal blood count, liver enzymes, metabolic tests

Cytopenia if bone marrow involved

Sites of Involvement

JXG involves and is generally confined to skin, head and neck, upper trunk and proximal extremities. Rarely ocular involvement, solitary lesion noted. Other extracutaneous sites of involvement- visceral, spinal, or intracranial area also reported rarely. (Instruction: Indicate physical sites; EXAMPLE: nodal, extranodal, bone marrow)

Morphologic Features

Gross appearance:

Cutaneous JXGs: Early lesions are orange-red papules/macules, later progress to form pale to tan, dome shaped lesions.

Visceral JXGs: Nodules with variable size and appearance.

Histopathology:

  • Unencapsulated, circumscribed lesions composed of classic histiocytes, large xanthomatous histiocytes, foamy histiocytes and Touton giant cells..
  • Variable numbers of lymphocytes, eosinophils, plasma cells, neutrophils, and mast cells are often intermixed along with epithelioid cells, spindle cells and oncocytic histiocytes.
  • These histiocytes should not show significant nuclear pleomorphism.

Cytology:

  • Mononuclear or multinucleated histiocytes with kidney shaped/oval nuclei, variable numbers of lymphocytes, neutrophils, and eosinophils.
  • Touton giant cells or foreign body giant cells may be present.

Immunophenotype

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Finding Marker
Positive (universal) CD68, CD163, CD4, CD14, factor XIIIa, and fascin
Positive (subset) S100 (light nuclear and cytoplasmic staining)
Negative (universal) CD1a and CD207 (langerin), ALK
Negative (subset) N/A

Chromosomal Rearrangements (Gene Fusions)

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Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
NTRK1 fusions TPM3::NTRK1 fusion

PRDX1–NTRK1

Unknown Unknown Unknown Unknown Unknown Often associated with localized xanthogranuloma [3]
BRAF fusions FNBP1-BRAF

RNF11-BRAF

MS4A6A::BRAF BICD2::BRAF

GAB2-BRAF

Unknown Unknown Unknown Unknown Disseminated JXG with GAB2::BRAF fusion showed favorable response to treatment with Trametinib (MEK1/2 inhibitor). [5]. BRAF gene fusions are more often seen in adult and Juvenile JXG as compared with other histiocytic disorders. [10]
RET fusions NCOA4–RET rearrangement Unknown Unknown Unknown Unknown Treatment with RET inhibitor Selpercatinib showed dramatic resolution of disfiguring skin lesions. [11] Disseminated cutaneous–xanthogranuloma [11]
SYK fusions CLTC::SYK fusions

-exon 5 or intron 5 of SYK that lead to fusion of CLTC exon 31 to SYK exon 6

ETV6::SYK fusion

Unknown Unknown Unknown Unknown May respond to oral SYK inhibitors-fostamatinib and entospletinib [12] Lacks or shows rare touton giant cells [12] IHC staining shows strong positivity for p-SYK, positive for cyclin D1 and p-S6. p-Akt negative. [12]

Children between 2months and 2 years of age with soft tissue involvement and no or limited cutaneous involvement. [12]

ALK fusions/rearrangements KIF5B–ALK

TPM3–ALK

Unknown Unknown Unknown Unknown A pediatric patient with systemic JXG, CNS lesions and KIF5B-ALK fusion achieved clinical improvement with ALK-inhibitor Alectinib therapy. [7] A unique group of infants with an aggressive form of JXG with spleen, liver, and bone marrow showed infiltration with histiocytes with activating ALK fusions. [8] KIF5B–ALK seen in systemic JXG with CNS involvement. [7] child with JXG of soft tissue
MRC1-PDGFRB fusion t(5;10)(q32; p12.33) translocation in-frame MRC1-PDGFRB gene fusion

Can be seen with large deletion of exons 21 and 22 [12]

Unknown Unknown Unknown Targeted therapy of treatment resistant systemic JXG with Dasatinib showed a steady and dramatic clinical response with a reduction in the size of the primary tumor. [9] JXG case showing large deletion of CSF1R exons 21 and 22 and MRC1::PDGFRB fusion was a 3 month old female with large intra-abdominal tumor involving greater omentum, intestinal walls and liver hilum. Achieved complete remission without relapse during 24 years of follow up. [12] IHC staining showed diffuse expression of cyclin D1 in tumor cells.[9] . Child with chemotherapy-refractory left chest wall JXG, MRC1::PDGFRB fusion was treated with dasatinib. [12]
TBL1XR1::BOD1L1 fusion (and reciprocal BOD1L1::ABHD10) Unknown Unknown Unknown Unknown Unknown Unknown Unifocal soft tissue JXG in the nasopharynx [12]

Individual Region Genomic Gain / Loss / LOH

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Chr # Gain / Loss / Amp / LOH Minimal Region Genomic Coordinates [Genome Build] Minimal Region Cytoband Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
EXAMPLE:

7

EXAMPLE: Loss EXAMPLE:

chr7:1- 159,335,973 [hg38]

EXAMPLE:

chr7

Yes Yes No EXAMPLE:

Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference).

EXAMPLE:

8

EXAMPLE: Gain EXAMPLE:

chr8:1-145,138,636 [hg38]

EXAMPLE:

chr8

No No No EXAMPLE:

Common recurrent secondary finding for t(8;21) (add reference).

17 Gain Unknown Unknown Unknown Unknown Unknown Diffuse cutaneous juvenile xanthogranuloma [2]
5 Gain, Heterozygosity Unknown Unknown Unknown Unknown Unknown Trisomy 5 and 5q heterozygosity in diffuse cutaneous juvenile xanthogranuloma [2]
3 Loss Unknown Unknown Unknown Unknown Unknown 3p deletion in systemic juvenile xanthogranuloma [2]

Characteristic Chromosomal Patterns

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Chromosomal Pattern Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
EXAMPLE:

Co-deletion of 1p and 18q

Yes No No EXAMPLE:

See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).

Gains on 1q and 11q Unknown Unknown Unknown Gains on 1q and 11q in systemic juvenile xanthogranuloma [2]

Gene Mutations (SNV / INDEL)

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Gene; Genetic Alteration Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other) Prevalence (COSMIC / TCGA / Other) Concomitant Mutations Mutually Exclusive Mutations Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
EXAMPLE: TP53; Variable LOF mutations

EXAMPLE:

EGFR; Exon 20 mutations

EXAMPLE: BRAF; Activating mutations

EXAMPLE: TSG EXAMPLE: 20% (COSMIC)

EXAMPLE: 30% (add Reference)

EXAMPLE: IDH1 R123H EXAMPLE: EGFR amplification EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).


MAP2K1 p.T28I, p.L37P,p.E129Q, p.Y130C Unknown Unknown Unknown Unknown Unknown May respond to targeted treatment with (MEK) inhibitors. [5] Systemic juvenile xanthogranuloma [4]


CSF1R mutations Kinase driver mutations

-Deletion in exon 12

-multiple missense mutations in exons 9 and 10

-large deletion of exons 21 and 22

-Alternative CSF1R mutations in exons 9 and 10

-Missense mutations in exon 10

[12]

Unknown Unknown Unknown Unknown Unknown CSF-1R-specific small-molecule inhibitors Pexidartinib and BLZ945 is being studied. [11] -Exon 10 mutations affect the extracellular region of CSF-1R and might enhance receptor dimerization. [12]

-Large deletion of CSF1R exons 21 and 22 affects the intracellular c-CBL binding domain leading to defective receptor ubiquitination, and degradation [12]


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
KRAS p.G12D Unknown Unknown Unknown Unknown Unknown Unknown [4]
NRAS p.Q61R Unknown Unknown Unknown Unknown Unknown Unknown [4]
ARAF p.N217K or p.F351L Unknown Unknown Unknown Unknown Unknown Unknown [4]
BRAF V600E mutation Proto-oncogene Unknown Unknown Unknown Yes,

Might represent pediatric Erdheim–Chester disease.

Yes

Aggressive course

Unknown.

Targeted therapy with BRAF-inhibitor dabrafenib needs to be studied further .

Pediatric cases with systemic JXG with CNS involvement and BRAF V600E mutations show male preponderance and are associated with aggressive disease at presentation. These cases needs to be followed up, they probably represent Erdheim–Chester disease.[6]

Note: A more extensive list of mutations can be found in Bioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

Epigenomic Alterations

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Genes and Main Pathways Involved

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Gene; Genetic Alteration Pathway Pathophysiologic Outcome
NRAS, KRAS, ARAF, MAP2K1, and CSF1R, NTRK1 and BRAF gene fusions MAPK/ERK pathway alterations Increased cell growth, proliferation, differentiation, apoptosis and stress responses
PIK3CD mutations PI3K pathway Unregulated cell survival, growth, and proliferation

Genetic Diagnostic Testing Methods

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Familial Forms

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Additional Information

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Links

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References

(use the "Cite" icon at the top of the page) (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. 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.)

EXAMPLE Book

  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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