Langerhans cell histiocytosis (LCH) is a rare proliferative disease characterized by the presence of large and mononuclear cells that are normally involved in the antigen-presenting function. These cells are defined by the positivity of CD1a, CD68, S100, and CD207 at immunohistochemistry.1 In lesions, LCH cells are included in a particular microenvironment, which is made of T cells, macrophages, and eosinophils that support disease progression through a local production of cytokines.2 The prevalence of LCH is higher in childhood but not exclusive to this period.3 In adults, the diagnosis is made typically between the 5th and 7th decades of life, with both sexes being equally affected.4
Clinical presentation at diagnosis is heterogeneous and includes many different symptoms, according to organs or tissues involved. The disease can be localized, with a good prognosis, or can be multifocal or multisystemic, with a lower survival rate, especially when high-risk organs are involved (eg, lung, spleen, liver, bone marrow).5 Patient stratification into high- and low-risk groups is very important to increase response rate in multisystemic disease and reduce overtreatment in single sites.6 Local treatment, such as a surgical excision or intralesional injection, is indicated when the disease is monofocal. Alternately, when a patient presents with multifocal localization or multisystemic disease, systemic therapy should be considered. Because of the rarity of this disease and its wide spectrum of clinical presentations, many aspects of patient management are still controversial and a matter of debate. Diagnosis and treatment recommendations and guidelines, based on agreement between experts in the field, have been recently published for adults7 and for use in the pediatric8 setting.
A series of clinical trials by the Histiocyte Society considered vinblastine plus prednisolone in combination with either etoposide, 6-mercaptopurine, cladribine, cytarabine, or methotrexate first-line therapy in high-risk patients.9,10 Intensive combination chemotherapy, such as a weekly MACOP-B (doxorubicin, methotrexate, cyclophosphamide, vincristine, prednisone, and bleomycin) regimen or stem cell transplantation, has shown promising results.11
Difficulties in treatment decision, especially for patients experiencing disease reactivation after previous systemic therapy, show a need for new therapeutic approaches against new targets within Langerhans cells or their tumor microenvironment, or the intralesional “cytokine storm.” Recently, detection the BRAF V600E mutation changed the perspective of LCH, suggesting a possible use of BRAF inhibitors (ie, vemurafenib) in its treatment.12,13
Hunger RE, Sieling PA, Ochoa MT et al.. Langerhans cells utilize CD1a and Langerin to efficiently present non peptide antigen to T cells. J Clin Invest 2004;113:701–708.
Egeler RM, Favara BE, Van Meurs M et al.. Differential in situ cytokine profiles of Langerhans-like cells and T cells in Langerhans cell Histiocytosis: abundant expression of cytokines relevant to disease and treatment. Blood 1999;94:4195–4201.
Guyot-Goubin A, Donadieu J, Barkaoui M et al.. Descriptive epidemiology of childhood Langerhans cell histiocytosis in France, 2000-2004. Pediatr Blood Cancer 2008;51:71–75.
Mazor RD, Manevich-Mazor M, Shoenfeld Y. Erdheim-Chester disease: a comprehensive review of the literature. Orphanet J Rare Dis 2013;8:137.
Badalian-Very G, Vergilio JA, Degar BA et al.. Recent advances in the understanding of Langerhans cell histiocytosis. Br J Haematol 2012;156:163–172.
Girschikofsky M, Arico M, Castillo D et al.. Management of adult patients with Langerhans cell histiocytosis: recommendations from an expert panel on behalf of Euro-Histio-Net. Orphanet J Rare Dis 2013;8:72–82.
Haupt R, Minkov M, Astigarraga I et al.. Langerhan cell histiocytosis (LCH): guidelines for diagnosis, clinical work-up, and treatment for patients till the age of 18 years. Pediatr Blood Cancer 2013;60:175–184.
Gadner H, Grois N, Potschger U et al.. Improved outcome in multisystem Langerhans cell histiocytosis is associated with therapy intensification. Blood 2008;111:2556–2562.
Gadner H, Minkov M, Grois N et al.. Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis. Blood 2013;121:5006–5014.
Derenzini E, Fina MP, Stefoni V et al.. MACOP-B regimen in the treatment of adult Langerhans cell histiocytosis: experience on seven patients. Ann Oncol 2012;21:1173–1178.
Haroche J, Cohen-Aubart F, Emile JF et al.. Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation. Blood 2013;121:1495–1500.
Charles J, Beani JC, Fiandrino G, Busser B. Major response to vemurafenib in patient with severe cutaneous Langerhans cell histiocytosis harbouring BRAF V600E mutation. J Am Acad Dermatol 2014;71:e97–99.
Tadmor T, Tiacci E, Falini B, Polliack A. The BRAF-V600E mutation in hematological malignancies: a new player in hairy cell leukemia and Langerhans cell histiocytosis. Leuk Lymphoma 2012;53:2339–2340.
Rizzo FM, Cives M, Simone V, Silvestris F. New insights into the molecular pathogenesis of Langerhans cell histiocytosis. Oncologist 2014;19:151–163.
Phillips M, Allen C, Gerson P, McClain K. Comparison of FDG-PET scans to conventional radiography and bone scans in management of Langerhans cell histiocytosis. Pediatr Blood Cancer 2009;52:97–101.
Lee HJ, Ahn BC, Lee SW, Lee J. The usefulness of F-18 fluorodeoxyglucose positron emission tomography/computed tomography in patients with Langerhans cell histiocytosis. Ann Nucl Med 2012;26:730–737.
Arnaud L, Malek Z, Archambaud F et al.. 18F-fluorodeoxyglucose-positron emission tomography scanning is more useful in followup than in the initial assessment of patients with Erdheim-Chester disease. Arthritis Rheum 2009;60:3128–3138.