HAEM5:Juvenile xanthogranuloma: Difference between revisions

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

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

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.

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>

|Asymptomatic in the beginning

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

|Abnormal blood count, liver enzymes, metabolic tests

Cytopenia if bone marrow involved

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>

*Unencapsulated, circumscribed lesions composed of classic histiocytes, large xanthomatous histiocytes, foamy histiocytes and Touton giant cells..

|NTRK1 fusions||TPM3::NTRK1 fusion

PRDX1–NTRK1

|Often associated with localized xanthogranuloma [3]

|BRAF fusions

|FNBP1-BRAF  

RNF11-BRAF

GAB2-BRAF

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

|SYK fusions

|CLTC::SYK fusions

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

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

|ALK fusions/rearrangements

|KIF5B–ALK

|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  

|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)

|Gain, Heterozygosity  

!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)'''

|<span class="blue-text">EXAMPLE:</span> TP53; Variable LOF mutations

 

 

 

 

|MAP2K1

|Systemic juvenile xanthogranuloma [4]

<br />

|CSF1R 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]

| -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

|NF1

|

|KRAS

|NRAS

|ARAF

|Yes,

Might represent pediatric Erdheim–Chester disease.

|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]

|MAPK/ERK pathway alterations

|PI3K pathway

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