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ERROR: type should be string, got "https://profreg.medscape.com/px/getpracticeprofile.do?method=getProfessionalProfile&urlCache=aHR0cHM6Ly9lbWVkaWNpbmUubWVkc2NhcGUuY29tL2FydGljbGUvMTEwMDU3OS1vdmVydmlldw==\nDrugs & Diseases > Dermatology\nAuthor: Christopher R Shea, MD; Chief Editor: William D James, MD more...\nSections Langerhans Cell Histiocytosis\nPhototherapy agents\nBisphosphonate derivatives\nLangerhans cell histiocytosis (LCH) is a group of idiopathic disorders characterized by the presence of cells with characteristics similar to bone marrow–derived Langerhans cells juxtaposed against a backdrop of hematopoietic cells, including T-cells, macrophages, and eosinophils.\nIn 1868, Paul Langerhans discovered the epidermal dendritic cells that now bear his name. The ultrastructural hallmark of the Langerhans cell, the Birbeck granule, was described a century later. The term Langerhans cell histiocytosis is generally preferred to the older term, histiocytosis X. This newer name emphasizes the histogenesis of the condition by specifying the type of lesional cell and removes the connotation of the unknown (\"X\") because its cellular basis has now been clarified. [1]\nAlthough the epidermal Langerhans cell has been presumed to be the cell of origin in LCH, recent studies have called this belief into question. Specifically, a variety of other cellular populations have been identified that possess phenotypic characteristics similar to Langerhans cells, including expression of CD207 and Birbeck granules. Therefore, in addition to epidermal Langerhans cells, other potential cellular origins for LCH include dermal langerin+ dendritic cells, lymphoid tissue-resident langerin+ dendritic cells, and monocytes that can be induced by local environmental stimuli to acquire a Langerhans cell phenotype. [2, 3]\nNotably, LCH cells have been found to express markers of both resting epidermal Langerhans cells (CD1a, intracellular major histocompatibility complex II [MHCII], Birbeck granules) and activated Langerhans cells (including CD54 and CD58). As a result, the pathologic cells of LCH have been hypothesized to represent Langerhans cells in a state of arrested maturation. [3] Taken together, these findings have led some to speculate that LCH is not a specific disease of epidermal Langerhans cells, but rather one of mononuclear phagocyte dysregulation. [3]\nThe working group of the Histiocyte Society divided histocytic disorders into three groups: (1) dendritic cell histiocytosis, (2) macrophage-related disorders, and (3) malignant histiocytosis. [4] LCH belongs in group 1 and encompasses a number of diseases. On one end, the clinical spectrum includes an acute, fulminant, disseminated disease called Letterer-Siwe disease, and, on the other end, solitary or few, indolent and chronic lesions of bone or other organs called eosinophilic granulomas. The intermediate clinical form called Hand-Schüller-Christian disease is characterized by multifocal, chronic involvement and classically presents as the triad of diabetes insipidus, proptosis, and lytic bone lesions. A congenital, self-healing form called Hashimoto-Pritzker disease has also been described.\nMore recently, histiocytic diseases have been reclassified into five groups: (1) Langerhans-related, (2) cutaneous and mucocutaneous, (3) malignant histiocytosis, (4) Rosai-Dorfman disease, and (5) hemophagocytic lymphohistiocytosis and macrophage activation syndrome. LCH belongs in the first category, along with Erdheim-Chester disease and juvenile xanthogranuloma. [5]\nThe pathogenesis of Langerhans cell histiocytosis (LCH) is unknown. It has been debated whether LCH is a reactive or neoplastic process, although the latter is now more commonly accepted. Arguments supporting the reactive nature of LCH include the occurrence of spontaneous remissions, the extensive elaboration of multiple cytokines by dendritic cells and T-cells (the so-called cytokine storm) in LCH lesions, and the good survival rate in patients without organ dysfunction. [6] Furthermore, a rigorous investigation of potential chromosomal aberrations in LCH via analysis of ploidy, karyotype, single-nucleotide polymorphism arrays, and array-based comparative genomic hybridization did not reveal consistent abnormalities; these findings were considered to support the idea of LCH as a reactive process. [7]\nOn the other hand, the infiltration of organs by a monoclonal population of aberrant cells, the possibility of lethal evolution, and the cancer-based modalities of successful treatment are all consistent with a neoplastic process. [8, 9] In addition, the demonstration, by use of X chromosome–linked DNA probes, of LCH as a monoclonal proliferation supports a neoplastic origin for this proliferation; however, the presence of this finding in distinct subtypes with different evolutions demands further investigations to elucidate its significance. A breakthrough was made when genomic studies demonstrated activating, somatic BRAF V600E mutations in approximately half of human specimens. The mutation was also found in CD34+ hematopoietic cell progenitors and mature dendritic cells of patients, with mouse models, demonstrating that BRAF V600E mutation is sufficient to develop an LCH phenotype. [10] Other studies found mutations in MAPK, with both BRAF and MAPK acting through a common MEK/ERK pathway. [11, 12] These studies further supported the concept of LCH as a myeloid neoplasm.\nA 2010 study comparing gene expression of cells expressing CD207 (a marker of Langerhans cells) in LCH lesions with epidermal CD207+ control cells identified differential expression of more than 2000 genes between these 2 subsets. These differences were found in genes involved in cell cycle regulation, apoptosis, cell signaling, metastasis, and myeloid differentiation. [13] Interestingly, this analysis found no differences in expression of proliferation markers between these subsets of CD207+ cells, consistent with the hypothesis that LCH may be a disease of abnormal cellular accumulation.\nThe extensive variability in gene expression between these 2 cellular populations has prompted speculation that LCH cells develop from a population of cells distinct from epidermal Langerhans cells. Specifically, it is hypothesized that \"misguided\" blood-derived myeloid dendritic cells are recruited to specific anatomic sites and their subsequent stimulation of T-cell trafficking and local immunomodulation is responsible for the characteristic lesions of LCH. [13]\nEvidence suggests a role for immune dysfunction in the pathogenesis of LCH, through the creation of a permissive immunosurveillance system. Specifically, findings from immunohistochemical and immunofluorescence analyses of LCH biopsy specimens have led to the hypothesis that semimature LCH cells stimulate the expansion of a polyclonal population of regulatory T cells. These regulatory T cells may, in turn, inhibit the immune system (in part via the elaboration of interleukin (IL)–10 and prevent it from effectively resolving LCH lesions. [14] These T cells generate transforming growth factor-β, but do not produce inflammatory cytokines. [12] In active LCH patients, the increase in regulatory T cells in active lesions is accompanied by the decrease of CD8+CD56+ T cells elsewhere in the blood. [12] These findings support that regulatory T cells may, in turn, inhibit the immune system and prevent it from effectively resolving LCH lesions.\nDetection of high serum levels of the proinflammatory cytokine IL-17A in patients with LCH has given rise to speculation that IL-17A is also involved in the pathogenesis of the disease. Further investigation into this phenomenon has led to the proposal that IL-17A induces dendritic cell/Langerhans cell fusion into multinucleated giant cells that in turn recruit other inflammatory cells and cause local tissue destruction, creating the characteristic lesions of LCH. [15] However, these findings have not been independently reproduced, and the role of IL-17A in the pathogenesis of LCH remains controversial. [16]\nSome studies have also indicated that expression of vascular endothelial growth factor (VEGF); Bcl-2 family proteins; and FADD, FLICE, and FLIP proteins in the Fas signaling pathway may be involved in the pathogenesis of LCH. [17, 18, 19] The E-cadherin-beta-catenin-Wnt signaling pathway has also been implicated in LCH, and down-regulation of E-cadherin may be associated with disease dissemination. [3, 20] More recently, the expression of CSF1 receptor has been found to be essential in the differentiation and migration of Langerhans cells. [21]\nThe etiology of Langerhans cell histiocytosis (LCH) remains unknown.\nLangerhans cell proliferation may be induced by a viral infection, a defect in intercellular communication (T cell and macrophage interaction), and/or a cytokine-driven process mediated by tumor necrosis factor, IL-11, and leukemia inhibitory factor. [22, 23, 24] Specifically, human herpesvirus 6 (HHV-6) has been proposed to contribute to the initiation and/or modulation of persistent LCH. However, other studies have not shown a correlation between HHV-6 and LCH, and their reported associations may represent coincidental findings. [25, 26]\nCigarette smoking may play a role as a chronic irritant in the development of eosinophilic granuloma of the lung. In addition, studies have shown that over 90% of pulmonary LCH were in smokers, with cigarette smoking driving the pathogenesis of pulmonary LCH in mouse models of BRAF V600E mutated mice. [27]\nLangerhans cell histiocytosis (LCH) is a rare disease. The estimated annual incidence ranges from 0.5-5.4 cases per million persons per year. Approximately 1200 new cases per year are reported in the United States.\nThe prevalence of LCH seems to be higher among whites than in persons of other races.\nThe frequency of LCH is greater in males than in females, with a male-to-female ratio of 2:1.\nLCH affects patients from the neonatal period to adulthood, although it appears to be more common in children aged 0-15 years (reportedly approximately 4 cases per million population). [28] The age at onset varies according to the variant of LCH, as follows [3] :\nLetterer-Siwe disease occurs predominantly in children younger than 2 years.\nThe chronic multifocal form, including Hand-Schüller-Christian syndrome, has a peak of onset in children aged 2-10 years.\nLocalized eosinophilic granuloma occurs mostly frequently in children aged 5-15 years.\nPulmonary LCH is more common during the third and fourth decades of life. [3]\nAlso see Histiocytosis.\nMore than half the patients younger than 2 years with disseminated Langerhans cell histiocytosis (LCH) and organ dysfunction die of the disease, whereas unifocal LCH and most cases of congenital self-healing histiocytosis are self-limited. Multifocal chronic LCH is self-limited in most cases, but increased mortality has been observed among infants with pulmonary involvement.\nThe clinical course of LCH is variable. Patients with unifocal disease generally have an excellent prognosis. After initial bone scanning and radiographic survey to assess the extent of the disease, follow-up studies after treatment should be performed at 6-month intervals for 3 years. If no additional lesions are present at 1 year, the development of subsequent lesions is unlikely. A full recovery is also expected in cases of solitary lymph node involvement or isolated skin disease. In pulmonary LCH, prognosis is more unpredictable. Remission may occur following smoking cessation, while others progress to chronic lung disease. [29, 30] Owing to its unpredictable nature, it is recommended for patients with pulmonary LCH to undergo follow up at least twice a year.\nMultifocal LCH has a variable prognosis, especially in patients at the extremes of age with pulmonary involvement. The prognosis is worse than in patients with unifocal disease but better than those with disseminated disease. Sixty percent of patients with multifocal disease have a chronic course, 30% of patients undergo complete remission, and 10% of patients with multifocal LCH die from the disease. [31] Response to chemotherapy in the first 6 weeks (induction therapy) is among the most important prognostic indicators for multifocal LCH. A good response to chemotherapy during this period is associated with significantly improved survival. [4, 32] Conversely, hematologic involvement or involvement of organs such as the lungs, spleen, and liver is associated with worse long-term outcomes. [4]\nStudies found that children with V600E BRAF mutations are associated with disease relapse and a worse prognosis. [33] BRAF V600E‒positive mutations were also more likely present in systemic LCH, while patients without the mutation had diseases limited to the skin. [34, 35] However, it is important to note that those studies treated patients with conventional therapy with vinblastine and prednisone. Direct therapies targeting BRAF V600E mutations (vemurafenib) have shown improvements in refractory BRAF V600E‒positive patients, although relapses are still common. [36]\nLetterer-Siwe disease (disseminated) has a high mortality rate. The prognosis in these patients depends on the patient's age, the extent of disease, and the degree of organ dysfunction. The mortality rate is 50% or higher.\nThe congenital form of histiocytosis tends to resolve spontaneously within weeks to months. [37] Although the absence of systemic disease at presentation and the tendency of resolution of the disease are favorable, long-term follow-up care to detect evidence of relapse or progression in these patients is suggested. [37] Relapse in these patients has been reported up to 5 years after the initial disappearance of the disease. Cutaneous lesions usually disappear by 3 months, leaving residual hypopigmentation.\nInfrequently, cases originally diagnosed as chronic focal LCH may progress to multifocal or even disseminated disease.\nKomp DM. Historical perspectives of Langerhans cell histiocytosis. Hematol Oncol Clin North Am. 1987 Mar. 1(1):9-21. [Medline].\nMerad M, Ginhoux F, Collin M. Origin, homeostasis and function of Langerhans cells and other langerin-expressing dendritic cells. Nat Rev Immunol. 2008 Dec. 8(12):935-47. [Medline].\nEgeler RM, van Halteren AG, Hogendoorn PC, Laman JD, Leenen PJ. Langerhans cell histiocytosis: fascinating dynamics of the dendritic cell-macrophage lineage. Immunol Rev. 2010 Mar. 234(1):213-32. [Medline].\nSatter EK, High WA. Langerhans cell histiocytosis: a review of the current recommendations of the Histiocyte Society. Pediatr Dermatol. 2008 May-Jun. 25(3):291-5. [Medline].\nEmile JF, Abla O, Fraitag S, et al. Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood. 2016 Jun 2. 127 (22):2672-81. [Medline].\nEgeler RM, Favara BE, van Meurs M, Laman JD, Claassen E. 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 Dec 15. 94(12):4195-201. [Medline].\nda Costa CE, Szuhai K, van Eijk R, et al. No genomic aberrations in Langerhans cell histiocytosis as assessed by diverse molecular technologies. Genes Chromosomes Cancer. 2009 Mar. 48(3):239-49. [Medline].\nWillman CL. Detection of clonal histiocytes in Langerhans cell histiocytosis: biology and clinical significance. Br J Cancer Suppl. 1994 Sep. 23:S29-33. [Medline].\nWillman CL, Busque L, Griffith BB, et al. Langerhans'-cell histiocytosis (histiocytosis X)--a clonal proliferative disease. N Engl J Med. 1994 Jul 21. 331(3):154-60. [Medline].\nBerres ML, Lim KP, Peters T, Price J, Takizawa H, Salmon H, et al. BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups. J Exp Med. 2014 Apr 7. 211 (4):669-83. [Medline].\nChakraborty R, Hampton OA, Shen X, et al. Mutually exclusive recurrent somatic mutations in MAP2K1 and BRAF support a central role for ERK activation in LCH pathogenesis. Blood. 2014 Nov 6. 124 (19):3007-15. [Medline].\nMitchell J, Kelly J, Kvedaraite E, et al. Foxp3+ Tregs from Langerhans cell histiocytosis lesions co-express CD56 and have a definitively regulatory capacity. Clin Immunol. 2020 Apr 10. 215:108418. [Medline].\nAllen CE, Li L, Peters TL, Leung HC, Yu A, Man TK. Cell-specific gene expression in Langerhans cell histiocytosis lesions reveals a distinct profile compared with epidermal Langerhans cells. J Immunol. 2010 Apr 15. 184(8):4557-67. [Medline].\nSenechal B, Elain G, Jeziorski E, Grondin V, Patey-Mariaud de Serre N, Jaubert F. Expansion of regulatory T cells in patients with Langerhans cell histiocytosis. PLoS Med. 2007 Aug. 4(8):e253. [Medline].\nCoury F, Annels N, Rivollier A, et al. Langerhans cell histiocytosis reveals a new IL-17A-dependent pathway of dendritic cell fusion. Nat Med. 2008 Jan. 14(1):81-7. [Medline].\nAllen CE, McClain KL. Interleukin-17A is not expressed by CD207(+) cells in Langerhans cell histiocytosis lesions. Nat Med. 2009 May. 15(5):483-4; author reply 484-5. [Medline]. [Full Text].\nBank MI, Gudbrand C, Rengtved P, et al. Immunohistochemical detection of the apoptosis-related proteins FADD, FLICE, and FLIP in Langerhans cell histiocytosis. J Pediatr Hematol Oncol. 2005 Jun. 27(6):301-6. [Medline].\nDina A, Zahava V, Iness M. The role of vascular endothelial growth factor in Langerhans cell histiocytosis. J Pediatr Hematol Oncol. 2005 Feb. 27(2):62-6. [Medline].\nMarchal J, Kambouchner M, Tazi A, Valeyre D, Soler P. Expression of apoptosis-regulatory proteins in lesions of pulmonary Langerhans cell histiocytosis. Histopathology. 2004 Jul. 45(1):20-8. [Medline].\nBattistella M, Fraitag S, Teillac DH, Brousse N, de Prost Y, Bodemer C. Neonatal and early infantile cutaneous langerhans cell histiocytosis: comparison of self-regressive and non-self-regressive forms. Arch Dermatol. 2010 Feb. 146(2):149-56. [Medline].\nLonardi S, Scutera S, Licini S, Lorenzi L, Cesinaro AM, Benerini Gatta L, et al. CSF1R is required for differentiation and migration of Langerhans cells and Langerhans cell histiocytosis. Cancer Immunol Res. 2020 Apr 1. [Medline].\nAndersson By U, Tani E, Andersson U, Henter JI. Tumor necrosis factor, interleukin 11, and leukemia inhibitory factor produced by Langerhans cells in Langerhans cell histiocytosis. J Pediatr Hematol Oncol. 2004 Nov. 26(11):706-11. [Medline].\nKawakubo Y, Kishimoto H, Sato Y, et al. Human cytomegalovirus infection in foci of Langerhans cell histiocytosis. Virchows Arch. 1999 Feb. 434(2):109-15. [Medline].\nKannourakis G, Abbas A. The role of cytokines in the pathogenesis of Langerhans cell histiocytosis. Br J Cancer Suppl. 1994 Sep. 23:S37-40. [Medline].\nCsire M, Mikala G, Jako J, Masszi T, Janosi J, Dolgos J. Persistent long-term human herpesvirus 6 (HHV-6) infection in a patient with langerhans cell histiocytosis. Pathol Oncol Res. 2007. 13(2):157-60. [Medline].\nStrenger V, Urban C. Chromosomal integration of the HHV-6 genome as a possible cause of persistent HHV-6 detection in a patient with langerhans cell histiocytosis. Pathol Oncol Res. 2010 Mar. 16(1):125-6. [Medline].\nLiu H, Osterburg AR, Flury J, et al. MAPK mutations and cigarette smoke promote the pathogenesis of pulmonary Langerhans cell histiocytosis. JCI Insight. 2020 Feb 27. 5 (4):[Medline].\nWindebank KP, Nanduri V. Langerhans Cell Histiocytosis. Arch Dis Child. 2009 May 19. [Medline].\nWolters PJ, Elicker BM. Subacute onset of pulmonary langerhans cell histiocytosis with resolution after smoking cessation. Am J Respir Crit Care Med. 2014 Dec 1. 190 (11):e64. [Medline].\nVassallo R, Harari S, Tazi A. Current understanding and management of pulmonary Langerhans cell histiocytosis. Thorax. 2017 Oct. 72 (10):937-945. [Medline].\nLahey E. Histiocytosis x--an analysis of prognostic factors. J Pediatr. 1975 Aug. 87(2):184-9. [Medline].\nGadner H, Grois N, Arico M, et al. A randomized trial of treatment for multisystem Langerhans' cell histiocytosis. J Pediatr. 2001 May. 138(5):728-34. [Medline].\nNann D, Schneckenburger P, Steinhilber J, et al. Pediatric Langerhans cell histiocytosis: the impact of mutational profile on clinical progression and late sequelae. Ann Hematol. 2019 Jul. 98 (7):1617-1626. [Medline].\nOzer E, Sevinc A, Ince D, Yuzuguldu R, Olgun N. BRAF V600E Mutation: A Significant Biomarker for Prediction of Disease Relapse in Pediatric Langerhans Cell Histiocytosis. Pediatr Dev Pathol. 2019 Oct. 22 (5):449-455. [Medline].\nCui L, Zhang L, Ma HH, et el. Circulating cell-free BRAFV600E during chemotherapy is associated with prognosis of children with Langerhans cell histiocytosis. Haematologica. 2020 Jan 9. [Medline].\nVisser J, Hutter C, Sieni E, et al. Vemurafenib for Refractory Multisystem Langerhans Cell Histiocytosis in Children: An International Observational Study. J Clin Oncol. 2019 Nov 1. 37 (31):2857-2865. [Medline].\nMinkov M, Prosch H, Steiner M, et al. Langerhans cell histiocytosis in neonates. Pediatr Blood Cancer. 2005 Nov. 45(6):802-7. [Medline].\nShaffer MP, Walling HW, Stone MS. Langerhans cell histiocytosis presenting as blueberry muffin baby. J Am Acad Dermatol. 2005 Aug. 53(2 Suppl 1):S143-6. [Medline].\nHwang C, Kim YJ, Seo YJ, Park JK, Lee JH, Lee Y. Isolated langerhans cell histiocytosis of the vulva in an infant. Pediatr Dermatol. 2009 Nov-Dec. 26(6):751-3. [Medline].\nLin MW, Chang YL, Lee YC, Cheng HL, Chen JS, Hsu HH. Pulmonary Langerhans cell histiocytosis. Lung. 2009 Aug. 187(4):261-2. [Medline].\nShima H, Takahashi T, Shimada H. Protein-losing enteropathy caused by gastrointestinal tract-involved Langerhans cell histiocytosis. Pediatrics. 2010 Feb. 125(2):e426-32. [Medline].\nUchiyama M, Watanabe R, Ito I, Ikeda T. Thyroid involvement in pulmonary langerhans cell histiocytosis. Intern Med. 2009. 48(23):2047-8. [Medline].\nKluge G, Sorge I, Bierbach U, Hirsch W. Scapula as an uncommon site of Langerhans cell histiocytosis in an infant. Pediatr Int. 2010 Feb. 52(1):142-4. [Medline].\nCunningham MJ, Curtin HD, Jaffe R, Stool SE. Otologic manifestations of Langerhans' cell histiocytosis. Arch Otolaryngol Head Neck Surg. 1989 Jul. 115(7):807-13. [Medline].\nCallebaut W, Demedts M, Verleden G. Pulmonary Langerhans' cell granulomatosis (histiocytosis X): clinical analysis of 8 cases. Acta Clin Belg. 1998 Oct. 53(5):337-43. [Medline].\nOkten A, Mocan H, Erduran E, Aslan Y, Gumele HR, Ozoran Y. Langerhans cell histiocytosis associated with recurrent pneumothorax: a case report. Turk J Pediatr. 1996 Jan-Mar. 38(1):125-30. [Medline].\nHaupt R, Nanduri V, Calevo MG, et al. Permanent consequences in Langerhans cell histiocytosis patients: a pilot study from the Histiocyte Society-Late Effects Study Group. Pediatr Blood Cancer. 2004 May. 42(5):438-44. [Medline].\nVrijmoet-Wiersma CM, Kooloos VM, Koopman HM, et al. Health-related quality of life, cognitive functioning and behaviour problems in children with Langerhans cell histiocytosis. Pediatr Blood Cancer. 2009 Jan. 52(1):116-22. [Medline].\nDunger DB, Broadbent V, Yeoman E, et al. The frequency and natural history of diabetes insipidus in children with Langerhans-cell histiocytosis. N Engl J Med. 1989 Oct 26. 321(17):1157-62. [Medline].\nGrois N, Potschger U, Prosch H, et al. Risk factors for diabetes insipidus in langerhans cell histiocytosis. Pediatr Blood Cancer. 2006 Feb. 46(2):228-33. [Medline].\nAbla O, Weitzman S, Minkov M, et al. Diabetes insipidus in Langerhans cell histiocytosis: When is treatment indicated?. Pediatr Blood Cancer. 2009 May. 52(5):555-6. [Medline].\nWeitzman S, Egeler RM. Langerhans cell histiocytosis: update for the pediatrician. Curr Opin Pediatr. 2008 Feb. 20(1):23-9. [Medline].\nBillings TL, Barr R, Dyson S. Langerhans cell histiocytosis mimicking malignant melanoma: a diagnostic pitfall. Am J Dermatopathol. 2008 Oct. 30(5):497-9. [Medline].\nCalming U, Henter JI. Elevated erythrocyte sedimentation rate and thrombocytosis as possible indicators of active disease in Langerhans' cell histiocytosis. Acta Paediatr. 1998 Oct. 87(10):1085-7. [Medline].\nSteiner M, Prayer D, Asenbaum S, et al. Modern imaging methods for the assessment of Langerhans' cell histiocytosis-associated neurodegenerative syndrome: case report. J Child Neurol. 2005 Mar. 20(3):253-7. [Medline].\nPhillips 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 Jan. 52(1):97-101. [Medline].\nDerenzini E, Fina MP, Stefoni V, Pellegrini C, Venturini F, Broccoli A. MACOP-B regimen in the treatment of adult Langerhans cell histiocytosis: experience on seven patients. Ann Oncol. 2009 Oct 27. [Medline].\nNanduri V, Tatevossian R, Sirimanna T. High incidence of hearing loss in long-term survivors of multisystem Langerhans cell histiocytosis. Pediatr Blood Cancer. 2010 Mar. 54(3):449-53. [Medline].\nGavhed D, Akefeldt SO, Osterlundh G, Laurencikas E, Hjorth L, Blennow K. Biomarkers in the cerebrospinal fluid and neurodegeneration in Langerhans cell histiocytosis. Pediatr Blood Cancer. 2009 Dec 15. 53(7):1264-70. [Medline].\nFavara BE, Feller AC, Pauli M, et al. Contemporary classification of histiocytic disorders. The WHO Committee On Histiocytic/Reticulum Cell Proliferations. Reclassification Working Group of the Histiocyte Society. Med Pediatr Oncol. 1997 Sep. 29(3):157-66. [Medline].\nValladeau J, Ravel O, Dezutter-Dambuyant C, et al. Langerin, a novel C-type lectin specific to Langerhans cells, is an endocytic receptor that induces the formation of Birbeck granules. Immunity. 2000 Jan. 12(1):71-81. [Medline].\nGadner H. Treatment of adult-onset Langerhans cell histiocytosis--is it different from the pediatric approach?. Ann Oncol. 2009 Nov 25. [Medline].\nMontella L, Merola C, Merola G, Petillo L, Palmieri G. Zoledronic acid in treatment of bone lesions by Langerhans cell histiocytosis. J Bone Miner Metab. 2009. 27(1):110-3. [Medline].\nMunn SE, Olliver L, Broadbent V, Pritchard J. Use of indomethacin in Langerhans cell histiocytosis. Med Pediatr Oncol. 1999 Apr. 32(4):247-9. [Medline].\nGoldberg SA, O'Connor SC, Sprinz PG. Prostaglandin inhibitors in the treatment of single-system Langerhans cell histiocytosis: pharmacologic rationale and report of two cases. J Pediatr Hematol Oncol. 2008 Oct. 30(10):778-80. [Medline].\nCardoso JC, Cravo M, Cardoso R, Brites MM, Reis JP, Tellechea O. Langerhans cell histiocytosis in an adult: good response of cutaneous lesions to acitretin. Clin Exp Dermatol. 2010 Feb 22. [Medline].\nSakai H, Ibe M, Takahashi H, et al. Satisfactory remission achieved by PUVA therapy in Langerhans cell hisiocytosis in an elderly patient. J Dermatol. 1996 Jan. 23(1):42-6. [Medline].\nVogel CA, Aughenbaugh W, Sharata H. Excimer laser as adjuvant therapy for adult cutaneous Langerhans cell histiocytosis. Arch Dermatol. 2008 Oct. 144(10):1287-90. [Medline].\nLazor R, Etienne-Mastroianni B, Khouatra C, Tazi A, Cottin V, Cordier JF. Progressive diffuse pulmonary Langerhans cell histiocytosis improved by cladribine chemotherapy. Thorax. 2009 Mar. 64(3):274-5. [Medline].\nNéel A, Artifoni M, Fontenoy AM, et al. Long-term efficacy and safety of 2CdA (cladribine) in extra-pulmonary adult-onset Langerhans cell histiocytosis: analysis of 23 cases from the French Histiocytosis Group and systematic literature review. Br J Haematol. 2020 Mar 19. [Medline].\nGadner H, Heitger A, Grois N, Gatterer-Menz I, Ladisch S. Treatment strategy for disseminated Langerhans cell histiocytosis. DAL HX-83 Study Group. Med Pediatr Oncol. 1994. 23(2):72-80. [Medline].\nGadner H, Grois N, Potschger U, et al. Improved outcome in multisystem Langerhans cell histiocytosis is associated with therapy intensification. Blood. 2008 Mar 1. 111(5):2556-62. [Medline].\nWeitzman S, Braier J, Donadieu J, Egeler RM, Grois N, Ladisch S. 2'-Chlorodeoxyadenosine (2-CdA) as salvage therapy for Langerhans cell histiocytosis (LCH). results of the LCH-S-98 protocol of the Histiocyte Society. Pediatr Blood Cancer. 2009 Dec 15. 53(7):1271-6. [Medline].\nDonadieu J, Bernard F, van Noesel M, Barkaoui M, Bardet O, Mura R, et al. Cladribine and cytarabine in refractory multisystem Langerhans cell histiocytosis: results of an international phase 2 study. Blood. 2015 Sep 17. 126 (12):1415-23. [Medline].\nImamura T, Sato T, Shiota Y, et al. Outcome of pediatric patients with Langerhans cell histiocytosis treated with 2 chlorodeoxyadenosine: a nationwide survey in Japan. Int J Hematol. 2010 May. 91(4):646-51. [Medline].\nConter V, Reciputo A, Arrigo C, Bozzato N, Sala A, Aricò M. Bone marrow transplantation for refractory Langerhans' cell histiocytosis. Haematologica. 1996 Sep-Oct. 81(5):468-71. [Medline].\nSteiner M, Matthes-Martin S, Attarbaschi A, et al. Improved outcome of treatment-resistant high-risk Langerhans cell histiocytosis after allogeneic stem cell transplantation with reduced-intensity conditioning. Bone Marrow Transplant. 2005 Aug. 36(3):215-25. [Medline].\nKesik V, Citak C, Kismet E, Koseoglu V, Akyuz C. Hematopoietic stem cell transplantation in Langerhans cell histiocytosis: case report and review of the literature. Pediatr Transplant. 2009 May. 13(3):371-4. [Medline].\nVeys PA, Nanduri V, Baker KS, et al. Haematopoietic stem cell transplantation for refractory Langerhans cell histiocytosis: outcome by intensity of conditioning. Br J Haematol. 2015 Jun. 169 (5):711-8. [Medline].\nKudo K, Ohga S, Morimoto A, Ishida Y, Suzuki N, Hasegawa D. Improved outcome of refractory Langerhans cell histiocytosis in children with hematopoietic stem cell transplantation in Japan. Bone Marrow Transplant. 2009 Sep 21. [Medline].\nMcClain KL, Kozinetz CA. A phase II trial using thalidomide for Langerhans cell histiocytosis. Pediatr Blood Cancer. 2007 Jan. 48(1):44-9. [Medline].\nBadalian-Very G, Vergilio JA, Degar BA, MacConaill LE, Brandner B, Calicchio ML, et al. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood. September 2010. 116:1919-23. [Medline].\nHaroche J, Cohen-Aubart F, Emile JF, Arnaud L, Maksud P, Charlotte F, 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 Feb 28. 121 (9):1495-500. [Medline].\nHyman DM, Puzanov I, Subbiah V, Faris JE, Chau I, Blay JY, et al. Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations. N Engl J Med. 2015 Aug 20. 373 (8):726-36. [Medline]. [Full Text].\nZelboraf (vemurafenib) [package insert]. South San Francisco, Calif: Genentech. November 6, 2017. Available at [Full Text].\nDiamond EL, Subbiah V, Lockhart AC, et al. Vemurafenib for BRAF V600-Mutant Erdheim-Chester Disease and Langerhans Cell Histiocytosis: Analysis of Data From the Histology-Independent, Phase 2, Open-label VE-BASKET Study. JAMA Oncol. 2018 Mar 1. 4 (3):384-388. [Medline].\nDiamond EL, Durham BH, Ulaner GA, et al. Efficacy of MEK inhibition in patients with histiocytic neoplasms. Nature. 2019 Mar. 567 (7749):521-524. [Medline].\nJordan MB, McClain KL, Yan X, Hicks J, Jaffe R. Anti-CD52 antibody, alemtuzumab, binds to Langerhans cells in Langerhans cell histiocytosis. Pediatr Blood Cancer. 2005 Mar. 44(3):251-4. [Medline].\nIdbaih A, Donadieu J, Barthez MA, et al. Retinoic acid therapy in \"degenerative-like\" neuro-langerhans cell histiocytosis: a prospective pilot study. Pediatr Blood Cancer. 2004 Jul. 43(1):55-8. [Medline].\nNakajima K, Morisawa R, Kodama H, Sano S. Successful treatment with cyclophosphamide of Langerhans cell histiocytosis involving the skin and lymph nodes in an adult patient. Clin Exp Dermatol. 2010 Mar 19. [Medline].\nWagner C, Mohme H, Kromer-Olbrisch T, Stadler R, Goerdt S, Kurzen H. Langerhans cell histiocytosis: treatment failure with imatinib. Arch Dermatol. 2009 Aug. 145(8):949-50. [Medline].\nMontella L, Insabato L, Palmieri G. Imatinib mesylate for cerebral Langerhans'-cell histiocytosis. N Engl J Med. 2004 Sep 2. 351(10):1034-5. [Medline].\nLetterer-Siwe disease. Bilateral inguinal erosive plaques and erythematous papules on the abdomen. Courtesy of Dr Neil S. Prose.\nAbdominal area of an infant with multiple erythematous papules covered by scale and/or crust.\nTypical purpuric lesions in Langerhans cell histiocytosis (must be distinguished from seborrheic dermatitis).\nOn a plain skull radiograph, lesions are typically lytic, with sharp borders and a punched out appearance.\nHigh-power views. Marked epidermotropism is noted (left). The lesional cells are large, with abundant pink cytoplasm and reniform nuclei. An admixture of inflammatory cells, including occasional eosinophils, is present (right).\nHigh-power views. Diffuse immunoreactivity for S-100 protein (right). Langerhans cells and lymphocytes (left, hematoxylin and eosin).\nWidespread positivity for CD1a. Note the presence of epidermotropism (right). Langerhans cells and lymphocytes are present in the epidermis and the papillary dermis (left, hematoxylin and eosin).\nElectron microscopy. Tennis racquet form of Birbeck granules with a small terminal expansion.\nChristopher R Shea, MD Eugene J Van Scott Professor in Dermatology, Chief, Section of Dermatology, Department of Medicine, University of Chicago, The Pritzker School of Medicine\nChristopher R Shea, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Society of Dermatopathology, Arthur Purdy Stout Society, Association of Professors of Dermatology, Chicago Dermatological Society, Dermatology Foundation, Illinois Dermatological Society, International Society of Dermatopathology, Society for Investigative Dermatology\nShay X Huang MD Candidate, The University of Chicago Pritzker School of Medicine\nRichard P Vinson, MD Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA\nRichard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Texas Medical Association, Association of Military Dermatologists, Texas Dermatological Society\nWilliam D James, MD Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine\nWilliam D James, MD is a member of the following medical societies: American Academy of Dermatology, Society for Investigative Dermatology\nDisclosure: Received income in an amount equal to or greater than $250 from: Elsevier; WebMD.\nMarkus D Boos, MD, PhD Assistant Professor of Pediatrics, University of Washington School of Medicine\nMarkus D Boos, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics\nThe authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author, M. Angelica Selim, MD, to the development and writing of this article.\nencoded search term (Langerhans Cell Histiocytosis) and Langerhans Cell Histiocytosis\nSkin Cancer - Melanoma\nSkin Cancer - Merkel Cell Carcinoma\nThe Role of Sentinel Node Biopsy in Skin Cancer\nFast Five Quiz: Skin Cancer\nCutaneous Manifestations of Smoking\nMuir-Torre Syndrome\nDermatologic Manifestations of Metastatic Carcinomas\nDoes Screening for Skin Cancer Result in Melanoma Overdiagnosis?\nUV-Induced Mutations in Seemingly Normal Skin May Predict Skin Cancer\nMole or Melanoma? Test Yourself With These Suspicious Lesions\nCSCC Is a Skin Cancer! 0.25 CME / ABIM MOC Credits\n0.25 CME / ABIM MOC\nCSCC Is a Skin Cancer!\n2010 http://reference.medscape.com/slideshow/melanoma-6004849 Slideshow\nSlideshow Mole or Melanoma? Test Yourself With These Suspicious Lesions"