Table 1.
Consensus recommendations for the diagnosis and management of adult LCH
| Statement number | Consensus statements | Consensus recommendation category |
|---|---|---|
| Diagnosis | ||
| 1. | A biopsy of lesional tissue is recommended even in circumstances of highly suggestive clinical and imaging features to confirm LCH diagnosis and establish BRAF or another MAPK-ERK pathway mutational status. Cases of single-system PLCH with typical radiologic findings and clinical context are a reasonable exception, although a biopsy is recommended in these cases as well. | A |
| 2. | LCH should be considered in the presence of characteristic clinical/radiologic features (Table 3), even when a histopathologic review is equivocal. Molecular analysis of tissue for BRAF and MAPK-ERK pathway mutations can be helpful in the diagnosis of questionable lesions. | B |
| 3. | Baseline full-body (vertex-to-toes) FDG-PET/CT, including the distal extremities, is recommended to aid in diagnosis and defining the extent of disease. | B |
| 4. | Organ-specific imaging (CT, MRI) is recommended to further assess involved sites of disease based on initial imaging studies. | A |
| 5. | MRI of the brain with gadolinium, with a dedicated examination of the sella turcica, should be undertaken at diagnosis in cases with pituitary dysfunction or neurologic symptoms. | A |
| 6. | In patients with suspected/confirmed PLCH, HRCT of the chest should be performed. | A |
| 7. | In patients with single-system PLCH, a surgical lung biopsy may be necessary to confirm the diagnosis if a bronchoscopic biopsy or other methods are nondiagnostic. | A |
| 8. | All patients with PLCH should undergo pulmonary function testing (spirometry with lung volumes, diffusion capacity, and plethysmography) at the time of diagnosis. | A |
| 9. | All patients with PLCH who are symptomatic or have an abnormal diffusing capacity for carbon monoxide should undergo a resting transthoracic echocardiogram to screen for pulmonary hypertension. | B |
| 10. | Right-sided heart catheterization and vasoreactivity testing should be considered in selected patients with echocardiographically demonstrated pulmonary hypertension to assess its severity and aid with further management. | B |
| 11. | MRCP or ERCP should be performed in cases with elevated serum cholestasis markers or sonomorphologically-dilated bile ducts to evaluate for sclerosing cholangitis related to LCH. | A |
| 12. | For patients with suspected sclerosing cholangitis as a manifestation of LCH, early liver biopsy should be performed for histopathologic and mutational assessment. | A |
| 13. | Laboratory studies to assess for liver insufficiency, cytopenias, markers of inflammation (C-reactive protein) should be performed at diagnosis. | A |
| 14. | For patients with polyuria/polydipsia or involvement of pituitary/hypothalamus axis on cranial imaging, laboratory evaluation should be undertaken to rule out DI and anterior pituitary function. | A |
| 15. | Currently, there is no role for routine bone marrow biopsy in adult LCH. However, due to a high prevalence of concomitant and subsequent myeloid neoplasms in patients with LCH, bone marrow biopsy should be considered in the context of otherwise unexplained cytopenias or cytosis. | A |
| 16. | All patients with LCH should undergo BRAF-V600E mutational testing to aid in diagnosis and treatment. | A |
| 17. | IHC for VE1 may not be a sensitive or specific marker for BRAF-V600E mutational analysis and should be confirmed with another molecular assay if feasible. | B |
| 18. | For BRAF-V600-wt LCH cases, next-generation sequencing should be undertaken to assess for MAPK-ERK pathway mutations, especially in situations where the diagnosis is questionable or second-line treatment is needed. | A |
| 19. | In the absence of sufficient tumor tissue, cell-free DNA analysis from peripheral blood can be used for the assessment of BRAF-mutational status. However, the sensitivity of such assays may be variable. | A |
| Treatment | Unifocal LCH | |
| 20. | For unifocal LCH (except DI), observation or local therapies such as surgical excision, intralesional steroids, or radiation are recommended as first-line treatments. | B |
| 21. | For unifocal LCH involving specific sites (nervous system, liver, spleen, etc), systemic treatment should be implemented. | A |
| 22. | For unifocal LCH of pituitary/hypothalamus resulting in DI and anterior pituitary dysfunction, hormone replacement should be undertaken. The role of systemic therapy is unclear and is recommended in cases with symptoms that are recent-onset or when a radiologic lesion is present. | B |
| Single-system pulmonary LCH | ||
| 23. | Cessation of smoking, vaping, inhalation of marijuana or other substances is recommended as first-line therapy for single-system PLCH. | A |
| 24. | Systemic therapy is recommended for single-system PLCH in the presence of progressive disease (regardless of smoking status) or for stable disease with clinically significant respiratory symptoms or dysfunction. | A |
| 25. | For patients who develop advanced single-system PLCH refractory to or ineligible for systemic treatments, lung transplantation referral should be undertaken. | A |
| Multifocal and multisystem LCH | ||
| 26. | For multifocal osseous LCH, recommended treatments are radiation therapy (<3 lesions safely amenable to radiation), bisphosphonates, or systemic chemotherapy. | B |
| 27. | For multifocal cutaneous LCH, recommended treatments are topical therapy, oral low-dose weekly methotrexate ± prednisone/6-MP, hydroxyurea, or IMiDs. | B |
| 28. | For multisystem LCH or extensive/refractory multifocal single-system LCH, systemic chemotherapy agents such as cladribine, cytarabine, or vinblastine + prednisone are recommended. | B |
| 29. | For LCH involving the brain parenchyma, first-line treatment with chemotherapy with cladribine or cytarabine is recommended. | A |
| 30. | For LCH refractory to first-line treatment or with end-organ dysfunction (e.g., neurologic impairment, sclerosing cholangitis), alternate conventional treatment or targeted therapies (BRAF or MEK inhibitors) should be implemented. | A |
| Response assessment and monitoring | ||
| 31. | The type and frequency of response assessments and follow-up examinations are variable and dependent on the degree of involvement with LCH (Table 7). | A |
| 32. | For initially FDG PET avid LCH, it is recommended to repeat an FDG PET-based imaging study for assessment of disease response after 2-3 mo of initiation of therapy, with subsequent imaging frequency tailored individually based on the specific clinical scenario. | A |
A (strong consensus: ≥95%), B (consensus: 75-94%), and C (majority agreement: 50-74%).
6-MP, 6-mercaptopurine; CNS, central nervous system; CT, computed tomography; DI, diabetes insipidus; ERCP, endoscopic retrograde cholangiopancreatography; FDG-PET, 18Fluorodeoxyglucose positron emission tomography; IMiDs, immunomodulators (thalidomide, lenalidomide); MRCP, magnetic resonance cholangiopancreatography; MRI, magnetic resonance imaging.