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Langerhans cell histiocytosis
Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports
Langerhans cell histiocytosis (LCH) is a rare, proliferative neoplastic condition of inflammatory cells with clonal proliferation of a subtype of epidermal dendritic cells, the Langerhans cells. It affects children about five times more frequently than adults. The individual disease evolution may vary from self-healing to life-threatening disseminated disease.
The former classification of histiocytosis distinguished between Langerhans cell, non-Langerhans cell-related, or malignant histiocytosis. Considering clinical picture, pathological, and radiological findings, LCH is now part of the ‘L’ group according to the new classification of histiocytic neoplasms. The group is accompanied by Erdheim–Chester disease (ECD), indeterminate histiocytosis (IDH), and extracutaneous juvenile xanthogranuloma due to similar findings of clonal mutations involving genes of the MAPK pathway and similar clinical complications; 20% of patients with ECD also have LCH lesions.
The names histiocytosis X, eosinophilic granuloma, Hand–Schüller–Christian disease, Letterer–Siwe disease, congenital self-healing reticulohistiocytosis (Hashimoto – Pritzker), Langerhans cell granulomatosis, and non-lipid reticuloendotheliosis lost their importance due to impracticability. LCH is newly grouped into single-system disease, lung involvement, multisystem disease with/without risk organ involvement, and association with another myeloproliferative/myelodysplastic disorder.
Management Strategy
Due to the range of clinical outcomes, an extensive workup is important at the time of diagnosis. It includes a full clinical exam; bloodwork; skin biopsy with immunohistochemistry, notably CD1a and CD207 denoting Birbeck granules; skeletal radiography; and wide molecular testing, including the search for mutations in major signaling pathways (e.g., BRAF mutation).
Treatment strategies depend on the age of onset, organ involvement, and severity of disease. Most available data are from case reports, case series, or small studies up to 20 patients. Recommendations for children may not be directly applicable for adults and vice versa. According to careful clinical, serological, and radiological workup, disease extension can be staged into single-system (SS) disease with unifocal or multifocal involvement, lung involvement, multisystem (MS) disease with/without risk organ involvement. Risk organs include liver, spleen, and bone marrow. If involved, it results in poor prognosis. The most frequent organs affected in children are the bones (80% of cases), skin (33%), pituitary gland (25%), liver, spleen, hematopoietic system, or lungs (15% each), lymph nodes (5–10%), and central nervous system (2–4%, excluding pituitary gland). In adults, lung involvement is more frequent and typically associated with smoking. Therefore, smoking cessation should be the first therapeutic intervention in those cases.
As a topical option in SS disease with skin involvement, surgical excision could be a practical consideration in certain cases (localized disease). Other topical treatments include topical nitrogen mustard (20%), topical tacrolimus , topical steroids , and phototherapy . For extensive skin disease that does not respond to these measures, low-dose, weekly methotrexate (5–10 mg/week) or treatment with azathioprine (2 mg/kg/day) can lead to resolution.
In SS, LCH with localized bone involvement radiotherapy could be a topical treatment option with acceptable side effects for adult patients. In the presence of multifocal bone lesions, hydroxyurea , with or without methotrexate or bisphosphonate , might be effective.
For MS-LCH or SS-LCH with multifocal bone lesions, no clear standard treatments are yet available. In pediatric patients the first-line treatment recommendation is a combination of vinblastine and prednisolone therapy. Adult patients show a higher toxicity for that regimen, resulting in a poor overall response; hence, cytarabine or cladribine (2-Chlorodeoxyadenosine, 2CdA) might be preferred as the first-line option. In patients with central nervous system (CNS) lesions, 2CdA and cytarabine show a better efficacy due to higher blood–brain barrier penetration. Short-course chemotherapy with methotrexate , doxorubicin , cyclophosphamide , vincristine , prednisone , and bleomycin are reserved for aggressive LCH in adults and should be applied only in very severe cases. As a second-line option for aggressive cases, allogeneic hematopoietic stem cell transplantation has been documented successful in various cases.
Findings of BRAF V600E mutations and other genetic variants in the MAPK pathway within the last 10 years opened new treatment options. The BRAF inhibitor vemurafenib , the combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib, and monotherapy with the MEK inhibitor trametinib were used successfully in adult patients, although some experienced early relapse after discontinuation. Most patients suffered adverse side effects that led to dose reduction or discontinuation. Due to this toxicity, dose finding is still ongoing for children. A recent international observational study showed promising results for the use of vemurafenib in children. Regarding those developments, a change in treatment recommendation is developing and a targeted therapy regimen is expected to replace chemotherapy as first-line treatments. Vemurafenib is already FDA approved for the indication of Erdheim–Chester disease. The efficacy of imatinib, a tyrosine kinase inhibitor, has been shown in refractory MS-LCH cases, although unfavorable outcomes were reported also, so it is rarely recommended as a treatment option.
Specific Investigations
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Revised classification of histiocytosis and neoplasms of the macrophage-dendritic cell lineages
Emile JF, Abla O, Fraitag S, et al. Blood 2016; 127: 2672–81.
Histiocytoses are thought to be rare, proliferative disorders deriving from dendritic cells or macrophages. Classification should regard clinical, radiographic, pathological, phenotypic, genetic, and molecular features. LCH belongs to the ‘L’ group, together with indeterminate histiocytosis and Erdheim–Chester disease. The ‘C’ group contains cutaneous and mucocutaneous histiocytoses, while the ‘R’ group stands for Rosai–Dorfman disease and miscellaneous non-cutaneous, non-Langerhans cell histiocytoses. The ‘M’ (malignant) group and ‘H’ (hemophagocytic lymphohistiocytosis and macrophage activation syndrome) group include more aggressive disease prolongation with worse outcomes.
Langerhans cell histiocytosis (LCH): guidelines for diagnosis, clinical work-up, and treatment for patients till the age of 18 years
Haupt R, Minkov M, Astigarraga I, et al. Pediatr Blood Cancer 2013; 60: 175–84.
The wide clinical spectrum of LCH implies a broad differential according to different organ involvement. Diagnostic workup in children includes full blood count, prolonged blood chemistry, erythrocyte sedimentation reaction, coagulation studies and imaging studies with abdominal ultrasound, chest X-ray, and skeletal radiographic survey. Additional testing is recommended for specific clinical scenarios.
First-Line Therapies
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Management of adult patients with Langerhans cell histiocytosis: Recommendations from an expert panel on behalf of Euro-Histio-Net
Michael G, Maurizio A, Diego C, et al. Orphanet J Rare Dis 2013; 8: 72.
Single-system disease, especially of the skin, can be treated first line with excision if solitary lesions or topical regimens such as nitrogen mustard or UV therapy. Second-line options are thalidomide (100 mg/day), azathioprine (2 mg/kg/day), or methotrexate (up to 20 mg once weekly). Radiotherapy is an effective treatment option for adult patients with localized disease (e.g., bone, lungs) in which lesions are unresectable. A general dose range of 10–20 Gy is recommended. There is no standard treatment defined for adults with SS multifocal disease or MS disease. Vinblastine/prednisolone as first line in children show higher toxicities in adults. Cytarabine 100 mg/m 2 d1–5 q4w intravenous showed superiority to cladribine 6 mg/m 2 d1–5 q4w subcutaneous/intravenous in a study with 58 patients with bone lesions. Experts recommend cladribine as a first option with risk organ involvement, but cytarabine is a good alternative. Follow-ups with restaging should take place every 2–3 months due to possible reactivation, development of chronic local symptoms, or organ dysfunction. Additionally, there is a rare association to malignant tumors.
Current therapy for Langerhans cell histiocytosis
Broadbents V, Gadner H. Hematology/Oncology Clinics of North America 1998; 12: 327–38.
Painful skin lesions may respond to intralesional steroids. Single-system skin disease, if mild, may respond to topical steroid application. For severe single-system skin disease, topical nitrogen mustard on lesional skin is recommended.
Langerhans cell histiocytosis in children: diagnosis, differential diagnosis, treatment, sequelae and standardized follow-up
Krooks J, Minkov M, Weatherall AG. J Am Acad Dermatol 2018; 8(6): 1047–56.
Isolated cutaneous disease can be treated with topical applications of nitrogen mustard, but use should be limited to severe, refractory disease due to oncogenic potential and high rate of contact sensitivity. Case reports show some good results with topical imiquimod, which could be reapplied in case of recurrence. For UV-treatment, narrowband UVB is a safer option than PUVA. For more extensive disease, systemic treatments with methotrexate, azathioprine, or vitamin A derivates have been documented with good results in case reports.
Langerhans cell histiocytosis
Rodriguez-Galindo C, Allen CE. Blood 2020; 135(16): 1319–31.
Patients with SS disease with only a local site affected can be treated with local therapy or observation. Patients with more extensive disease with risk of organ involvement require systemic therapy. First-line treatment is vinblastine + prednisone for 1 year with the potential addition of mercaptopurine for high-risk LCH. For recurrent but low-risk disease, less toxic regimens including 6-mercaptopurine and methotrexate, indomethacin, bisphosphonates, and hydroxyurea may be considered. Treatment with MAPK pathway inhibitors shows great responses in adults with LCH and ECD, although rapid reactivations occur after treatment discontinuation. In those cases, retreatment with BRAF inhibitors is still effective.
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