What are the diagnostic criteria and treatment options for Erdheim Chester disease?

Diagnosis of Erdheim-Chester Disease

Erdheim-Chester disease (ECD) diagnosis requires tissue biopsy showing CD68+/CD163+/CD1a-/Langerin- foamy histiocytes combined with characteristic imaging findings, particularly symmetric long bone osteosclerosis on FDG-PET-CT and/or classic extra-osseous lesions (perinephric stranding, periaortic infiltrates, right atrial pseudotumor), with BRAF and MAPK pathway mutational analysis mandatory for treatment planning. 1

Diagnostic Algorithm

Step 1: Clinical Suspicion and Initial Imaging

Obtain full-body FDG-PET-CT (vertex-to-toes) including distal extremities as the primary diagnostic imaging modality. 1 This is superior to 99mTc bone scanning for detecting extra-osseous involvement, though bone scans can demonstrate the characteristic symmetric diaphyseal and metaphyseal uptake in femurs and tibias. 1

• Look for bilateral symmetric osteosclerosis affecting the metaphyses and diaphyses of long bones (present in >90% of cases) 2
• Identify "hairy kidney" appearance (perinephric fat infiltration) on CT, present in approximately 50-68% of cases 1
• Document periaortic infiltration, right atrial pseudotumor, or retroperitoneal involvement 1

Critical caveat: Approximately 4-10% of ECD patients lack bone lesions entirely; diagnosis in these cases requires highly characteristic non-osseous lesions plus supportive histopathology and mutational data. 1

Step 2: Tissue Biopsy and Histopathologic Confirmation

Biopsy lesional tissue even when clinical and imaging features are highly suggestive—this is mandatory not only for diagnosis but to establish mutational status. 1

Histopathologic criteria:

• Foamy or lipid-laden histiocytes with surrounding fibrosis 1
• Touton giant cells often present (though not always) 1
• Immunohistochemistry profile: CD68+, CD163+, Factor XIIIa+, CD1a-, Langerin (CD207)- 1
• S100 may be weakly or focally positive in 20-30% of cases (not exclusionary) 1

Biopsy site selection:

• Cutaneous lesions (xanthelasma) via shave biopsy are least invasive 1
• Obtain multiple samples as histologic changes vary field-to-field 1
• For bone biopsies, preserve fresh material without decalcification for genetic analysis 1

Important pitfall: ECD should still be considered even when biopsy doesn't show classic xanthomatous histiocytes—meticulous osseous imaging and mutational analysis become critical in such cases. 1

Step 3: Mutational Analysis (Mandatory)

Perform BRAF V600E genotyping on all lesional tissue using molecular assays, not VE1 immunohistochemistry alone. 1

• BRAF V600E mutation present in approximately 50-51% of cases 2, 3
• If BRAF V600E negative, perform targeted next-generation sequencing for MAPK-ERK pathway mutations: ARAF, NRAS, KRAS, MAP2K1, PIK3CA, and fusion assays 1
• MAP2K1 mutations found in 14-50% of BRAF-wild-type cases 1
• Confirm negative BRAF testing using >1 genotyping modality and/or biopsies from >1 anatomic site (particularly when bone lesions are BRAF wild-type) 1

Alternative when tissue insufficient: Cell-free DNA (cfDNA) analysis from peripheral blood can assess BRAF status, though sensitivity may be variable. 1

Step 4: Comprehensive Baseline Evaluation

Mandatory imaging for all patients:

• Brain MRI with gadolinium (CNS involvement is strong prognostic factor and independent predictor of death) 1, 3
• Cardiac MRI (or CT/echocardiogram if MRI unavailable) 1
• Contrast-enhanced CT chest/abdomen/pelvis if FDG-PET not performed 1

Laboratory evaluation:

• Complete blood count with differential 1
• Comprehensive metabolic panel (renal and hepatic function) 1
• C-reactive protein (marker of inflammation) 1
• Endocrine assessment: morning urine and serum osmolality, morning cortisol with ACTH, FSH/LH with testosterone (males) or estradiol (females), TSH and free T4, prolactin, IGF-1 1

Bone marrow biopsy should be performed, especially with unexplained cytopenias, cytosis, or monocytosis, due to high prevalence of concomitant myeloid neoplasms. 1

Additional organ-specific imaging based on symptoms:

• CT sinuses, MRI sella turcica, MRI orbits, MRI spine, renal artery ultrasound, high-resolution chest CT, pulmonary function tests, testicular ultrasound 1

Key Diagnostic Pitfalls to Avoid

Do not rely on VE1 immunohistochemistry as the sole method for BRAF V600E detection—it lacks sufficient sensitivity and specificity and must be confirmed with molecular assay. 1

Do not dismiss ECD diagnosis based on absence of bone lesions alone—while rare (<10%), ECD without osseous involvement occurs and requires characteristic non-osseous findings plus mutational support. 1

Do not overlook the differential diagnosis with Langerhans cell histiocytosis (LCH)—LCH histiocytes are CD1a+, S100+, and Langerin+, whereas ECD is CD1a- and Langerin-. 1 However, mixed ECD-LCH presentations can occur. 1

Do not fail to assess for CNS involvement—this is the most important prognostic factor, with symptoms including ataxia, dysarthria, dysphagia, limb weakness, cognitive decline, and psychiatric manifestations (depression, anxiety, disinhibition). 1, 3

Clinical Presentation Patterns

Common presenting symptoms to recognize:

• Bone pain (most common initial symptom, present in 95% at diagnosis) 2, 4
• Diabetes insipidus (polydipsia/polyuria) 1, 2
• Exophthalmos and retro-orbital infiltration 2, 5
• Xanthelasma and skin xanthomas 1, 2
• Cardiovascular involvement (cardiac mass, periaortic infiltration, pericardial involvement) 2, 5
• Respiratory symptoms (interstitial lung disease in approximately 35% of cases) 5

Diagnostic delay is common, averaging 4.2 years from initial presentation to diagnosis, due to the rarity and varied presentations of the disorder. 2, 4