Is immunohistochemistry (IH) indicated for diagnosing Multicentric Juvenile Xanthogranuloma (MXJ) in a pediatric patient with suspected skin lesions or systemic symptoms?

Immunohistochemistry for Multicentric Juvenile Xanthogranuloma

Yes, immunohistochemistry is indicated and essential for diagnosing Multicentric Juvenile Xanthogranuloma (MXG), as histologic confirmation with immunohistochemical characterization is required to establish the diagnosis and distinguish it from other histiocytic disorders.

Diagnostic Approach

Tissue Biopsy Requirement

• Tissue biopsy with histologic and immunohistochemical confirmation is mandatory to demonstrate a homogenous infiltrate of histiocytes 1, 2
• The diagnosis cannot be established on clinical grounds alone, particularly in multicentric presentations where systemic involvement must be differentiated from other histiocytic neoplasms 3

Essential Immunohistochemical Panel

Core markers that should be performed:

• CD163: This is the most characteristic marker, showing universal positivity (100%) in juvenile xanthogranuloma and is particularly useful for distinguishing JXG from benign fibrous histiocytoma 1
• CD11c: Shows near-universal expression (97%) and has not been previously well-described but appears highly sensitive for JXG 1
• Factor XIIIa: Positive in 88% of cases, though negative cases can still be JXG if other markers are positive 1
• CD4: Positive in 94% of cases 1
• Lysozyme: Positive in 77% of cases and supports histiocytic lineage 1, 4

Critical negative markers for differential diagnosis:

• S-100 protein: Should be negative (0% positivity) - this is crucial to exclude Langerhans cell histiocytosis 1, 2, 4
• CD1a: Should be negative to exclude Langerhans cell histiocytosis 2, 4

Diagnostic Algorithm

1. When to suspect multicentric JXG:

   • Multiple cutaneous nodules in a pediatric patient (81% of JXG are solitary, so multiple lesions raise concern) 2
   • Systemic symptoms suggesting visceral involvement (occurs in 3.9% of cases) 2
   • Congenital presentation with widespread lesions 2

2. Biopsy approach:

   • Obtain tissue from representative lesion(s) for histologic examination 2, 3
   • Request immunohistochemistry upfront if clinical presentation suggests histiocytic disorder 1, 3

3. Interpretation strategy:

   • Positive CD163 and CD11c with negative S-100 and CD1a strongly supports JXG diagnosis 1
   • If factor XIIIa is negative, do not exclude JXG - rely on CD4, CD11c, and CD163 positivity 1
   • All five factor XIIIa-negative cases in one study showed 2+ to 3+ expression of CD4, CD11c, and CD163 1

Critical Diagnostic Pitfalls

CD31 Expression Warning

• CD31 can be positive in 45% of JXG cases, which may mislead pathologists to consider vascular lesions 1
• This represents a significant diagnostic trap since many pathologists are unaware that histiocytes can express CD31 1

Morphologic Variants Requiring IHC

• Unusual variants (nonlipidized, giant, intramuscular, subcutaneous, clustered JXG) often require immunohistochemistry and/or electron microscopy for definitive diagnosis 3
• Early JXG (27.1% of cases) may have less characteristic morphology requiring immunophenotyping 2

Systemic Disease Considerations

• In the rare systemic/multicentric cases (3.9%), immunohistochemistry is essential to confirm histiocytic lineage and exclude more aggressive histiocytic disorders 2
• One death was reported among 5 patients with widespread congenital systemic disease, emphasizing the importance of accurate diagnosis 2

Clinical Context

Prognosis implications:

• Correct immunohistochemical diagnosis prevents unnecessary invasive procedures, as JXG has a favorable prognosis with 7% relapse rate and potential for spontaneous involution even after incomplete resection 2, 3
• Simple tumor excision is adequate for localized disease, while systemic JXG may require multimodal chemotherapy - making accurate diagnosis critical for treatment planning 2