What are the diagnostic criteria for Langerhans Cell Histiocytosis (LCH)?

Diagnostic Criteria for Langerhans Cell Histiocytosis

The diagnosis of LCH requires histopathologic confirmation with tissue biopsy demonstrating characteristic Langerhans cells that are positive for CD1a, S100, and Langerin (CD207) by immunohistochemistry. 1

Histopathologic Requirements

Tissue biopsy is mandatory for diagnosis and must demonstrate:

• Langerhans cells with characteristic morphology including reniform or coffee bean-shaped nuclei with nuclear grooves, abundant eosinophilic cytoplasm, and variable numbers of multinucleated giant cells (present in 62.6% of cases) 2

• Immunohistochemical positivity for all three markers:

  • CD1a: 100% sensitivity 2
  • S100 protein: 99.1% sensitivity 2
  • Langerin (CD207): 98.5% sensitivity 2

• Eosinophilic infiltration is the predominant non-neoplastic cell component, with eosinophilic abscesses seen in 21.5% of cases 2

• BRAF V600E mutation testing should be performed on all tissue samples using immunohistochemistry, PCR, or next-generation sequencing, as this mutation is present in over 90% of LCH cases 3, 4, 5

Clinical Features That Raise Suspicion

Major characteristics requiring further evaluation include: 4

• Aggressive cortically-based osteolytic "punched-out" bone lesions, particularly involving the skull (60% of patients have bone involvement) 1
• Central diabetes insipidus without other etiology (occurs in 50-70% of LCH patients) 1
• Atypical histiocytic infiltrate (CD68/CD163+) on tissue biopsy 4

Additional suggestive features include: 1

• Upper lobe-predominant nodular cystic lung lesions in smokers (50-60% have respiratory involvement) 1
• Hypothalamic and pituitary stalk lesions 1
• Papular rash or subcutaneous nodules (15-30% have dermatologic involvement) 1
• Dural lesions, often extending from calvarium (5% have nervous system involvement) 1

Required Staging and Evaluation

Once histopathologic diagnosis is confirmed, complete staging includes: 1, 4

Imaging Studies

• Full-body FDG PET-CT (vertex-to-toes protocol) to evaluate organ involvement, as all histiocytic neoplasms are PET-avid 1, 4
• Brain MRI with gadolinium contrast due to high rates of CNS, dural, and orbital involvement that may be asymptomatic 1, 4
• High-resolution chest CT to evaluate pulmonary involvement 1, 4

Laboratory Tests

• Complete blood count with differential (abnormalities may suggest concomitant myeloid malignancy requiring bone marrow biopsy) 1, 4
• Comprehensive metabolic panel including sodium, potassium, calcium, AST, ALT, alkaline phosphatase, bilirubin, BUN, creatinine 1, 4
• C-reactive protein and LDH 1, 4

Endocrine Evaluation (Mandatory for LCH)

Complete endocrine assessment is required because imaging is insufficiently sensitive: 1, 4

• Morning urine and serum osmolality (to detect diabetes insipidus) 1, 4
• FSH and LH with testosterone (males) or estradiol (females) 1, 4
• Corticotropin with morning cortisol 1, 4
• Thyrotropin and free T4 1, 4
• Prolactin and IGF-1 1, 4

Critical Diagnostic Pitfalls

Ambiguous cases require re-evaluation at centers with histiocytosis expertise, particularly when histopathologic findings show atypical histiocytic infiltrates in the appropriate clinical context 1, 4

Diabetes insipidus develops in 20-30% of multisystem LCH patients and may occur years after initial diagnosis, necessitating long-term endocrine surveillance 3, 4

Negative BRAF V600E immunohistochemistry should be confirmed with molecular testing (PCR or next-generation sequencing), as immunohistochemistry may have insufficient sensitivity 4

The diagnosis requires integration of clinical, radiologic, and histopathologic features, as no single finding is pathognomonic 1