Initial Evaluation of Histiocytosis

Essential Imaging Studies

The American College of Radiology recommends PET-CT with FDG as the modality of choice for evaluating organ involvement, as all histiocytic neoplasms are PET-avid 1, 2
The protocol should be "vertex-to-toes" instead of the conventional protocol from the base of the skull to the thighs, as these pathologies can involve the lower limbs 1, 2
PET-CT also helps identify the safest and most productive biopsy site 3
The American College of Radiology recommends brain MRI with gadolinium contrast for all patients due to high rates of central nervous system, dural, and orbital involvement, which can be asymptomatic, especially in ECD and LCH 1, 2
Cardiac MRI is specifically recommended for patients with suspected Erdheim-Chester disease to identify lesions that might otherwise be missed 1, 2, 3
High-resolution chest CT is necessary to evaluate pulmonary involvement 3

The panel should include CD163 or CD68, S100, CD1a, Langerin, and factor XIIIa 4
The American Society for Clinical Pathology recommends that the BRAF V600E mutation test be performed on all tissue samples using immunohistochemistry, PCR, or next-generation target capture sequencing 3
Molecular testing methods are recommended to exclude a mutation definitively, as immunohistochemistry may have insufficient sensitivity 6
The presence of a BRAF V600 mutation almost completely excludes RDD 1

A complete hematochemical panel is required, including complete blood count with leukocyte formula, sodium, potassium, calcium, AST, ALT, alkaline phosphatase, bilirubin, azotemia, creatinine, and C-reactive protein 1, 3, 6, 7
Abnormalities in the complete blood count may suggest the presence of a concomitant myeloid neoplasm, which requires a bone marrow biopsy 1

A complete endocrine evaluation is recommended because imaging studies are not sufficiently sensitive 1, 3
The evaluation should include morning urinary and serum osmolality, FSH and LH with testosterone (males) and estradiol (females), corticotropin with morning cortisol, thyrotropin and free T4, prolactin, and IGF-1 1, 3, 5
Central diabetes insipidus occurs in 20-30% of patients with multisystemic LCH and can develop years after diagnosis 5
Central diabetes insipidus is present in 25-50% of patients with ECD and can precede the diagnosis by many years 3

Major characteristics that require further evaluation include osteosclerosis of the metaphyseal regions of the femur, tibia, or fibula, central idiopathic diabetes insipidus, and atypical histiocytic infiltrate (CD68/CD163+) on tissue biopsy 7
Other characteristics that should increase suspicion, in combination with major characteristics, include dense soft tissue proliferation in the retroperitoneum, "coating" of medium to large caliber vessels with soft tissue, nodular cystic lung lesions with upper lobe predominance in a smoker, and "punched-out" lytic bone lesions often involving flat bones (skull, sternum, ribs, pelvis) 6, 7, 8

The American Society for Clinical Pathology recommends that ambiguous cases be re-evaluated histopathologically at centers with experience in these neoplasms, especially those with atypical histiocytic infiltrates in the appropriate clinical context 1, 2
This is particularly true for ECD, where histopathological findings are often non-diagnostic due to abundant fibrosis and inflammatory infiltrate 4, 8