Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate®

Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis

Kenneth L McClain, MD, PhD
Section Editor
Peter Newburger, MD
Deputy Editor
Alan G Rosmarin, MD


Langerhans cell histiocytosis (LCH) is a rare histiocytic disorder most commonly characterized by single or multiple osteolytic bone lesions demonstrating infiltration with histiocytes having bean-shaped nuclei on biopsy. These histiocytes, along with lymphocytes, macrophages, and eosinophils may infiltrate nearly every organ (most notably the skin, lymph nodes, lungs, thymus, liver, spleen, bone marrow, or central nervous system with the exception of the heart and kidneys).

LCH is so named because the morphology and immunophenotype of the pathologic cells resemble Langerhans cells, which are specialized dendritic cells found in the skin and mucosa. However, LCH is derived from myeloid progenitor cells from the bone marrow, and is not derived from the Langerhans cell of the skin.

For now, "Langerhans cell histiocytosis" remains the preferred nomenclature; the historical terms histiocytosis-X, Letterer-Siwe disease, Hand-Schüller-Christian disease, and diffuse reticuloendotheliosis have been abandoned. The term "eosinophilic granuloma" is sometimes used to describe the pathology of an individual lesion, particularly isolated lytic processes in bone.

The epidemiology, clinical manifestations, pathologic features, diagnosis, and differential diagnosis of LCH will be presented here. The management of LCH is presented separately, as are specific discussions of solitary LCH involving lung or bone. (See "Treatment of Langerhans cell histiocytosis" and "Pulmonary Langerhans cell histiocytosis" and "Langerhans cell histiocytosis (eosinophilic granuloma) of bone in children and adolescents".)


The archaic term "histiocyte" refers to large white blood cells resident in tissues, including Langerhans cells, monocytes/macrophages, and dermal/interstitial dendritic cells [1].


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Aug 2017. | This topic last updated: Aug 28, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Jaffe R. The diagnostic histopathology of Langerhans cell histiocytosis. In: Histiocytic Disorders of Children and Adults. Basic Science, Clinical Features, and Therapy, Weitzman S, Egeler RM (Eds), Cambridge University Press, Cambridge 2005. p.14.
  2. Jaffe R, Weiss LM, Facchetti F. Tumours derived from Langerhans cells. In: World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Swerdlow SH, Campo E, Harris NL, et al (Eds), IARC Press, Lyon 2008. p.358.
  3. Emile JF, Abla O, Fraitag S, et al. Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood 2016; 127:2672.
  4. Carstensen H, Ornvold K. The epidemiology of LCH in children in Denmark, 1975-89. Med Pediatr Oncol 1993; 21:387.
  5. Baumgartner I, von Hochstetter A, Baumert B, et al. Langerhans'-cell histiocytosis in adults. Med Pediatr Oncol 1997; 28:9.
  6. Malpas JS, Norton AJ. Langerhans cell histiocytosis in the adult. Med Pediatr Oncol 1996; 27:540.
  7. Howarth DM, Gilchrist GS, Mullan BP, et al. Langerhans cell histiocytosis: diagnosis, natural history, management, and outcome. Cancer 1999; 85:2278.
  8. Islinger RB, Kuklo TR, Owens BD, et al. Langerhans' cell histiocytosis in patients older than 21 years. Clin Orthop Relat Res 2000; :231.
  9. Götz G, Fichter J. Langerhans'-cell histiocytosis in 58 adults. Eur J Med Res 2004; 9:510.
  10. Aricò M, Girschikofsky M, Généreau T, et al. Langerhans cell histiocytosis in adults. Report from the International Registry of the Histiocyte Society. Eur J Cancer 2003; 39:2341.
  11. Nicholson HS, Egeler RM, Nesbit ME. The epidemiology of Langerhans cell histiocytosis. Hematol Oncol Clin North Am 1998; 12:379.
  12. Aricò M, Nichols K, Whitlock JA, et al. Familial clustering of Langerhans cell histiocytosis. Br J Haematol 1999; 107:883.
  13. Shahla A, Parvaneh V, Hossein HD. Langerhans cells histiocytosis in one family. Pediatr Hematol Oncol 2004; 21:313.
  14. Bhatia S, Nesbit ME Jr, Egeler RM, et al. Epidemiologic study of Langerhans cell histiocytosis in children. J Pediatr 1997; 130:774.
  15. Pineles SL, Liu GT, Acebes X, et al. Presence of Erdheim-Chester disease and Langerhans cell histiocytosis in the same patient: a report of 2 cases. J Neuroophthalmol 2011; 31:217.
  16. Wang KH, Cheng CJ, Hu CH, Lee WR. Coexistence of localized Langerhans cell histiocytosis and cutaneous Rosai-Dorfman disease. Br J Dermatol 2002; 147:770.
  17. Allen CE, Li L, Peters TL, et al. Cell-specific gene expression in Langerhans cell histiocytosis lesions reveals a distinct profile compared with epidermal Langerhans cells. J Immunol 2010; 184:4557.
  18. Berres ML, Lim KP, Peters T, et al. BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups. J Exp Med 2014; 211:669.
  19. Milne P, Bigley V, Bacon CM, et al. Hematopoietic origin of Langerhans cell histiocytosis and Erdheim-Chester disease in adults. Blood 2017; 130:167.
  20. Durham BH, Roos-Weil D, Baillou C, et al. Functional evidence for derivation of systemic histiocytic neoplasms from hematopoietic stem/progenitor cells. Blood 2017; 130:176.
  21. Badalian-Very G, Vergilio JA, Degar BA, et al. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood 2010; 116:1919.
  22. Haroche J, Charlotte F, Arnaud L, et al. High prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other non-Langerhans cell histiocytoses. Blood 2012; 120:2700.
  23. Chakraborty 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; 124:3007.
  24. Sahm F, Capper D, Preusser M, et al. BRAFV600E mutant protein is expressed in cells of variable maturation in Langerhans cell histiocytosis. Blood 2012; 120:e28.
  25. Satoh T, Smith A, Sarde A, et al. B-RAF mutant alleles associated with Langerhans cell histiocytosis, a granulomatous pediatric disease. PLoS One 2012; 7:e33891.
  26. Brown NA, Furtado LV, Betz BL, et al. High prevalence of somatic MAP2K1 mutations in BRAF V600E-negative Langerhans cell histiocytosis. Blood 2014; 124:1655.
  27. Nelson DS, Quispel W, Badalian-Very G, et al. Somatic activating ARAF mutations in Langerhans cell histiocytosis. Blood 2014; 123:3152.
  28. Berres ML, Allen CE, Merad M. Pathological consequence of misguided dendritic cell differentiation in histiocytic diseases. Adv Immunol 2013; 120:127.
  29. Héritier S, Emile JF, Barkaoui MA, et al. BRAF Mutation Correlates With High-Risk Langerhans Cell Histiocytosis and Increased Resistance to First-Line Therapy. J Clin Oncol 2016; 34:3023.
  30. Tazi A, Moreau J, Bergeron A, et al. Evidence that Langerhans cells in adult pulmonary Langerhans cell histiocytosis are mature dendritic cells: importance of the cytokine microenvironment. J Immunol 1999; 163:3511.
  31. Grois N, Pötschger U, Prosch H, et al. Risk factors for diabetes insipidus in langerhans cell histiocytosis. Pediatr Blood Cancer 2006; 46:228.
  32. Braier J, Latella A, Balancini B, et al. Outcome in children with pulmonary Langerhans cell Histiocytosis. Pediatr Blood Cancer 2004; 43:765.
  33. Odame I, Li P, Lau L, et al. Pulmonary Langerhans cell histiocytosis: a variable disease in childhood. Pediatr Blood Cancer 2006; 47:889.
  34. Slater JM, Swarm OJ. Eosinophilic granuloma of bone. Med Pediatr Oncol 1980; 8:151.
  35. Garg S, Mehta S, Dormans JP. Langerhans cell histiocytosis of the spine in children. Long-term follow-up. J Bone Joint Surg Am 2004; 86-A:1740.
  36. Huang W, Yang X, Cao D, et al. Eosinophilic granuloma of spine in adults: a report of 30 cases and outcome. Acta Neurochir (Wien) 2010; 152:1129.
  37. D'Ambrosio N, Soohoo S, Warshall C, et al. Craniofacial and intracranial manifestations of langerhans cell histiocytosis: report of findings in 100 patients. AJR Am J Roentgenol 2008; 191:589.
  38. Annibali S, Cristalli MP, Solidani M, et al. Langerhans cell histiocytosis: oral/periodontal involvement in adult patients. Oral Dis 2009; 15:596.
  39. Newman B, Hu W, Nigro K, Gilliam AC. Aggressive histiocytic disorders that can involve the skin. J Am Acad Dermatol 2007; 56:302.
  40. Munn S, Chu AC. Langerhans cell histiocytosis of the skin. Hematol Oncol Clin North Am 1998; 12:269.
  41. Kapur P, Erickson C, Rakheja D, et al. Congenital self-healing reticulohistiocytosis (Hashimoto-Pritzker disease): ten-year experience at Dallas Children's Medical Center. J Am Acad Dermatol 2007; 56:290.
  42. Stein SL, Paller AS, Haut PR, Mancini AJ. Langerhans cell histiocytosis presenting in the neonatal period: a retrospective case series. Arch Pediatr Adolesc Med 2001; 155:778.
  43. Minkov M, Prosch H, Steiner M, et al. Langerhans cell histiocytosis in neonates. Pediatr Blood Cancer 2005; 45:802.
  44. Lau L, Krafchik B, Trebo MM, Weitzman S. Cutaneous Langerhans cell histiocytosis in children under one year. Pediatr Blood Cancer 2006; 46:66.
  45. Simko SJ, Garmezy B, Abhyankar H, et al. Differentiating skin-limited and multisystem Langerhans cell histiocytosis. J Pediatr 2014; 165:990.
  46. Hicks J, Flaitz CM. Langerhans cell histiocytosis: current insights in a molecular age with emphasis on clinical oral and maxillofacial pathology practice. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005; 100:S42.
  47. Minkov M, Pötschger U, Grois N, et al. Bone marrow assessment in Langerhans cell histiocytosis. Pediatr Blood Cancer 2007; 49:694.
  48. McClain K, Ramsay NK, Robison L, et al. Bone marrow involvement in histiocytosis X. Med Pediatr Oncol 1983; 11:167.
  49. Braier JL, Rosso D, Latella A, et al. Importance of multi-lineage hematologic involvement and hypoalbuminemia at diagnosis in patients with "risk-organ" multi-system Langerhans cell histiocytosis. J Pediatr Hematol Oncol 2010; 32:e122.
  50. Kaplan KJ, Goodman ZD, Ishak KG. Liver involvement in Langerhans' cell histiocytosis: a study of nine cases. Mod Pathol 1999; 12:370.
  51. König CW, Pfannenberg C, Trübenbach J, et al. MR cholangiography in the diagnosis of sclerosing cholangitis in Langerhans' cell histiocytosis. Eur Radiol 2001; 11:2516.
  52. Haas S, Theuerkauf I, Kühnen A, et al. [Langerhans' cell histiocytosis of the liver. Differential diagnosis of a rare chronic destructive sclerosing cholangitis]. Pathologe 2003; 24:119.
  53. Braier J, Ciocca M, Latella A, et al. Cholestasis, sclerosing cholangitis, and liver transplantation in Langerhans cell Histiocytosis. Med Pediatr Oncol 2002; 38:178.
  54. Prasad SR, Wang H, Rosas H, et al. Fat-containing lesions of the liver: radiologic-pathologic correlation. Radiographics 2005; 25:321.
  55. Wong A, Ortiz-Neira CL, Reslan WA, et al. Liver involvement in Langerhans cell histiocytosis. Pediatr Radiol 2006; 36:1105.
  56. Nondahl SR, Finlay JL, Farrell PM, et al. A case report and literature review of "primary" pulmonary histiocytosis X of childhood. Med Pediatr Oncol 1986; 14:57.
  57. Grois NG, Favara BE, Mostbeck GH, Prayer D. Central nervous system disease in Langerhans cell histiocytosis. Hematol Oncol Clin North Am 1998; 12:287.
  58. Grois N, Fahrner B, Arceci RJ, et al. Central nervous system disease in Langerhans cell histiocytosis. J Pediatr 2010; 156:873.
  59. Prosch H, Grois N, Prayer D, et al. Central diabetes insipidus as presenting symptom of Langerhans cell histiocytosis. Pediatr Blood Cancer 2004; 43:594.
  60. Wnorowski M, Prosch H, Prayer D, et al. Pattern and course of neurodegeneration in Langerhans cell histiocytosis. J Pediatr 2008; 153:127.
  61. Mittheisz E, Seidl R, Prayer D, et al. Central nervous system-related permanent consequences in patients with Langerhans cell histiocytosis. Pediatr Blood Cancer 2007; 48:50.
  62. van der Knaap MS, Arts WF, Garbern JY, et al. Cerebellar leukoencephalopathy: most likely histiocytosis-related. Neurology 2008; 71:1361.
  63. Prayer D, Grois N, Prosch H, et al. MR imaging presentation of intracranial disease associated with Langerhans cell histiocytosis. AJNR Am J Neuroradiol 2004; 25:880.
  64. Fahrner B, Prosch H, Minkov M, et al. Long-term outcome of hypothalamic pituitary tumors in Langerhans cell histiocytosis. Pediatr Blood Cancer 2012; 58:606.
  65. Laurencikas E, Gavhed D, Stålemark H, et al. Incidence and pattern of radiological central nervous system Langerhans cell histiocytosis in children: a population based study. Pediatr Blood Cancer 2011; 56:250.
  66. Grois N, Prosch H, Waldhauser F, et al. Pineal gland abnormalities in Langerhans cell histiocytosis. Pediatr Blood Cancer 2004; 43:261.
  67. García Gallo MS, Martínez MP, Abalovich MS, et al. Endocrine manifestations of Langerhans cell histiocytosis diagnosed in adults. Pituitary 2010; 13:298.
  68. Donadieu J, Rolon MA, Thomas C, et al. Endocrine involvement in pediatric-onset Langerhans' cell histiocytosis: a population-based study. J Pediatr 2004; 144:344.
  69. Maghnie M, Cosi G, Genovese E, et al. Central diabetes insipidus in children and young adults. N Engl J Med 2000; 343:998.
  70. Gadner H, Minkov M, Grois N, et al. Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis. Blood 2013; 121:5006.
  71. Maghnie M, Bossi G, Klersy C, et al. Dynamic endocrine testing and magnetic resonance imaging in the long-term follow-up of childhood langerhans cell histiocytosis. J Clin Endocrinol Metab 1998; 83:3089.
  72. Kaltsas GA, Powles TB, Evanson J, et al. Hypothalamo-pituitary abnormalities in adult patients with langerhans cell histiocytosis: clinical, endocrinological, and radiological features and response to treatment. J Clin Endocrinol Metab 2000; 85:1370.
  73. Grois N, Prayer D, Prosch H, et al. Course and clinical impact of magnetic resonance imaging findings in diabetes insipidus associated with Langerhans cell histiocytosis. Pediatr Blood Cancer 2004; 43:59.
  74. Robison NJ, Prabhu SP, Sun P, et al. Predictors of neoplastic disease in children with isolated pituitary stalk thickening. Pediatr Blood Cancer 2013; 60:1630.
  75. Geissmann F, Thomas C, Emile JF, et al. Digestive tract involvement in Langerhans cell histiocytosis. The French Langerhans Cell Histiocytosis Study Group. J Pediatr 1996; 129:836.
  76. Hait E, Liang M, Degar B, et al. Gastrointestinal tract involvement in Langerhans cell histiocytosis: case report and literature review. Pediatrics 2006; 118:e1593.
  77. Singhi AD, Montgomery EA. Gastrointestinal tract langerhans cell histiocytosis: A clinicopathologic study of 12 patients. Am J Surg Pathol 2011; 35:305.
  78. De Young B, Egeler RM, Rollins BJ. Langerhans cell histiocytosis. In: WHO Classification of Tumours of Soft Tissue and Bone, 4th ed, Fletcher CD, Bridge JA, Hogendoorn PC, Mertens F (Eds), International Agency for Research on Cancer, Lyons 2013. p.356.
  79. Gatalica Z, Bilalovic N, Palazzo JP, et al. Disseminated histiocytoses biomarkers beyond BRAFV600E: frequent expression of PD-L1. Oncotarget 2015; 6:19819.
  80. Grois N, Prayer D, Prosch H, et al. Neuropathology of CNS disease in Langerhans cell histiocytosis. Brain 2005; 128:829.
  81. Surico G, Muggeo P, Rigillo N, Gadner H. Concurrent Langerhans cell histiocytosis and myelodysplasia in children. Med Pediatr Oncol 2000; 35:421.
  82. Favara BE, Jaffe R, Egeler RM. Macrophage activation and hemophagocytic syndrome in langerhans cell histiocytosis: report of 30 cases. Pediatr Dev Pathol 2002; 5:130.
  83. Allen CE, Ladisch S, McClain KL. How I treat Langerhans cell histiocytosis. Blood 2015; 126:26.
  84. Hervier B, Haroche J, Arnaud L, et al. Association of both Langerhans cell histiocytosis and Erdheim-Chester disease linked to the BRAFV600E mutation. Blood 2014; 124:1119.
  85. Foucar E, Rosai J, Dorfman R. Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): review of the entity. Semin Diagn Pathol 1990; 7:19.
  86. Pulsoni A, Anghel G, Falcucci P, et al. Treatment of sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): report of a case and literature review. Am J Hematol 2002; 69:67.
  87. Utikal J, Ugurel S, Kurzen H, et al. Imatinib as a treatment option for systemic non-Langerhans cell histiocytoses. Arch Dermatol 2007; 143:736.
  88. Frater JL, Maddox JS, Obadiah JM, Hurley MY. Cutaneous Rosai-Dorfman disease: comprehensive review of cases reported in the medical literature since 1990 and presentation of an illustrative case. J Cutan Med Surg 2006; 10:281.
  89. Wang KH, Chen WY, Liu HN, et al. Cutaneous Rosai-Dorfman disease: clinicopathological profiles, spectrum and evolution of 21 lesions in six patients. Br J Dermatol 2006; 154:277.