Consensus recommendations for diagnosis and treatment of ECD
| Consensus recommendations . | Category of consensus* . |
|---|---|
| Diagnosis | |
| A biopsy of lesional tissue is strongly recommended even in circumstances of highly suggestive clinical and imaging features not only to confirm ECD diagnosis, but also to establish BRAF mutational status and perform sequencing for MAPK-ERK pathway and other somatic mutations | A |
| ECD without any bone lesions can occur (<10%) but should only be considered in the context of suggestive histopathology or highly characteristic nonosseous lesions (ie, perinephric stranding, periaortic infiltrates, right atrial pseudotumor, or a combination of these with or without central diabetes insipidus) and ideally with supportive mutational data (BRAF or MAPK-ERK pathway mutations) | A |
| ECD should still be considered in the presence of characteristic clinical/radiologic features, even when biopsy does not demonstrate classic xanthomatous histiocytes; meticulous osseous imaging for lesions in the tibia and femur are critical in such cases, as well as mutational analysis of tissue for BRAF and MAPK-ERK pathway mutations | A |
| Baseline full-body (vertex-to-toes) FDG-PET-CT, including the distal extremities, is recommended in all cases to aid in diagnosis and define the extent of disease; if FDG-PET cannot be performed, contrast-enhanced CT of the chest, abdomen, and pelvis can be performed as well as imaging of the lower extremities (CT, MRI, or 99Tc bone scan) | A |
| MRI of the brain with gadolinium is recommended in all patients at diagnosis | A |
| MRI of the heart is recommended in all patients at diagnosis; if an MRI cannot be performed, CT scan and/or echocardiogram should be performed | B |
| Laboratory studies are performed to assess for renal insufficiency, cytopenias, markers of inflammation (C-reactive protein), and evidence of endocrinopathy and anterior pituitary function | A |
| Due to a high prevalence of concomitant myeloid neoplasms in patients with ECD, bone marrow biopsy should be considered, especially in the context of otherwise unexplained cytopenias/cytosis or monocytosis | A |
| Confirmation of negative BRAF-V600E mutational testing using >1 genotyping modality and/or genotyping of biopsies from >1 anatomic site should be performed (particularly when lesions from bone are found to be BRAF wild type) | A |
| IHC for VE1 is not felt to be sensitive or specific as the sole method for BRAF-V600E mutational analysis and should be confirmed with another molecular assay if feasible | B |
| In the absence of sufficient tumor tissue, cfDNA analysis from peripheral blood can be used for assessment of BRAF-mutational status; however, the sensitivity of such assays may be variable | A |
| Treatment | |
| Treatment is indicated for most ECD patients, except some select cases of asymptomatic minimal burden disease, which can be monitored closely | B |
| Systemic corticosteroids, surgery, and radiation therapy may be used to relieve edema or acute symptoms, but are not recommended as monotherapies for ECD | A |
| For patients with BRAF-V600E ECD who have cardiac/neurologic disease or end-organ dysfunction, BRAF-inhibitor therapy with vemurafenib or dabrafenib should be implemented as first-line therapy | A |
| For BRAF-V600E ECD without end-organ dysfunction, BRAF-inhibitors or conventional therapy may both be considered for first-line therapy based on toxicity profile and drug availability/experience of clinician | A |
| For ECD patients without BRAF-V600E and cardiac/neurologic disease or end-organ dysfunction, empiric treatment with MEK-inhibitor should be strongly considered as first-line therapy | A |
| Optimal duration and dosing of targeted therapies is not known, although relapse has been observed in the majority of cases following complete cessation of BRAF-inhibitors; maintenance treatment in the setting of metabolic remission with low-dose therapy as tolerated may be considered | A |
| For patients without access to targeted therapies and high-burden disease, IFN-α/PEG–IFN-α or cladribine therapy may be considered | A |
| For patients with low-burden disease involving bones and retroperitoneum, cytokine-directed therapy such as anakinra may be appropriate first-line therapy | B |
| Response assessment and monitoring | |
| Full-body (vertex-to-toes) FDG-PET-CT should be performed every 2-6 mo after initiation of a new therapy for response assessment; once best response is established on 2 scans and disease is stabilized with steady dose of drug, the frequency of PET imaging can be individualized, ranging from every 6 mo to longer intervals | B |
| Organ-specific imaging of involved disease sites (CT or MRI) should be performed every 2-6 mo initially after beginning treatment of response assessment; once best response is established on 2 scans and disease is stabilized with steady dose of drug, the frequency of imaging can be individualized, ranging from every 6 mo to longer intervals; a separate CT may not be necessary if performed in conjunction with FDG-PET | B |
| Endocrinopathies persist or can develop despite treatment of ECD; therefore, annual endocrine evaluation is recommended | A |
| Treatment with targeted and immunosuppressive agents (including IFN-α/PEG–IFN-α) should be continued indefinitely if tolerated, however, attempting cessation of treatment or lowering of dose for patients with minimal or stable disease for a prolonged period of time may by reasonable on case-by-case basis | A |
| Consensus recommendations . | Category of consensus* . |
|---|---|
| Diagnosis | |
| A biopsy of lesional tissue is strongly recommended even in circumstances of highly suggestive clinical and imaging features not only to confirm ECD diagnosis, but also to establish BRAF mutational status and perform sequencing for MAPK-ERK pathway and other somatic mutations | A |
| ECD without any bone lesions can occur (<10%) but should only be considered in the context of suggestive histopathology or highly characteristic nonosseous lesions (ie, perinephric stranding, periaortic infiltrates, right atrial pseudotumor, or a combination of these with or without central diabetes insipidus) and ideally with supportive mutational data (BRAF or MAPK-ERK pathway mutations) | A |
| ECD should still be considered in the presence of characteristic clinical/radiologic features, even when biopsy does not demonstrate classic xanthomatous histiocytes; meticulous osseous imaging for lesions in the tibia and femur are critical in such cases, as well as mutational analysis of tissue for BRAF and MAPK-ERK pathway mutations | A |
| Baseline full-body (vertex-to-toes) FDG-PET-CT, including the distal extremities, is recommended in all cases to aid in diagnosis and define the extent of disease; if FDG-PET cannot be performed, contrast-enhanced CT of the chest, abdomen, and pelvis can be performed as well as imaging of the lower extremities (CT, MRI, or 99Tc bone scan) | A |
| MRI of the brain with gadolinium is recommended in all patients at diagnosis | A |
| MRI of the heart is recommended in all patients at diagnosis; if an MRI cannot be performed, CT scan and/or echocardiogram should be performed | B |
| Laboratory studies are performed to assess for renal insufficiency, cytopenias, markers of inflammation (C-reactive protein), and evidence of endocrinopathy and anterior pituitary function | A |
| Due to a high prevalence of concomitant myeloid neoplasms in patients with ECD, bone marrow biopsy should be considered, especially in the context of otherwise unexplained cytopenias/cytosis or monocytosis | A |
| Confirmation of negative BRAF-V600E mutational testing using >1 genotyping modality and/or genotyping of biopsies from >1 anatomic site should be performed (particularly when lesions from bone are found to be BRAF wild type) | A |
| IHC for VE1 is not felt to be sensitive or specific as the sole method for BRAF-V600E mutational analysis and should be confirmed with another molecular assay if feasible | B |
| In the absence of sufficient tumor tissue, cfDNA analysis from peripheral blood can be used for assessment of BRAF-mutational status; however, the sensitivity of such assays may be variable | A |
| Treatment | |
| Treatment is indicated for most ECD patients, except some select cases of asymptomatic minimal burden disease, which can be monitored closely | B |
| Systemic corticosteroids, surgery, and radiation therapy may be used to relieve edema or acute symptoms, but are not recommended as monotherapies for ECD | A |
| For patients with BRAF-V600E ECD who have cardiac/neurologic disease or end-organ dysfunction, BRAF-inhibitor therapy with vemurafenib or dabrafenib should be implemented as first-line therapy | A |
| For BRAF-V600E ECD without end-organ dysfunction, BRAF-inhibitors or conventional therapy may both be considered for first-line therapy based on toxicity profile and drug availability/experience of clinician | A |
| For ECD patients without BRAF-V600E and cardiac/neurologic disease or end-organ dysfunction, empiric treatment with MEK-inhibitor should be strongly considered as first-line therapy | A |
| Optimal duration and dosing of targeted therapies is not known, although relapse has been observed in the majority of cases following complete cessation of BRAF-inhibitors; maintenance treatment in the setting of metabolic remission with low-dose therapy as tolerated may be considered | A |
| For patients without access to targeted therapies and high-burden disease, IFN-α/PEG–IFN-α or cladribine therapy may be considered | A |
| For patients with low-burden disease involving bones and retroperitoneum, cytokine-directed therapy such as anakinra may be appropriate first-line therapy | B |
| Response assessment and monitoring | |
| Full-body (vertex-to-toes) FDG-PET-CT should be performed every 2-6 mo after initiation of a new therapy for response assessment; once best response is established on 2 scans and disease is stabilized with steady dose of drug, the frequency of PET imaging can be individualized, ranging from every 6 mo to longer intervals | B |
| Organ-specific imaging of involved disease sites (CT or MRI) should be performed every 2-6 mo initially after beginning treatment of response assessment; once best response is established on 2 scans and disease is stabilized with steady dose of drug, the frequency of imaging can be individualized, ranging from every 6 mo to longer intervals; a separate CT may not be necessary if performed in conjunction with FDG-PET | B |
| Endocrinopathies persist or can develop despite treatment of ECD; therefore, annual endocrine evaluation is recommended | A |
| Treatment with targeted and immunosuppressive agents (including IFN-α/PEG–IFN-α) should be continued indefinitely if tolerated, however, attempting cessation of treatment or lowering of dose for patients with minimal or stable disease for a prolonged period of time may by reasonable on case-by-case basis | A |
cfDNA, cell-free DNA; CT, computed tomography; FDG, 18F-fluoro-deoxyglucose; IFN-α, interferon-α; IHC, immunohistochemistry; MRI, magnetic resonance imaging; PEG-IFN-α, pegylated interferon-α.
A (strong consensus: ≥95%), B (consensus: 75% to 95%).