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Pulmonary Langerhans cell histiocytosis

Talmadge E King, Jr, MD
Section Editor
Kevin R Flaherty, MD, MS
Deputy Editor
Helen Hollingsworth, MD


Pulmonary Langerhans cell histiocytosis (PLCH), also called eosinophilic granuloma of the lung, pulmonary Langerhans cell granulomatosis, and pulmonary histiocytosis X, is an uncommon interstitial lung disease that primarily affects young adults [1-7]. The true incidence and prevalence are unknown. However, the diagnosis is made in less than 5 percent of lung biopsies and has been seen in less than 2 percent of the patients presenting to the Denver Specialized Center of Research program in Interstitial Lung Disease (a total of approximately 3000 patients over 14 years). No occupational or geographic predisposition has been reported, but nearly all affected individuals have a history of current or prior cigarette smoking. Thus, tobacco smoke is thought to be an etiologic factor.

Pulmonary Langerhans cell histiocytosis will be reviewed here. A general review of Langerhans cell histiocytosis, including the extrapulmonary manifestations of this disorder, is presented separately. (See "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis".)


The Langerhans cell, a differentiated cell of the monocyte-macrophage line, is the pathologic cell type of pulmonary Langerhans cell histiocytosis. It is distinguished by pale staining cytoplasm, a large nucleus and nucleoli, and, on electron microscopy, by classic pentalaminar cytoplasmic inclusions or Birbeck granules (X-bodies (picture 1)). Langerhans cells also demonstrate positive immunohistochemical staining for S100 protein. Another characteristic is the strong presence of CD1 antigen (CD1a) on the cell surface, a feature not observed in other cells of histiocytic origin [2].

Langerhans cells are normally found in the dermis, the reticuloendothelial system, the lung, and the pleura. They can be found in association with cigarette smoking in otherwise healthy individuals and can also be seen in other pulmonary disorders, such as idiopathic pulmonary fibrosis [8,9]. (See "Pathogenesis of idiopathic pulmonary fibrosis".)

In pulmonary Langerhans cell histiocytosis, the Langerhans cells are characteristically found in clusters and significantly outnumber those seen in other lung diseases. However, quantitative guidelines for the diagnosis of pulmonary Langerhans cell histiocytosis have not been established.

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Literature review current through: Oct 2017. | This topic last updated: Aug 25, 2017.
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  1. Tazi A, Soler P, Hance AJ. Adult pulmonary Langerhans' cell histiocytosis. Thorax 2000; 55:405.
  2. Vassallo R, Ryu JH, Colby TV, et al. Pulmonary Langerhans'-cell histiocytosis. N Engl J Med 2000; 342:1969.
  3. Vassallo R, Ryu JH. Pulmonary Langerhans' cell histiocytosis. Clin Chest Med 2004; 25:561.
  4. Sundar KM, Gosselin MV, Chung HL, Cahill BC. Pulmonary Langerhans cell histiocytosis: emerging concepts in pathobiology, radiology, and clinical evolution of disease. Chest 2003; 123:1673.
  5. Tazi A. Adult pulmonary Langerhans' cell histiocytosis. Eur Respir J 2006; 27:1272.
  6. Wei P, Lu HW, Jiang S, et al. Pulmonary langerhans cell histiocytosis: case series and literature review. Medicine (Baltimore) 2014; 93:e141.
  7. Elia D, Torre O, Cassandro R, et al. Pulmonary Langerhans cell histiocytosis: a comprehensive analysis of 40 patients and literature review. Eur J Intern Med 2015; 26:351.
  8. Casolaro MA, Bernaudin JF, Saltini C, et al. Accumulation of Langerhans' cells on the epithelial surface of the lower respiratory tract in normal subjects in association with cigarette smoking. Am Rev Respir Dis 1988; 137:406.
  9. Soler P, Moreau A, Basset F, Hance AJ. Cigarette smoking-induced changes in the number and differentiated state of pulmonary dendritic cells/Langerhans cells. Am Rev Respir Dis 1989; 139:1112.
  10. Basset F, Corrin B, Spencer H, et al. Pulmonary histiocytosis X. Am Rev Respir Dis 1978; 118:811.
  11. Travis WD, Borok Z, Roum JH, et al. Pulmonary Langerhans cell granulomatosis (histiocytosis X). A clinicopathologic study of 48 cases. Am J Surg Pathol 1993; 17:971.
  12. Vassallo R, Jensen EA, Colby TV, et al. The overlap between respiratory bronchiolitis and desquamative interstitial pneumonia in pulmonary Langerhans cell histiocytosis: high-resolution CT, histologic, and functional correlations. Chest 2003; 124:1199.
  13. Fukuda Y, Basset F, Soler P, et al. Intraluminal fibrosis and elastic fiber degradation lead to lung remodeling in pulmonary Langerhans cell granulomatosis (histiocytosis X). Am J Pathol 1990; 137:415.
  14. Vassallo R, Limper AH. Pulmonary Langerhans cell histiocytosis. In: Interstitial Lung Disease, 4th ed, King TE Jr, Schwarz MI (Eds), B.C. Decker, Hamilton, ON, Canada 2003. p.838.
  15. Rowden G. The Langerhans cell. Crit Rev Immunol 1981; 3:95.
  16. King TE Jr, Schwarz MI, Dreisin RE, et al. Circulating immune complexes in pulmonary eosinophilic granuloma. Ann Intern Med 1979; 91:397.
  17. Schönfeld N, Dirks K, Costabel U, et al. A prospective clinical multicentre study on adult pulmonary Langerhans' cell histiocytosis. Sarcoidosis Vasc Diffuse Lung Dis 2012; 29:132.
  18. Aguayo SM, King TE Jr, Waldron JA Jr, et al. Increased pulmonary neuroendocrine cells with bombesin-like immunoreactivity in adult patients with eosinophilic granuloma. J Clin Invest 1990; 86:838.
  19. Aguayo SM, Kane MA, King TE Jr, et al. Increased levels of bombesin-like peptides in the lower respiratory tract of asymptomatic cigarette smokers. J Clin Invest 1989; 84:1105.
  20. Petronilho F, Roesler R, Schwartsmann G, Dal Pizzol F. Gastrin-releasing peptide receptor as a molecular target for inflammatory diseases. Inflamm Allergy Drug Targets 2007; 6:197.
  21. Youkeles LH, Grizzanti JN, Liao Z, et al. Decreased tobacco-glycoprotein-induced lymphocyte proliferation in vitro in pulmonary eosinophilic granuloma. Am J Respir Crit Care Med 1995; 151:145.
  22. Yousem SA, Colby TV, Chen YY, et al. Pulmonary Langerhans' cell histiocytosis: molecular analysis of clonality. Am J Surg Pathol 2001; 25:630.
  23. Yousem SA, Dacic S, Nikiforov YE, Nikiforova M. Pulmonary Langerhans cell histiocytosis: profiling of multifocal tumors using next-generation sequencing identifies concordant occurrence of BRAF V600E mutations. Chest 2013; 143:1679.
  24. Roden AC, Hu X, Kip S, et al. BRAF V600E expression in Langerhans cell histiocytosis: clinical and immunohistochemical study on 25 pulmonary and 54 extrapulmonary cases. Am J Surg Pathol 2014; 38:548.
  25. Vassallo R, Ryu JH, Schroeder DR, et al. Clinical outcomes of pulmonary Langerhans'-cell histiocytosis in adults. N Engl J Med 2002; 346:484.
  26. Götz G, Fichter J. Langerhans'-cell histiocytosis in 58 adults. Eur J Med Res 2004; 9:510.
  27. Mason RH, Foley NM, Branley HM, et al. Pulmonary Langerhans cell histiocytosis (PLCH): a new UK register. Thorax 2014; 69:766.
  28. Marcy TW, Reynolds HY. Pulmonary histiocytosis X. Lung 1985; 163:129.
  29. Crausman RS, Jennings CA, Tuder RM, et al. Pulmonary histiocytosis X: pulmonary function and exercise pathophysiology. Am J Respir Crit Care Med 1996; 153:426.
  30. Le Pavec J, Lorillon G, Jaïs X, et al. Pulmonary Langerhans cell histiocytosis-associated pulmonary hypertension: clinical characteristics and impact of pulmonary arterial hypertension therapies. Chest 2012; 142:1150.
  31. Tazi A, de Margerie C, Naccache JM, et al. The natural history of adult pulmonary Langerhans cell histiocytosis: a prospective multicentre study. Orphanet J Rare Dis 2015; 10:30.
  32. Epler GR, Carrington CB, Gaensler EA. Crackles (rales) in the interstitial pulmonary diseases. Chest 1978; 73:333.
  33. Mendez JL, Nadrous HF, Vassallo R, et al. Pneumothorax in pulmonary Langerhans cell histiocytosis. Chest 2004; 125:1028.
  34. Fartoukh M, Humbert M, Capron F, et al. Severe pulmonary hypertension in histiocytosis X. Am J Respir Crit Care Med 2000; 161:216.
  35. Chaowalit N, Pellikka PA, Decker PA, et al. Echocardiographic and clinical characteristics of pulmonary hypertension complicating pulmonary Langerhans cell histiocytosis. Mayo Clin Proc 2004; 79:1269.
  36. Knight RK. Haemoptysis in eosinophilic granuloma. Br J Dis Chest 1979; 73:181.
  37. Lombard CM, Medeiros LJ, Colby TV. Pulmonary histiocytosis X and carcinoma. Arch Pathol Lab Med 1987; 111:339.
  38. Sadoun D, Vaylet F, Valeyre D, et al. Bronchogenic carcinoma in patients with pulmonary histiocytosis X. Chest 1992; 101:1610.
  39. Tomashefski JF, Khiyami A, Kleinerman J. Neoplasms associated with pulmonary eosinophilic granuloma. Arch Pathol Lab Med 1991; 115:499.
  40. Tsuji T, Nakamura S, Tanaka M. Pulmonary Langerhans cell histiocytosis associated with lingual carcinoma. Intern Med 2004; 43:713.
  41. Coli A, Bigotti G, Ferrone S. Histiocytosis X arising in Hodgkin's disease: immunophenotypic characterization with a panel of monoclonal antibodies. Virchows Arch A Pathol Anat Histopathol 1991; 418:369.
  42. Gupta N, Langenderfer D, McCormack FX, et al. Chest Computed Tomographic Image Screening for Cystic Lung Diseases in Patients with Spontaneous Pneumothorax Is Cost Effective. Ann Am Thorac Soc 2017; 14:17.
  43. Aguayo SM, Schwarz MI, Mortenson RL. The role of the chest radiograph in the evaluation of disease severity and clinical course in eosinophilic granuloma. Am Rev Respir Dis 1990; 141:A61.
  44. Kulwiec EL, Lynch DA, Aguayo SM, et al. Imaging of pulmonary histiocytosis X. Radiographics 1992; 12:515.
  45. Lacronique J, Roth C, Battesti JP, et al. Chest radiological features of pulmonary histiocytosis X: a report based on 50 adult cases. Thorax 1982; 37:104.
  46. Castoldi MC, Verrioli A, De Juli E, Vanzulli A. Pulmonary Langerhans cell histiocytosis: the many faces of presentation at initial CT scan. Insights Imaging 2014; 5:483.
  47. Schönfeld N, Frank W, Wenig S, et al. Clinical and radiologic features, lung function and therapeutic results in pulmonary histiocytosis X. Respiration 1993; 60:38.
  48. Kim HJ, Lee KS, Johkoh T, et al. Pulmonary Langerhans cell histiocytosis in adults: high-resolution CT-pathology comparisons and evolutional changes at CT. Eur Radiol 2011; 21:1406.
  49. Brauner MW, Grenier P, Tijani K, et al. Pulmonary Langerhans cell histiocytosis: evolution of lesions on CT scans. Radiology 1997; 204:497.
  50. Canuet M, Kessler R, Jeung MY, et al. Correlation between high-resolution computed tomography findings and lung function in pulmonary Langerhans cell histiocytosis. Respiration 2007; 74:640.
  51. Tazi A, Marc K, Dominique S, et al. Serial computed tomography and lung function testing in pulmonary Langerhans' cell histiocytosis. Eur Respir J 2012; 40:905.
  52. Krajicek BJ, Ryu JH, Hartman TE, et al. Abnormal fluorodeoxyglucose PET in pulmonary Langerhans cell histiocytosis. Chest 2009; 135:1542.
  53. Chusid, EL. Pulmonary eosinophilic granuloma: aspects of pulmonary function. Mt Sinai J Med 1961; 33:116.
  54. Friedman PJ, Liebow AA, Sokoloff J. Eosinophilic granuloma of lung. Clinical aspects of primary histiocytosis in the adult. Medicine (Baltimore) 1981; 60:385.
  55. HOFFMAN L, COHN JE, GAENSLER EA. Respiratory abnormalities in eosinophilic granuloma of the lung. Longterm study of five cases. N Engl J Med 1962; 267:577.
  56. Rolland-Debord C, Fry S, Giovannelli J, et al. Physiologic Determinants of Exercise Capacity in Pulmonary Langerhans Cell Histiocytosis: A Multidimensional Analysis. PLoS One 2017; 12:e0170035.
  57. Harari S, Comel A. Pulmonary Langerhans cell Histiocytosis. Sarcoidosis Vasc Diffuse Lung Dis 2001; 18:253.
  58. Auerswald U, Barth J, Magnussen H. Value of CD-1-positive cells in bronchoalveolar lavage fluid for the diagnosis of pulmonary histiocytosis X. Lung 1991; 169:305.
  59. Baqir M, Vassallo R, Maldonado F, et al. Utility of bronchoscopy in pulmonary Langerhans cell histiocytosis. J Bronchology Interv Pulmonol 2013; 20:309.
  60. Harari S, Torre O, Cassandro R, et al. Bronchoscopic diagnosis of Langerhans cell histiocytosis and lymphangioleiomyomatosis. Respir Med 2012; 106:1286.
  61. Housini I, Tomashefski JF Jr, Cohen A, et al. Transbronchial biopsy in patients with pulmonary eosinophilic granuloma. Comparison with findings on open lung biopsy. Arch Pathol Lab Med 1994; 118:523.
  62. Ornvold K, Ralfkiaer E, Carstensen H. Immunohistochemical study of the abnormal cells in Langerhans cell histiocytosis (histiocytosis x). Virchows Arch A Pathol Anat Histopathol 1990; 416:403.
  63. Ye F, Huang SW, Dong HJ. Histiocytosis X. S-100 protein, peanut agglutinin, and transmission electron microscopy study. Am J Clin Pathol 1990; 94:627.
  64. Kahn HJ, Thorner PS. Monoclonal antibody MT1: a marker for Langerhans cell histiocytosis. Pediatr Pathol 1990; 10:375.
  65. Soler P, Chollet S, Jacque C, et al. Immunocytochemical characterization of pulmonary histiocytosis X cells in lung biopsies. Am J Pathol 1985; 118:439.
  66. King TE Jr. Bronchoscopy in interstitial lung disease. In: Textbook of Bronchoscopy, Feinsilver SH, Fein AM (Eds), Williams & Wilkins, Baltimore 1995. p.185.
  67. Mogulkoc N, Veral A, Bishop PW, et al. Pulmonary Langerhans' cell histiocytosis: radiologic resolution following smoking cessation. Chest 1999; 115:1452.
  68. Tsele E, Thomas DM, Chu AC. Treatment of adult Langerhans cell histiocytosis with etoposide. J Am Acad Dermatol 1992; 27:61.
  69. Ladisch S, Gadner H. Treatment of Langerhans cell histiocytosis--evolution and current approaches. Br J Cancer Suppl 1994; 23:S41.
  70. Vassallo R, Harari S, Tazi A. Current understanding and management of pulmonary Langerhans cell histiocytosis. Thorax 2017; 72:937.
  71. Lazor R, Etienne-Mastroianni B, Khouatra C, et al. Progressive diffuse pulmonary Langerhans cell histiocytosis improved by cladribine chemotherapy. Thorax 2009; 64:274.
  72. Aerni MR, Aubry MC, Myers JL, Vassallo R. Complete remission of nodular pulmonary Langerhans cell histiocytosis lesions induced by 2-chlorodeoxyadenosine in a non-smoker. Respir Med 2008; 102:316.
  73. Lorillon G, Bergeron A, Detourmignies L, et al. Cladribine is effective against cystic pulmonary Langerhans cell histiocytosis. Am J Respir Crit Care Med 2012; 186:930.
  74. Epaud R, Ducou Le Pointe H, Fasola S, et al. Cladribine improves lung cysts and pulmonary function in a child with histiocytosis. Eur Respir J 2015; 45:831.
  75. Grobost V, Khouatra C, Lazor R, et al. Effectiveness of cladribine therapy in patients with pulmonary Langerhans cell histiocytosis. Orphanet J Rare Dis 2014; 9:191.
  76. Mourah S, How-Kit A, Meignin V, et al. Recurrent NRAS mutations in pulmonary Langerhans cell histiocytosis. Eur Respir J 2016; 47:1785.
  77. Hyman DM, Puzanov I, Subbiah V, et al. Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations. N Engl J Med 2015; 373:726.
  78. May A, Kane G, Yi E, et al. Dramatic and sustained responsiveness of pulmonary Langerhans cell histiocytosis-associated pulmonary hypertension to vasodilator therapy. Respir Med Case Rep 2015; 14:13.
  79. Fukuda Y, Miura S, Fujimi K, et al. Effects of treatment with a combination of cardiac rehabilitation and bosentan in patients with pulmonary Langerhans cell histiocytosis associated with pulmonary hypertension. Eur J Prev Cardiol 2014; 21:1481.
  80. Gabbay E, Dark JH, Ashcroft T, et al. Recurrence of Langerhans' cell granulomatosis following lung transplantation. Thorax 1998; 53:326.
  81. Habib SB, Congleton J, Carr D, et al. Recurrence of recipient Langerhans' cell histiocytosis following bilateral lung transplantation. Thorax 1998; 53:323.
  82. Delobbe A, Durieu J, Duhamel A, Wallaert B. Determinants of survival in pulmonary Langerhans' cell granulomatosis (histiocytosis X). Groupe d'Etude en Pathologie Interstitielle de la Société de Pathologie Thoracique du Nord. Eur Respir J 1996; 9:2002.
  83. 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.