Skeletal Radiology

, Volume 36, Issue 2, pp 95–104 | Cite as

Langerhans cell histiocytosis

  • Kevin Bradford HooverEmail author
  • Daniel I. Rosenthal
  • Henry Mankin
Review Article


Langerhans cell histiocytosis (LCH) is a complex disease entity comprised of three distinct clinical syndromes that demonstrate indistinguishable histology. These syndromes are: eosinophilic granuloma, which is predominantly osseous or pulmonary; Hand-Schûller-Christian’s disease, which involves multiple organ systems and, most typically, the skull base; and Letterer-Siwe’s disease, the most severe disease manifestation, which typically involves the abdominal viscera. This article reviews our current understanding of Langerhans cell histiocytosis by discussing the history, histology, etiology, and treatment of the disease. It focuses on the radiographic findings and imaging modalities that are the most useful in disease diagnosis and management.


Langerhans cell histiocytosis Hand-Schûller-Christian’s disease Letterer-Siwe’s disease Eosinophilic granuloma Radiography MRI 


  1. 1.
    Coppes-Zantinga A, Egeler RM. The Langerhans cell histiocytosis X files revealed. Br J Haematol 2002;116(1):3–9.PubMedCrossRefGoogle Scholar
  2. 2.
    Komp DM. Historical perspectives of Langerhans cell histiocytosis. Hematol Oncol Clin North Am 1987;1(1):9–21.PubMedGoogle Scholar
  3. 3.
    Smith T. Skull cap showing congenital deficiency of bone. Trans Path Soc London 1865;16:224–5.Google Scholar
  4. 4.
    Langerhans P. Uber die Nerven der menschlichen Haut. Arch Pathol Anat 1868;44:325–37.CrossRefGoogle Scholar
  5. 5.
    Hand A. Polyuria and tuberculosis. Arch Pediatr 1893;10:673–75.Google Scholar
  6. 6.
    Hand A. Defects of membranous bones, exophthalmos, and polyuria in childhood: is it dyspitutitarism? Am J Med Sci 1921;162:509–15.CrossRefGoogle Scholar
  7. 7.
    Schüller A. Uber eigenartige schadeldefekte im jugendalter. Fortsch Gebiete Roentgenstrahlen 1915;23:12–8.Google Scholar
  8. 8.
    Christian HA. Defects in membranous bones, exophthalmos and diabetes insipidus: an unusual syndrome of dyspituitarism. Med Clin N Amer 1920;3:849–71.Google Scholar
  9. 9.
    Letterer E. Aleukamische retikulose (ein Beitrag zu den proliferativen Erkrankungen des Retikuloendothelialapparates). Frankfurt Zeitsch Pathol 1924;30:377–94.Google Scholar
  10. 10.
    Siwe S. Die reticuloendotheliose—ein neues krankheitsbild unter den hepatosplenomegalien. Zeitsch Kinderheilkunde 1933;55:212–47.CrossRefGoogle Scholar
  11. 11.
    Abt A, Denenholz E. Letterer-Siwe’s disease: splenohepatomegaly, associated with widespread hyperplasia of non-lipoid-storing macrophages; discussion of the so-called reticulo-endotheliosis. Am J Dis Child 1936;51:499–22.Google Scholar
  12. 12.
    Otani S, Ehrlich J. Solitary granuloma of bone simulating primary neoplasm. Amer J Pathol 1940;16:479–90.Google Scholar
  13. 13.
    Lichtenstein L, Jaffe HL. Eosinophilic granuloma of bone. With report of a case. Amer J Pathol 1940;16:595–604.Google Scholar
  14. 14.
    Farber S. The nature of “Solitary or Eosinophilic Granuloma” of bone. Am J Pathol 1941;17:625–9.Google Scholar
  15. 15.
    Green WT, Farber S. Eosinophilic or solitary granuloma of bone. J Bone Jt Surg 1942;24:499–526.Google Scholar
  16. 16.
    Jaffe HL, Lichtenstein L. Eosinophilic granuloma of bone. A condition affecting one, several or many bones but apparently limited to the skeleton, and representing the mildest clinical expression of the peculiar inflammatory histiocytosis also underlying Letterer-Siwe disease and Schuller-Christian disease. Arch Pathol 1944;37:99–118.Google Scholar
  17. 17.
    Lichtenstein L. Histiocytosis X: integration of eosinophilic granuloma of bone, Letterer-Siwe disease, and Schuller-Christian disease as related manifestations of a single nosologic entity. Amer Med Assoc Arch Pathol 1953;56(1):84–102.Google Scholar
  18. 18.
    Friedman B, Hanaoka H. Langerhans cell granules in eosinophilic granuloma of bone. J Bone Jt Surg Am 1969;51(2):367–74.Google Scholar
  19. 19.
    Nezelof C, Basset F, Rousseau MF. Histiocytosis X histogenetic arguments for a Langerhans cell origin. Biomedicine 1973;18(5):365–71.PubMedGoogle Scholar
  20. 20.
    Arico M, Girschikofsky M, Genereau T, Klersy C, McClain K, Grois N, et al. Langerhans cell histiocytosis in adults. Report from the International Registry of the Histiocyte Society. Eur J Cancer 2003;39(16):2341–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Broadbent V, Gadner H, Komp DM, Ladisch S. Histiocytosis syndromes in children: II. Approach to the clinical and laboratory evaluation of children with Langerhans cell histiocytosis. Clinical Writing Group of the Histiocyte Society. Med Pediatr Oncol 1989;17(6):492–5.PubMedGoogle Scholar
  22. 22.
    Campanacci M. Bone and soft tissue tumors, 2nd edn. Springer, Berlin Heidelberg New York, 1999.pp. 857–76.Google Scholar
  23. 23.
    Chu T, D’Angio GJ, Favara BE, Ladisch S, Nesbit M, Pritchard J. Histiocytosis syndromes in children. Lancet 1987;2(8549):41–2.PubMedCrossRefGoogle Scholar
  24. 24.
    Dorfman HD, Czerniak B. Bone tumors. Mosby, St. Louis, Missouri, 1997. pp. 690–701.Google Scholar
  25. 25.
    Egeler RM, D’Angio GJ. Langerhans cell histiocytosis. J Pediatr 1995;127(1):1–11.PubMedCrossRefGoogle Scholar
  26. 26.
    Egeler RM, Favara BE, Laman JD, Claassen E. Abundant expression of CD40 and CD40-ligand (CD154) in paediatric Langerhans cell histiocytosis lesions. Eur J Cancer 2000;36(16):2105–10.PubMedCrossRefGoogle Scholar
  27. 27.
    Jenson HB, McClain KL, Leach CT, Deng JH, Gao SJ. Evaluation of human herpesvirus type 8 infection in childhood langerhans cell histiocytosis. Am J Hematol 2000;64(4):237–41.PubMedCrossRefGoogle Scholar
  28. 28.
    Jordan 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;44(3):251–4.PubMedCrossRefGoogle Scholar
  29. 29.
    Leahy MA, Krejci SM, Friednash M, Stockert SS, Wilson H, Huff JC, et al. Human herpesvirus 6 is present in lesions of Langerhans cell histiocytosis. J Invest Dermatol 1993;101(5):642–5.PubMedCrossRefGoogle Scholar
  30. 30.
    McClain K, Jin H, Gresik V, Favara B. Langerhans cell histiocytosis: lack of a viral etiology. Am J Hematol 1994;47(1):16–20.PubMedGoogle Scholar
  31. 31.
    McClain K, Ramsay NK, Robison L, Sundberg RD, Nesbit M Jr. Bone marrow involvement in histiocytosis X. Med Pediatr Oncol 1983;11(3):167–71.PubMedGoogle Scholar
  32. 32.
    Scappaticci S, Danesino C, Rossi E, Klersy C, Fiori GM, Clementi R, et al. Cytogenetic abnormalities in PHA-stimulated lymphocytes from patients with Langerhans cell histocytosis. AIEOP-Istiocitosi Group. Br J Haematol 2000;111(1):258–62.PubMedCrossRefGoogle Scholar
  33. 33.
    Willman CL, Busque L, Griffith BB, Favara BE, McClain KL, Duncan MH, et al. Langerhans’-cell histiocytosis (histiocytosis X)—a clonal proliferative disease. N Engl J Med 1994;331(3):154–60.PubMedCrossRefGoogle Scholar
  34. 34.
    Willman CL, McClain KL. An update on clonality, cytokines, and viral etiology in Langerhans cell histiocytosis. Hematol Oncol Clin North Am 1998;12(2):407–16.PubMedCrossRefGoogle Scholar
  35. 35.
    Dreyer ZE, Dowell BL, Chen H, Hawkins E, McClain KL. Infection-associated hemophagocytic syndrome. Evidence for Epstein-Barr virus gene expression. Am J Pediatr Hematol Oncol 1991;13(4):476–81.PubMedCrossRefGoogle Scholar
  36. 36.
    Betts DR, Leibundgut KE, Feldges A, Pluss HJ, Niggli FK. Cytogenetic abnormalities in Langerhans cell histiocytosis. Br J Cancer 1998;77(4):552–5.PubMedGoogle Scholar
  37. 37.
    Shahla A, Parvaneh V, Hossein HD. Langerhans cells histiocytosis in one family. Pediatr Hematol Oncol 2004;21(4):313–20.PubMedCrossRefGoogle Scholar
  38. 38.
    Jaffe HL. Metabolic, degenerative and inflammatory diseases of bones and joints. Lea and Febiger, Philadelphia, Pennsylvania, 1972. pp. 875–906.Google Scholar
  39. 39.
    Birbeck M, Breathnack A, Everall J. An electron microscope study of basal melanocytes and high-level clear cells (Langerhans cells) in vitiligo. J Invest Dermatology 1961;37:51–63.CrossRefGoogle Scholar
  40. 40.
    Bank MI, Rengtved P, Carstensen H, Petersen BL. p53 expression in biopsies from children with Langerhans cell histiocytosis. J Pediatr Hematol Oncol 2002;24(9):733–6.PubMedCrossRefGoogle Scholar
  41. 41.
    Ghanem I, Tolo VT, D’Ambra P, Malogalowkin MH. Langerhans cell histiocytosis of bone in children and adolescents. J Pediatr Orthop 2003;23(1):124–30.PubMedCrossRefGoogle Scholar
  42. 42.
    Kilpatrick SE, Wenger DE, Gilchrist GS, Shives TC, Wollan PC, Unni KK. Langerhans’ cell histiocytosis (histiocytosis X) of bone. A clinicopathologic analysis of 263 pediatric and adult cases. Cancer 1995;76(12):2471–84.PubMedCrossRefGoogle Scholar
  43. 43.
    Stull MA, Kransdorf MJ, Devaney KO. Langerhans cell histiocytosis of bone. Radiographics 1992;12(4):801–23.PubMedGoogle Scholar
  44. 44.
    David R, Oria RA, Kumar R, Singleton EB, Lindell MM, Shirkhoda A, et al. Radiologic features of eosinophilic granuloma of bone. AJR Am J Roentgenol 1989;153(3):1021–6.PubMedGoogle Scholar
  45. 45.
    Kilborn TN, Teh J, Goodman TR. Paediatric manifestations of Langerhans cell histiocytosis: a review of the clinical and radiological findings. Clin Radiol 2003;58(4):269–78.PubMedCrossRefGoogle Scholar
  46. 46.
    Ha SY, Helms P, Fletcher M, Broadbent V, Pritchard J. Lung involvement in Langerhans’ cell histiocytosis: prevalence, clinical features, and outcome. Pediatrics 1992;89(3):466–9.PubMedGoogle Scholar
  47. 47.
    Smets A, Mortele K, de Praeter G, Francois O, Benoit Y, Kunnen M. Pulmonary and mediastinal lesions in children with Langerhans cell histiocytosis. Pediatr Radiol 1997;27(11):873–6.PubMedCrossRefGoogle Scholar
  48. 48.
    Van Nieuwenhuyse JP, Clapuyt P, Malghem J, Everarts P, Melin J, Pauwels S, et al. Radiographic skeletal survey and radionuclide bone scan in Langerhans cell histiocytosis of bone. Pediatr Radiol 1996;26(10):734–8.PubMedCrossRefGoogle Scholar
  49. 49.
    Crone-Munzebrock W, Brassow F. A comparison of radiographic and bone scan findings in histiocytosis X. Skeletal Radiol 1983;9(3):170–3.PubMedCrossRefGoogle Scholar
  50. 50.
    Dogan AS, Conway JJ, Miller JH, Grier D, Bhattathiry MM, Mitchell CS. Detection of bone lesions in Langerhans cell histiocytosis: complementary roles of scintigraphy and conventional radiography. J Pediatr Hematol Oncol 1996;18(1):51–8.PubMedCrossRefGoogle Scholar
  51. 51.
    Howarth DM, Mullan BP, Wiseman GA, Wenger DE, Forstrom LA, Dunn WL. Bone scintigraphy evaluated in diagnosing and staging Langerhans’ cell histiocytosis and related disorders. J Nucl Med 1996;37(9):1456–60.PubMedGoogle Scholar
  52. 52.
    Azouz EM, Saigal G, Rodriguez MM, Podda A. Langerhans’ cell histiocytosis: pathology, imaging and treatment of skeletal involvement. Pediatr Radiol 2005;35(2):103–15.PubMedCrossRefGoogle Scholar
  53. 53.
    Schmidt GP, Schoenberg SO, Reiser MF, Baur-Melnyk A. Whole-body MR imaging of bone marrow. Eur J Radiol 2005;55(1):33–40.PubMedCrossRefGoogle Scholar
  54. 54.
    Kellenberger CJ, Epelman M, Miller SF, Babyn PS. Fast STIR whole-body MR imaging in children. Radiographics 2004;24(5):1317–30.PubMedGoogle Scholar
  55. 55.
    Binkovitz LA, Olshefski RS, Adler BH. Coincidence FDG-PET in the evaluation of Langerhans’ cell histiocytosis: preliminary findings. Pediatr Radiol 2003;33(9):598–02.PubMedCrossRefGoogle Scholar
  56. 56.
    Blum R, Seymour JF, Hicks RJ. Role of 18FDG-positron emission tomography scanning in the management of histiocytosis. Leuk Lymphoma 2002;43(11):2155–7.PubMedCrossRefGoogle Scholar
  57. 57.
    Dunger DB, Broadbent V, Yeoman E, Seckl JR, Lightman SL, Grant DB, et al. The frequency and natural history of diabetes insipidus in children with Langerhans-cell histiocytosis. N Engl J Med 1989;321(17):1157–62.PubMedCrossRefGoogle Scholar
  58. 58.
    Gotz G, Fichter J. Langerhans’-cell histiocytosis in 58 adults. Eur J Med Res 2004;9(11):510–14.PubMedGoogle Scholar
  59. 59.
    Donadieu J, Rolon MA, Pion I, Thomas C, Doz F, Barkaoui M, et al. Incidence of growth hormone deficiency in pediatric-onset Langerhans cell histiocytosis: efficacy and safety of growth hormone treatment. J Clin Endocrinol Metab 2004;89(2):604–9.PubMedCrossRefGoogle Scholar
  60. 60.
    Maghnie M, Cosi G, Genovese E, Manca-Bitti ML, Cohen A, Zecca S, et al. Central diabetes insipidus in children and young adults. N Engl J Med 2000;343(14):998–1007.PubMedCrossRefGoogle Scholar
  61. 61.
    Eckardt A, Schultze A. Maxillofacial manifestations of Langerhans cell histiocytosis: a clinical and therapeutic analysis of 10 patients. Oral Oncol 2003;39(7):687–94.PubMedCrossRefGoogle Scholar
  62. 62.
    Kusumakumary P, James FV. Permanent disabilities in childhood survivors of Langerhans cell histiocytosis. Pediatr Hematol Oncol 2000;17(5):375–81.PubMedCrossRefGoogle Scholar
  63. 63.
    Imashuku S, Ishida S, Koike K, Ichikawa M, Minato T, Suzuki Y, et al. Cerebellar ataxia in pediatric patients with Langerhans cell histiocytosis. J Pediatr Hematol Oncol 2004;26(11):735–9.PubMedCrossRefGoogle Scholar
  64. 64.
    Calming U, Bemstrand C, Mosskin M, Elander SS, Ingvar M, Henter JI. Brain 18-FDG PET scan in central nervous system langerhans cell histiocytosis. J Pediatr 2002;141(3):435–40.PubMedCrossRefGoogle Scholar
  65. 65.
    Caldwell SH, Brantley K, Dent J, Keeley RC, Pruett T, Angle JF, et al. The hepatopulmonary syndrome masquerading as pulmonary Langerhans-cell histiocytosis. Hepatopulmonary Syndrome Study Group. Ann Intern Med 1994;121(1):34–6.PubMedGoogle Scholar
  66. 66.
    Roberts EA. Primary sclerosing cholangitis in children. J Gastroenterol Hepatol 1999;14(6):588–93.PubMedCrossRefGoogle Scholar
  67. 67.
    Capanna R, Springfield DS, Ruggieri P, Biagini R, Picci P, Bacci G, et al. Direct cortisone injection in eosinophilic granuloma of bone: a preliminary report on 11 patients. J Pediatr Orthop 1985;5(3):339–42.PubMedGoogle Scholar
  68. 68.
    Cohen M, Zornoza J, Cangir A, Murray JA, Wallace S. Direct injection of methylprednisolone sodium succinate in the treatment of solitary eosinophilic granuloma of bone: a report of 9 cases. Radiology 1980;136(2):289–93.PubMedGoogle Scholar
  69. 69.
    Bavbek M, Atalay B, Altinors N, Caner H. Spontaneous resolution of lumbar vertebral eosinophilic granuloma. Acta Neurochir (Wien) 2004;146(6):165–7.CrossRefGoogle Scholar
  70. 70.
    Nesbit ME, Kieffer S, D’Angio GJ. Reconstitution of vertebral height in histiocytosis X: a long-term follow-up. J Bone Jt Surg Am 1969;51(7):1360–8.Google Scholar
  71. 71.
    Steen AE, Steen KH, Bauer R, Bieber T. Successful treatment of cutaneous Langerhans cell histiocytosis with low-dose methotrexate. Br J Dermatol 2001;145(1):137–40.PubMedCrossRefGoogle Scholar
  72. 72.
    Culic S, Jakobson A, Culic V, Kuzmic I, Scukanec-Spoljar M, Primorac D. Etoposide as the basic and interferon-alpha as the maintenance therapy for Langerhans cell histiocytosis: a RTC. Pediatr Hematol Oncol 2001;18(4):291–4.PubMedCrossRefGoogle Scholar
  73. 73.
    Ladisch S, Gadner H, Arico M, Broadbent V, Grois N, Jacobson A, et al. LCH-I: a randomized trial of etoposide vs. vinblastine in disseminated Langerhans cell histiocytosis. The Histiocyte Society. Med Pediatr Oncol 1994;23(2):107–10.PubMedGoogle Scholar
  74. 74.
    Goh NS, McDonald CE, MacGregor DP, Pretto JJ, Brodie GN. Successful treatment of Langerhans cell histiocytosis with 2-chlorodeoxyadenosine. Respirology 2003;8(1):91–4.PubMedCrossRefGoogle Scholar
  75. 75.
    Ottaviano F, Finlay JL. Diabetes insipidus and Langerhans cell histiocytosis: a case report of reversibility with 2-chlorodeoxyadenosine. J Pediatr Hematol Oncol 2003;25(7):575–7.PubMedCrossRefGoogle Scholar
  76. 76.
    Pardanani A, Phyliky RL, Li CY, Tefferi A. 2-Chlorodeoxyadenosine therapy for disseminated Langerhans cell histiocytosis. Mayo Clin Proc 2003;78(3):301–6.PubMedCrossRefGoogle Scholar
  77. 77.
    Rodriguez-Galindo C, Kelly P, Jeng M, Presbury GG, Rieman M, Wang W. Treatment of children with Langerhans cell histiocytosis with 2-chlorodeoxyadenosine. Am J Hematol 2002;69(3):179–84.PubMedCrossRefGoogle Scholar
  78. 78.
    Stine KC, Saylors RL, Saccente S, McClain KL, Becton DL. Efficacy of continuous infusion 2-CDA (cladribine) in pediatric patients with Langerhans cell histiocytosis. Pediatr Blood Cancer 2004;43(1):81–4.PubMedCrossRefGoogle Scholar
  79. 79.
    Nagarajan R, Neglia J, Ramsay N, Baker KS. Successful treatment of refractory Langerhans cell histiocytosis with unrelated cord blood transplantation. J Pediatr Hematol Oncol 2001;23(9):629–32.PubMedCrossRefGoogle Scholar
  80. 80.
    Farran RP, Zaretski E, Egeler RM. Treatment of Langerhans cell histiocytosis with pamidronate. J Pediatr Hematol Oncol 2001;23(1):54–6.PubMedCrossRefGoogle Scholar
  81. 81.
    Sander CS, Kaatz M, Elsner P. Successful treatment of cutaneous 3langerhans cell histiocytosis with thalidomide. Dermatology 2004;208(2):149–52.PubMedCrossRefGoogle Scholar

Copyright information

© ISS 2006

Authors and Affiliations

  • Kevin Bradford Hoover
    • 1
    Email author
  • Daniel I. Rosenthal
    • 2
  • Henry Mankin
    • 3
  1. 1.Musculoskeletal RadiologyMassachusetts General HospitalBostonUSA
  2. 2.Massachusetts General HospitalHarvard Medical SchoolBostonUSA
  3. 3.OrthopedicsMassachusetts General HospitalBostonUSA

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