References

1. Laman JD, Leenen PJ, Annels NE, et al.: Langerhans-cell histiocytosis 'insight into DC biology'. Trends Immunol 24 (4): 190-6, 2003. [PubMed: 12697451]
2. Willman CL, Busque L, Griffith BB, et al.: Langerhans'-cell histiocytosis (histiocytosis X)--a clonal proliferative disease. N Engl J Med 331 (3): 154-60, 1994. [PubMed: 8008029]
3. Yu RC, Chu C, Buluwela L, et al.: Clonal proliferation of Langerhans cells in Langerhans cell histiocytosis. Lancet 343 (8900): 767-8, 1994. [PubMed: 7510816]
4. Badalian-Very G, Vergilio JA, Fleming M, et al.: Pathogenesis of Langerhans cell histiocytosis. Annu Rev Pathol 8: 1-20, 2013. [PubMed: 22906202]
5. 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 124 (19): 3007-15, 2014. [PMC free article: PMC4224195] [PubMed: 25202140]
6. 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 184 (8): 4557-67, 2010. [PMC free article: PMC3142675] [PubMed: 20220088]
7. Ginhoux F, Merad M: Ontogeny and homeostasis of Langerhans cells. Immunol Cell Biol 88 (4): 387-92, 2010 May-Jun. [PubMed: 20309014]

Incidence

The annual incidence of LCH has been estimated to be two to ten cases per 1 million children aged 15 years or younger.[1,2] The male to female ratio (M/F) is close to one and the median age of presentation is 30 months.[3] A report from Stockholm County, Sweden, described an annual incidence of 8.9 cases of LCH per 1 million children with a total of 29 cases in 10 years.[4] Most of these cases were diagnosed between September and February (M/F = 1.2). A 4-year survey of 251 new LCH cases in France found an annual incidence of 4.6 cases per 1 million children younger than 15 years (M/F = 1.2).[5] A survey of LCH in northwest England (Manchester) revealed an overall incidence of 2.6 cases per 1 million child-years.[6]

Surveillance, Epidemiology, and End Results registry data from 2000 to 2009 were reviewed to identify high-risk LCH cases and assess various demographic variables.[7] On the basis of 145 cases, the age-standardized incidence was 0.7 per 1 million children per year, with lower incidence in black patients (0.41 per 1 million) and higher incidence in Hispanic patients (1.63 per 1 million) younger than 5 years. Living in crowded conditions and lower socioeconomic circumstances were associated with a higher risk of LCH.

Identical twins with LCH, and non-twin siblings or multiple cases in one family, have been reported.[8] Over 90% of adult pulmonary LCH occurs in young adults who smoke, often more than 20 cigarettes per day.[9,10]

Risk Factors

Although the following risk factors have been identified for LCH, strong and consistent associations have not been confirmed:

• Solvent exposure in parents.[11]
• Family history of cancer.[12]
• Personal or family history of thyroid disease.[11,13]
• Perinatal infections.[11,12]
• Parental occupational exposure to metal, granite, or wood dust.[12]
• Ethnicity and race.[7]
• Low socioeconomic status.[7]

Prognosis

Prognosis is closely linked to the extent of disease at presentation when high-risk organs (liver, spleen, and/or bone marrow) are involved and to the response to initial treatment. The high-risk designation comes from the high mortality rate (35%) in those who did not respond well to therapy in the first 6 weeks. For many years, lung was thought to be a high-risk organ but isolated lung involvement in pediatric LCH is no longer considered to pose a significant risk of death.[14] Because of treatment advances, the outcome for children with LCH involving high-risk organs has improved.[15,16] Data from HISTSOC-LCH-III (NCT00276757) showed an 84% overall survival (OS) rate for patients treated for 12 months with systemic chemotherapy.[17]

Patients with single-system disease and low-risk multisystem disease do not usually die from LCH, but recurrent disease may result in considerable morbidity and significant late effects.[18] The major treatment challenge is to reduce the 20% to 30% incidence of recurrent lesions and the significant incidence of permanent consequences in this group of patients. HISTSOC-LCH-III data showed that there was a significant difference in reactivation for risk organ subjects when comparing 6 months versus 12 months of treatment, with 12 months being better (54% vs. 37%).[17]

Prognostic factors in LCH have been identified and can be categorized as follows:

• Age at diagnosis: Although age younger than 2 years was once thought to portend a worse prognosis, data from the LCH-II study showed that patients aged 2 years or younger without high-risk organ involvement had the same response to therapy as older patients.[16] By contrast, the OS was poorer in neonates with risk-organ involvement compared with infants and children with the same extent of disease when patients were treated for only 6 months.[16]
• Response to treatment: Response to therapy at 6 to 12 weeks has been shown to be a more important prognostic factor than age.[19] The overall response to therapy is influenced by the duration and intensity of treatment.[15,16]
• Organ involvement: Involvement of craniofacial bones including orbital, mastoid, and temporal bones is associated with an increased risk of diabetes insipidus and an increased frequency of anterior pituitary hormone deficiencies and neurologic problems. (Refer to the Endocrine system subsection in the Multisystem Disease Presentation section of this summary for more information on diabetes insipidus.)

References

1. Carstensen H, Ornvold K: The epidemiology of Langerhans cell histiocytosis in children in Denmark, 1975-89. [Abstract] Med Pediatr Oncol 21 (5): A-15, 387-8, 1993.
2. Salotti JA, Nanduri V, Pearce MS, et al.: Incidence and clinical features of Langerhans cell histiocytosis in the UK and Ireland. Arch Dis Child 94 (5): 376-80, 2009. [PubMed: 19060008]
3. A multicentre retrospective survey of Langerhans' cell histiocytosis: 348 cases observed between 1983 and 1993. The French Langerhans' Cell Histiocytosis Study Group. Arch Dis Child 75 (1): 17-24, 1996. [PMC free article: PMC1511663] [PubMed: 8813865]
4. Stålemark H, Laurencikas E, Karis J, et al.: Incidence of Langerhans cell histiocytosis in children: a population-based study. Pediatr Blood Cancer 51 (1): 76-81, 2008. [PubMed: 18266220]
5. Guyot-Goubin A, Donadieu J, Barkaoui M, et al.: Descriptive epidemiology of childhood Langerhans cell histiocytosis in France, 2000-2004. Pediatr Blood Cancer 51 (1): 71-5, 2008. [PubMed: 18260117]
6. Alston RD, Tatevossian RG, McNally RJ, et al.: Incidence and survival of childhood Langerhans cell histiocytosis in Northwest England from 1954 to 1998. Pediatr Blood Cancer 48 (5): 555-60, 2007. [PubMed: 16652350]
7. Ribeiro KB, Degar B, Antoneli CB, et al.: Ethnicity, race, and socioeconomic status influence incidence of Langerhans cell histiocytosis. Pediatr Blood Cancer 62 (6): 982-7, 2015. [PubMed: 25586293]
8. Aricò M, Nichols K, Whitlock JA, et al.: Familial clustering of Langerhans cell histiocytosis. Br J Haematol 107 (4): 883-8, 1999. [PubMed: 10606898]
9. Tazi A, Soler P, Hance AJ: Adult pulmonary Langerhans' cell histiocytosis. Thorax 55 (5): 405-16, 2000. [PMC free article: PMC1745752] [PubMed: 10770823]
10. Vassallo R, Ryu JH, Colby TV, et al.: Pulmonary Langerhans'-cell histiocytosis. N Engl J Med 342 (26): 1969-78, 2000. [PubMed: 10877650]
11. Bhatia S, Nesbit ME Jr, Egeler RM, et al.: Epidemiologic study of Langerhans cell histiocytosis in children. J Pediatr 130 (5): 774-84, 1997. [PubMed: 9152288]
12. Venkatramani R, Rosenberg S, Indramohan G, et al.: An exploratory epidemiological study of Langerhans cell histiocytosis. Pediatr Blood Cancer 59 (7): 1324-6, 2012. [PubMed: 22434707]
13. Nicholson HS, Egeler RM, Nesbit ME: The epidemiology of Langerhans cell histiocytosis. Hematol Oncol Clin North Am 12 (2): 379-84, 1998. [PubMed: 9561907]
14. Ronceray L, Pötschger U, Janka G, et al.: Pulmonary involvement in pediatric-onset multisystem Langerhans cell histiocytosis: effect on course and outcome. J Pediatr 161 (1): 129-33.e1-3, 2012. [PubMed: 22284564]
15. Gadner H, Grois N, Arico M, et al.: A randomized trial of treatment for multisystem Langerhans' cell histiocytosis. J Pediatr 138 (5): 728-34, 2001. [PubMed: 11343051]
16. Gadner H, Grois N, Pötschger U, et al.: Improved outcome in multisystem Langerhans cell histiocytosis is associated with therapy intensification. Blood 111 (5): 2556-62, 2008. [PubMed: 18089850]
17. Gadner H, Minkov M, Grois N, et al.: Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis. Blood 121 (25): 5006-14, 2013. [PubMed: 23589673]
18. Haupt 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 42 (5): 438-44, 2004. [PubMed: 15049016]
19. Minkov M, Prosch H, Steiner M, et al.: Langerhans cell histiocytosis in neonates. Pediatr Blood Cancer 45 (6): 802-7, 2005. [PubMed: 15770639]

Cell of Origin and Biologic Correlates

Modern classification of the histiocytic diseases subdivides them into dendritic cell–related, monocyte/macrophage-related, or true malignancies. Langerhans cell histiocytosis (LCH) is a dendritic cell disease.[1,2] The Langerhans cells (LCH cells) in LCH lesions are immature dendritic cells making up less than 10% of the cells present in LCH lesions.[3,4] Comprehensive gene expression array data analysis on LCH cells is consistent with the concept that the skin LC is not the cell of origin for LCH.[5] Rather it is likely to be a myeloid dendritic cell, which expresses the same antigens (CD1a and CD207) as the skin LC.[6] This concept was further supported by a study reporting that the transcription profile of LCH cells was distinct from myeloid and plasmacytoid dendritic cells, as well as epidermal LCs.[6,7]

LCH lesions also contain lymphocytes, macrophages, neutrophils, eosinophils, fibroblasts, and sometimes multinucleated giant cells. In the brain, the following three types of histopathologic findings have been described in LCH:

• Mass lesions in meninges or choroid plexus with CD1a-positive LCH cells and predominantly CD8-positive lymphocytes.
• Mass lesions in connective tissue spaces with CD1a-positive LCH cells and predominantly CD8-positive lymphocytes causing an inflammatory response and neuronal loss.
• Predominantly CD8+ lymphocyte infiltration with neuronal degeneration, microglial activation, and gliosis.[8]

Immunologic Abnormalities

Normally, the LC is a primary presenter of antigen to naïve T-lymphocytes. However, in LCH, the pathologic dendritic cell does not efficiently stimulate primary T-lymphocyte responses.[9] Antibody staining for the dendritic cell markers, CD80, CD86, and class II antigens, has been used to show that in LCH, the abnormal cells are immature dendritic cells that present antigen poorly and are proliferating at a low rate.[3,9,10] Transforming growth factor-beta (TGF-beta) and interleukin (IL)-10 are possibly responsible for preventing LCH cell maturation in LCH.[3] The expansion of regulatory T cells in patients with LCH has been reported.[10] The population of CD4-positive CD25(high) FoxP3(high) cells was reported to comprise 20% of T cells and appeared to be in contact with LCH cells in the lesions. These T cells were present in higher numbers in the peripheral blood of patients with LCH than in controls and returned to a normal level when patients were in remission.[10]

Etiology

The etiology of LCH is unknown. Efforts to define a viral cause have not been successful.[11,12] One study has shown that 1% of patients have a positive family history for LCH.[13]

Cytogenetic and Genomic Studies

Studies showing clonality in LCH using polymorphisms of methylation-specific restriction enzyme sites on the X-chromosome regions coding for the human androgen receptor, DXS255, PGK, and HPRT were published in 1994.[14,15] Biopsies of lesions with single-system or multisystem disease were found to have a proliferation of LCH cells from a single clone. Pulmonary LCH in adults is usually nonclonal and it is possible that this group represents a reactive process to smoking.[16] However, a subset appeared to be clonal. An analysis of BRAF mutations showed that a significant proportion (25%–30%) of patients have evidence for mutant BRAF V600E, which has a statistically significant association with cigarette smoking.[17] Cytogenetic abnormalities in LCH have rarely been reported. One study described an abnormal clone t(7;12)(q11.2;p13) from a vertebral lesion of one patient.[18] This study also reported nonclonal karyotypic abnormalities in three patients. An increase in chromosomal breakage was also noted.

Figure

Figure courtesy of Rikhia Chakraborty, Ph.D. Permission to reuse the figure in any form must be obtained directly from Dr. Chakraborty.

An activating mutation of the BRAF oncogene (V600E) was detected in 35 of 61 (57%) LCH biopsy samples, with mutations being more common in patients younger than 10 years (76%) than in patients aged 10 years and older (44%).[19] A subsequent study with a larger sample size did not confirm this association.[20] The RAS signaling pathway (Figure) transmits signals from a cell surface receptor (e.g., a growth factor) through the RAS pathway (via one of the RAF proteins [A, B, or C]) to phosphorylate MEK and then extracellular signal-regulated kinase (ERK), which leads to nuclear signals affecting cell cycle and transcription regulation. The V600E mutation of BRAF leads to continuous phosphorylation, and thus activation, of MEK and ERK without the need for an external signal.

The RAS pathway was activated in a few samples that were tested for MEK and ERK expression, whether or not the BRAF V600E mutation was present. The BRAF V600E mutation in LCH has been demonstrated in flow-sorted CD1a-positive LCH cells from fresh lesions in 11 of 16 samples.[21] Another BRAF mutation (BRAF 600DLAT) was identified that resulted in the insertion of four amino acids and that also appeared to activate MAPK pathway signaling.[21] No clinical characteristics associated with the BRAF mutation have been identified.[19-21]

A series of 135 biopsies from 100 patients were tested for the BRAF V600E mutation by a sensitive quantitative polymerase chain reaction technique and found the mutation in 65% of patients.[20] Circulating cells with the BRAF V600E mutation could be detected in all high-risk patients and in a subset of low-risk multisystem patients. Presence of the circulating cells with the mutation conferred a twofold increased risk of relapse. The myeloid dendritic cell origin of LCH was confirmed by finding CD34+ stem cells with the mutation in the bone marrow of high-risk patients. Those with low-risk disease had more mature myeloid dendritic cells with the mutation, but not the stem cells suggesting the stage of cell development is critical in defining the clinical characteristics of LCH, which can now be considered a myeloid neoplasia in most cases. Of note, activating BRAF mutations are also found in select nonmalignant conditions (e.g., benign nevi) [22] and low-grade malignancies (e.g., pilocytic astrocytoma).[23,24] All of these conditions have a generally indolent course, with spontaneous resolution occurring in some cases. This distinctive clinical course may be a manifestation of oncogene-induced senescence.[22,25]

Whole-exome sequencing of BRAF-mutated versus BRAF–wild-type LCH biopsies revealed that MAP2K1 mutations were identified in 7 of 21 BRAF–wild-type specimens; no other mutations were found in these seven patients. The MAP2K1 and BRAF mutations lead to ERK phosphorylation. Among the BRAF-mutated specimens, only one specimen had a second mutation, ARAF. A BRAF mutation leads to universal phosphorylation of ERK, and both mechanisms can be inhibited by using targeted therapies in vitro.[26] Another study showed MAP2K1 mutations exclusively in 11 of 40 BRAF–wild-type cases.[27] Together, these studies show universal activation of ERK in LCH and the possibility of using targeted therapies to treat tumors with BRAF and MAP2K1 mutations. Larger studies will be needed to confirm the higher rates of relapse seen in BRAF-mutated and MAP2K1–wild-type tumors.[26]

Cytokine Analysis by Immunohistochemical Staining and Gene Expression Array Studies

Immunohistochemical staining of LCH lesions has shown apparent upregulation of the chemokines CCR6 and possibly CCR7.[28,29] In an analysis of gene expression in LCH by gene array techniques, 2,000 differentially expressed genes were identified. Of 65 genes previously reported to be associated with LCH, only 11 were found to be upregulated in the array results. The most highly upregulated gene in both CD207 and CD3-positive cells was osteopontin; other genes that activate and recruit T cells to sites of inflammation are also upregulated. The expression profile of the T cells was that of an activated regulatory T-cell phenotype with increased expression of FOXP3, CTLA4, and osteopontin. These findings support a previous report on the expansion of regulatory T cells in LCH.[10] There was pronounced expression of genes associated with early myeloid progenitors including CD33 and CD44, which is consistent with an earlier report of elevated myeloid dendritic cells in the blood of patients with LCH.[30] A model of "Misguided Myeloid Dendritic Cell Precursors" has been proposed, whereby myeloid dendritic cell precursors are recruited to sites of LCH by an unknown mechanism and the dendritic cells in turn recruit lymphocytes by excretion of osteopontin, neuropilin-1, and vannin-1.[5]

Several investigators have published studies evaluating the level of various cytokines or growth factors in the blood of patients with LCH that have included many of the genes found not to be upregulated by the gene expression results discussed above.[5] One explanation for elevated levels of these proteins is a systemic inflammatory response with the cytokines/growth factors being produced by cells outside the LCH lesions. A second possible explanation is that macrophages in the LCH lesions produce the cytokines measured in the blood or are concentrated in lesions.

IL-1 beta and prostaglandin GE₂ levels were measured in the saliva of patients with oral LCH lesions or multisystem high-risk patients with and without oral lesions; levels of both were higher in patients with active disease and decreased after successful therapy.[31]

Human Leukocyte Antigen (HLA) Type and Association With LCH

Specific associations of LCH with distinct HLA types and extent of disease have been reported. In a study of 84 Nordic patients, those with only skin or bone involvement more frequently had HLA-DRB1*03 type than those with multisystem disease.[32] In 29 patients and 37 family members in the United States, the Cw7 and DR4 types were significantly more prevalent in Caucasians with single-bone lesions.[33]

References

1. Laman JD, Leenen PJ, Annels NE, et al.: Langerhans-cell histiocytosis 'insight into DC biology'. Trends Immunol 24 (4): 190-6, 2003. [PubMed: 12697451]
2. Jaffe R: The diagnostic histopathology of langerhans' cell histiocytosis. In: Weitzman S, Egeler R M, eds.: Histiocytic Disorders of Children and Adults. Cambridge, United Kingdom: Cambridge University Press, 2005, pp 14-39.
3. Geissmann F, Lepelletier Y, Fraitag S, et al.: Differentiation of Langerhans cells in Langerhans cell histiocytosis. Blood 97 (5): 1241-8, 2001. [PubMed: 11222366]
4. Berres ML, Allen CE, Merad M: Pathological consequence of misguided dendritic cell differentiation in histiocytic diseases. Adv Immunol 120: 127-61, 2013. [PMC free article: PMC3985340] [PubMed: 24070383]
5. 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 184 (8): 4557-67, 2010. [PMC free article: PMC3142675] [PubMed: 20220088]
6. Ginhoux F, Merad M: Ontogeny and homeostasis of Langerhans cells. Immunol Cell Biol 88 (4): 387-92, 2010 May-Jun. [PubMed: 20309014]
7. Hutter C, Kauer M, Simonitsch-Klupp I, et al.: Notch is active in Langerhans cell histiocytosis and confers pathognomonic features on dendritic cells. Blood 120 (26): 5199-208, 2012. [PubMed: 23074278]
8. Grois N, Prayer D, Prosch H, et al.: Neuropathology of CNS disease in Langerhans cell histiocytosis. Brain 128 (Pt 4): 829-38, 2005. [PubMed: 15705614]
9. Yu RC, Morris JF, Pritchard J, et al.: Defective alloantigen-presenting capacity of 'Langerhans cell histiocytosis cells'. Arch Dis Child 67 (11): 1370-2, 1992. [PMC free article: PMC1793774] [PubMed: 1471889]
10. Senechal B, Elain G, Jeziorski E, et al.: Expansion of regulatory T cells in patients with Langerhans cell histiocytosis. PLoS Med 4 (8): e253, 2007. [PMC free article: PMC1945037] [PubMed: 17696642]
11. McClain K, Jin H, Gresik V, et al.: Langerhans cell histiocytosis: lack of a viral etiology. Am J Hematol 47 (1): 16-20, 1994. [PubMed: 8042610]
12. Jeziorski E, Senechal B, Molina TJ, et al.: Herpes-virus infection in patients with Langerhans cell histiocytosis: a case-controlled sero-epidemiological study, and in situ analysis. PLoS One 3 (9): e3262, 2008. [PMC free article: PMC2533395] [PubMed: 18810271]
13. Aricò M, Nichols K, Whitlock JA, et al.: Familial clustering of Langerhans cell histiocytosis. Br J Haematol 107 (4): 883-8, 1999. [PubMed: 10606898]
14. Willman CL, Busque L, Griffith BB, et al.: Langerhans'-cell histiocytosis (histiocytosis X)--a clonal proliferative disease. N Engl J Med 331 (3): 154-60, 1994. [PubMed: 8008029]
15. Yu RC, Chu C, Buluwela L, et al.: Clonal proliferation of Langerhans cells in Langerhans cell histiocytosis. Lancet 343 (8900): 767-8, 1994. [PubMed: 7510816]
16. Dacic S, Trusky C, Bakker A, et al.: Genotypic analysis of pulmonary Langerhans cell histiocytosis. Hum Pathol 34 (12): 1345-9, 2003. [PubMed: 14691922]
17. 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 38 (4): 548-51, 2014. [PubMed: 24625419]
18. Betts DR, Leibundgut KE, Feldges A, et al.: Cytogenetic abnormalities in Langerhans cell histiocytosis. Br J Cancer 77 (4): 552-5, 1998. [PMC free article: PMC2149945] [PubMed: 9484810]
19. Badalian-Very G, Vergilio JA, Degar BA, et al.: Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood 116 (11): 1919-23, 2010. [PMC free article: PMC3173987] [PubMed: 20519626]
20. 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 211 (4): 669-83, 2014. [PMC free article: PMC3978272] [PubMed: 24638167]
21. Satoh T, Smith A, Sarde A, et al.: B-RAF mutant alleles associated with Langerhans cell histiocytosis, a granulomatous pediatric disease. PLoS One 7 (4): e33891, 2012. [PMC free article: PMC3323620] [PubMed: 22506009]
22. Michaloglou C, Vredeveld LC, Soengas MS, et al.: BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436 (7051): 720-4, 2005. [PubMed: 16079850]
23. Jones DT, Kocialkowski S, Liu L, et al.: Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res 68 (21): 8673-7, 2008. [PMC free article: PMC2577184] [PubMed: 18974108]
24. Pfister S, Janzarik WG, Remke M, et al.: BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. J Clin Invest 118 (5): 1739-49, 2008. [PMC free article: PMC2289793] [PubMed: 18398503]
25. Jacob K, Quang-Khuong DA, Jones DT, et al.: Genetic aberrations leading to MAPK pathway activation mediate oncogene-induced senescence in sporadic pilocytic astrocytomas. Clin Cancer Res 17 (14): 4650-60, 2011. [PubMed: 21610151]
26. 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 124 (19): 3007-15, 2014. [PMC free article: PMC4224195] [PubMed: 25202140]
27. Brown NA, Furtado LV, Betz BL, et al.: High prevalence of somatic MAP2K1 mutations in BRAF V600E-negative Langerhans cell histiocytosis. Blood 124 (10): 1655-8, 2014. [PubMed: 24982505]
28. Fleming MD, Pinkus JL, Fournier MV, et al.: Coincident expression of the chemokine receptors CCR6 and CCR7 by pathologic Langerhans cells in Langerhans cell histiocytosis. Blood 101 (7): 2473-5, 2003. [PubMed: 12642342]
29. Annels NE, Da Costa CE, Prins FA, et al.: Aberrant chemokine receptor expression and chemokine production by Langerhans cells underlies the pathogenesis of Langerhans cell histiocytosis. J Exp Med 197 (10): 1385-90, 2003. [PMC free article: PMC2193776] [PubMed: 12743170]
30. Rolland A, Guyon L, Gill M, et al.: Increased blood myeloid dendritic cells and dendritic cell-poietins in Langerhans cell histiocytosis. J Immunol 174 (5): 3067-71, 2005. [PubMed: 15728521]
31. Preliasco VF, Benchuya C, Pavan V, et al.: IL-1 beta and PGE2 levels are increased in the saliva of children with Langerhans cell histiocytosis. J Oral Pathol Med 37 (9): 522-7, 2008. [PubMed: 18647218]
32. Bernstrand C, Carstensen H, Jakobsen B, et al.: Immunogenetic heterogeneity in single-system and multisystem langerhans cell histiocytosis. Pediatr Res 54 (1): 30-6, 2003. [PubMed: 12700369]
33. McClain KL, Laud P, Wu WS, et al.: Langerhans cell histiocytosis patients have HLA Cw7 and DR4 types associated with specific clinical presentations and no increased frequency in polymorphisms of the tumor necrosis factor alpha promoter. Med Pediatr Oncol 41 (6): 502-7, 2003. [PubMed: 14595706]

Single-System Disease Presentation

In single-system LCH, as the name implies, the disease presents with involvement of a single site or organ, including skin and nails, oral cavity, bone, lymph nodes and thymus, pituitary gland, and thyroid.

Multisystem Disease Presentation

In multisystem LCH, the disease presents in multiple organs or body systems including bone, abdominal/gastrointestinal system (liver and spleen), lung, bone marrow, endocrine system, eye, CNS, skin, and lymph nodes.

References

1. Minkov M, Prosch H, Steiner M, et al.: Langerhans cell histiocytosis in neonates. Pediatr Blood Cancer 45 (6): 802-7, 2005. [PubMed: 15770639]
2. Simko SJ, Garmezy B, Abhyankar H, et al.: Differentiating skin-limited and multisystem Langerhans cell histiocytosis. J Pediatr 165 (5): 990-6, 2014. [PMC free article: PMC4254414] [PubMed: 25441388]
3. Stein SL, Paller AS, Haut PR, et al.: Langerhans cell histiocytosis presenting in the neonatal period: a retrospective case series. Arch Pediatr Adolesc Med 155 (7): 778-83, 2001. [PubMed: 11434843]
4. Lau L, Krafchik B, Trebo MM, et al.: Cutaneous Langerhans cell histiocytosis in children under one year. Pediatr Blood Cancer 46 (1): 66-71, 2006. [PubMed: 16261594]
5. Munn S, Chu AC: Langerhans cell histiocytosis of the skin. Hematol Oncol Clin North Am 12 (2): 269-86, 1998. [PubMed: 9561900]
6. Ashena Z, Alavi S, Arzanian MT, et al.: Nail involvement in langerhans cell histiocytosis. Pediatr Hematol Oncol 24 (1): 45-51, 2007 Jan-Feb. [PubMed: 17130113]
7. Madrigal-Martínez-Pereda C, Guerrero-Rodríguez V, Guisado-Moya B, et al.: Langerhans cell histiocytosis: literature review and descriptive analysis of oral manifestations. Med Oral Patol Oral Cir Bucal 14 (5): E222-8, 2009. [PubMed: 19218906]
8. 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 100 (2 Suppl): S42-66, 2005. [PubMed: 16037792]
9. Slater JM, Swarm OJ: Eosinophilic granuloma of bone. Med Pediatr Oncol 8 (2): 151-64, 1980. [PubMed: 6999317]
10. Peng XS, Pan T, Chen LY, et al.: Langerhans' cell histiocytosis of the spine in children with soft tissue extension and chemotherapy. Int Orthop 33 (3): 731-6, 2009. [PMC free article: PMC2903089] [PubMed: 18338168]
11. Boztug K, Frimpong-Ansah K, Nanduri VR, et al.: Intraocular Langerhans cell histiocytosis in a neonate resulting in bilateral loss of vision. Pediatr Blood Cancer 47 (5): 633-5, 2006. [PubMed: 16444678]
12. Ducassou S, Seyrig F, Thomas C, et al.: Thymus and mediastinal node involvement in childhood Langerhans cell histiocytosis: long-term follow-up from the French national cohort. Pediatr Blood Cancer 60 (11): 1759-65, 2013. [PMC free article: PMC3824083] [PubMed: 23813854]
13. Burnett A, Carney D, Mukhopadhyay S, et al.: Thyroid involvement with Langerhans cell histiocytosis in a 3-year-old male. Pediatr Blood Cancer 50 (3): 726-7, 2008. [PubMed: 16944476]
14. Imashuku S, Kinugawa N, Matsuzaki A, et al.: Langerhans cell histiocytosis with multifocal bone lesions: comparative clinical features between single and multi-systems. Int J Hematol 90 (4): 506-12, 2009. [PubMed: 19779766]
15. Wong A, Ortiz-Neira CL, Reslan WA, et al.: Liver involvement in Langerhans cell histiocytosis. Pediatr Radiol 36 (10): 1105-7, 2006. [PubMed: 16819598]
16. Braier J, Ciocca M, Latella A, et al.: Cholestasis, sclerosing cholangitis, and liver transplantation in Langerhans cell Histiocytosis. Med Pediatr Oncol 38 (3): 178-82, 2002. [PubMed: 11836717]
17. Jaffe R: Liver involvement in the histiocytic disorders of childhood. Pediatr Dev Pathol 7 (3): 214-25, 2004 May-Jun. [PubMed: 15022067]
18. Hadzic N, Pritchard J, Webb D, et al.: Recurrence of Langerhans cell histiocytosis in the graft after pediatric liver transplantation. Transplantation 70 (5): 815-9, 2000. [PubMed: 11003364]
19. Newell KA, Alonso EM, Kelly SM, et al.: Association between liver transplantation for Langerhans cell histiocytosis, rejection, and development of posttransplant lymphoproliferative disease in children. J Pediatr 131 (1 Pt 1): 98-104, 1997. [PubMed: 9255199]
20. Goyal R, Das A, Nijhawan R, et al.: Langerhans cell histiocytosis infiltration into pancreas and kidney. Pediatr Blood Cancer 49 (5): 748-50, 2007. [PubMed: 16411199]
21. Hait E, Liang M, Degar B, et al.: Gastrointestinal tract involvement in Langerhans cell histiocytosis: case report and literature review. Pediatrics 118 (5): e1593-9, 2006. [PubMed: 17030599]
22. Geissmann F, Thomas C, Emile JF, et al.: Digestive tract involvement in Langerhans cell histiocytosis. The French Langerhans Cell Histiocytosis Study Group. J Pediatr 129 (6): 836-45, 1996. [PubMed: 8969725]
23. Vassallo R, Ryu JH, Colby TV, et al.: Pulmonary Langerhans'-cell histiocytosis. N Engl J Med 342 (26): 1969-78, 2000. [PubMed: 10877650]
24. Abbritti M, Mazzei MA, Bargagli E, et al.: Utility of spiral CAT scan in the follow-up of patients with pulmonary Langerhans cell histiocytosis. Eur J Radiol 81 (8): 1907-12, 2012. [PubMed: 21549535]
25. Bernstrand C, Cederlund K, Henter JI: Pulmonary function testing and pulmonary Langerhans cell histiocytosis. Pediatr Blood Cancer 49 (3): 323-8, 2007. [PubMed: 16317743]
26. Odame I, Li P, Lau L, et al.: Pulmonary Langerhans cell histiocytosis: a variable disease in childhood. Pediatr Blood Cancer 47 (7): 889-93, 2006. [PubMed: 16276522]
27. Ronceray L, Pötschger U, Janka G, et al.: Pulmonary involvement in pediatric-onset multisystem Langerhans cell histiocytosis: effect on course and outcome. J Pediatr 161 (1): 129-33.e1-3, 2012. [PubMed: 22284564]
28. McClain K, Ramsay NK, Robison L, et al.: Bone marrow involvement in histiocytosis X. Med Pediatr Oncol 11 (3): 167-71, 1983. [PubMed: 6602270]
29. Minkov M, Pötschger U, Grois N, et al.: Bone marrow assessment in Langerhans cell histiocytosis. Pediatr Blood Cancer 49 (5): 694-8, 2007. [PubMed: 17455318]
30. Galluzzo ML, Braier J, Rosenzweig SD, et al.: Bone marrow findings at diagnosis in patients with multisystem langerhans cell histiocytosis. Pediatr Dev Pathol 13 (2): 101-6, 2010 Mar-Apr. [PMC free article: PMC3740343] [PubMed: 19863448]
31. Favara BE, Jaffe R, Egeler RM: Macrophage activation and hemophagocytic syndrome in langerhans cell histiocytosis: report of 30 cases. Pediatr Dev Pathol 5 (2): 130-40, 2002 Mar-Apr. [PubMed: 11910507]
32. Donadieu J, Rolon MA, Thomas C, et al.: Endocrine involvement in pediatric-onset Langerhans' cell histiocytosis: a population-based study. J Pediatr 144 (3): 344-50, 2004. [PubMed: 15001940]
33. Prosch H, Grois N, Prayer D, et al.: Central diabetes insipidus as presenting symptom of Langerhans cell histiocytosis. Pediatr Blood Cancer 43 (5): 594-9, 2004. [PubMed: 15382278]
34. Richards GE, Thomsett MJ, Boston BA, et al.: Natural history of idiopathic diabetes insipidus. J Pediatr 159 (4): 566-70, 2011. [PubMed: 21592500]
35. Marchand I, Barkaoui MA, Garel C, et al.: Central diabetes insipidus as the inaugural manifestation of Langerhans cell histiocytosis: natural history and medical evaluation of 26 children and adolescents. J Clin Endocrinol Metab 96 (9): E1352-60, 2011. [PubMed: 21752883]
36. Dunger 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 321 (17): 1157-62, 1989. [PubMed: 2797079]
37. Grois N, Pötschger U, Prosch H, et al.: Risk factors for diabetes insipidus in langerhans cell histiocytosis. Pediatr Blood Cancer 46 (2): 228-33, 2006. [PubMed: 16047354]
38. Shioda Y, Adachi S, Imashuku S, et al.: Analysis of 43 cases of Langerhans cell histiocytosis (LCH)-induced central diabetes insipidus registered in the JLSG-96 and JLSG-02 studies in Japan. Int J Hematol 94 (6): 545-51, 2011. [PubMed: 22139588]
39. Gadner H, Grois N, Arico M, et al.: A randomized trial of treatment for multisystem Langerhans' cell histiocytosis. J Pediatr 138 (5): 728-34, 2001. [PubMed: 11343051]
40. Gadner H, Grois N, Pötschger U, et al.: Improved outcome in multisystem Langerhans cell histiocytosis is associated with therapy intensification. Blood 111 (5): 2556-62, 2008. [PubMed: 18089850]
41. Gadner H, Minkov M, Grois N, et al.: Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis. Blood 121 (25): 5006-14, 2013. [PubMed: 23589673]
42. Gadner H, Heitger A, Grois N, et al.: Treatment strategy for disseminated Langerhans cell histiocytosis. DAL HX-83 Study Group. Med Pediatr Oncol 23 (2): 72-80, 1994. [PubMed: 8202045]
43. Grois NG, Favara BE, Mostbeck GH, et al.: Central nervous system disease in Langerhans cell histiocytosis. Hematol Oncol Clin North Am 12 (2): 287-305, 1998. [PubMed: 9561901]
44. Grois N, Prayer D, Prosch H, et al.: Neuropathology of CNS disease in Langerhans cell histiocytosis. Brain 128 (Pt 4): 829-38, 2005. [PubMed: 15705614]
45. Fahrner B, Prosch H, Minkov M, et al.: Long-term outcome of hypothalamic pituitary tumors in Langerhans cell histiocytosis. Pediatr Blood Cancer 58 (4): 606-10, 2012. [PubMed: 22183971]
46. Prayer D, Grois N, Prosch H, et al.: MR imaging presentation of intracranial disease associated with Langerhans cell histiocytosis. AJNR Am J Neuroradiol 25 (5): 880-91, 2004. [PMC free article: PMC7974468] [PubMed: 15140741]
47. Wnorowski M, Prosch H, Prayer D, et al.: Pattern and course of neurodegeneration in Langerhans cell histiocytosis. J Pediatr 153 (1): 127-32, 2008. [PubMed: 18571550]
48. Mittheisz E, Seidl R, Prayer D, et al.: Central nervous system-related permanent consequences in patients with Langerhans cell histiocytosis. Pediatr Blood Cancer 48 (1): 50-6, 2007. [PubMed: 16470521]

References

1. Haupt R, Minkov M, Astigarraga I, et al.: Langerhans cell histiocytosis (LCH): guidelines for diagnosis, clinical work-up, and treatment for patients till the age of 18 years. Pediatr Blood Cancer 60 (2): 175-84, 2013. [PMC free article: PMC4557042] [PubMed: 23109216]
2. Calming U, Jacobsson H, Henter JI: Detection of Langerhans cell histiocytosis lesions with somatostatin analogue scintigraphy--a preliminary report. Med Pediatr Oncol 35 (5): 462-7, 2000. [PubMed: 11070478]
3. Calming U, Bemstrand C, Mosskin M, et al.: Brain 18-FDG PET scan in central nervous system langerhans cell histiocytosis. J Pediatr 141 (3): 435-40, 2002. [PubMed: 12219070]
4. Binkovitz LA, Olshefski RS, Adler BH: Coincidence FDG-PET in the evaluation of Langerhans' cell histiocytosis: preliminary findings. Pediatr Radiol 33 (9): 598-602, 2003. [PubMed: 12879314]
5. Phillips M, Allen C, Gerson P, et al.: Comparison of FDG-PET scans to conventional radiography and bone scans in management of Langerhans cell histiocytosis. Pediatr Blood Cancer 52 (1): 97-101, 2009. [PubMed: 18951435]
6. Ribeiro MJ, Idbaih A, Thomas C, et al.: 18F-FDG PET in neurodegenerative Langerhans cell histiocytosis : results and potential interest for an early diagnosis of the disease. J Neurol 255 (4): 575-80, 2008. [PubMed: 18227990]
7. 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 43 (1): 59-65, 2004. [PubMed: 15170891]
8. Ha SY, Helms P, Fletcher M, et al.: Lung involvement in Langerhans' cell histiocytosis: prevalence, clinical features, and outcome. Pediatrics 89 (3): 466-9, 1992. [PubMed: 1741222]
9. Prasad SR, Wang H, Rosas H, et al.: Fat-containing lesions of the liver: radiologic-pathologic correlation. Radiographics 25 (2): 321-31, 2005 Mar-Apr. [PubMed: 15798052]
10. Prayer D, Grois N, Prosch H, et al.: MR imaging presentation of intracranial disease associated with Langerhans cell histiocytosis. AJNR Am J Neuroradiol 25 (5): 880-91, 2004. [PMC free article: PMC7974468] [PubMed: 15140741]
11. Chikwava K, Jaffe R: Langerin (CD207) staining in normal pediatric tissues, reactive lymph nodes, and childhood histiocytic disorders. Pediatr Dev Pathol 7 (6): 607-14, 2004 Nov-Dec. [PubMed: 15630529]

References

1. Wnorowski M, Prosch H, Prayer D, et al.: Pattern and course of neurodegeneration in Langerhans cell histiocytosis. J Pediatr 153 (1): 127-32, 2008. [PubMed: 18571550]
2. Allen CE, Flores R, Rauch R, et al.: Neurodegenerative central nervous system Langerhans cell histiocytosis and coincident hydrocephalus treated with vincristine/cytosine arabinoside. Pediatr Blood Cancer 54 (3): 416-23, 2010. [PMC free article: PMC3444163] [PubMed: 19908293]
3. Bernstrand C, Cederlund K, Henter JI: Pulmonary function testing and pulmonary Langerhans cell histiocytosis. Pediatr Blood Cancer 49 (3): 323-8, 2007. [PubMed: 16317743]
4. Nanduri VR, Pritchard J, Levitt G, et al.: Long term morbidity and health related quality of life after multi-system Langerhans cell histiocytosis. Eur J Cancer 42 (15): 2563-9, 2006. [PubMed: 16959486]

Standard Treatment Options by Organ, Site or System Involvement for Pediatric Patients

The standard treatment for LCH is best chosen based on data from international trials with large numbers of patients. However, some patients may have LCH involving only the skin, mouth, pituitary gland, or other sites not studied in these international trials. In such cases therapy recommendations are based upon case series that lack the evidence-based strength of the trials.

Treatment Options for Childhood LCH No Longer Considered Effective

Treatments that have been used in the past but are no longer recommended for pediatric patients with LCH in any location include cyclosporine [40] and interferon-alpha.[41] Extensive surgery is also not indicated. Curettage of a circumscribed skull lesion may be sufficient if the lesion in not in the temporal, mastoid, or orbital areas (CNS risk). Patients with disease in these particular sites are recommended to receive 6 months of systemic therapy with vinblastine and prednisone. For lesions of the mandible, extensive surgery may destroy any possibility of secondary tooth development. Surgical resection of groin or genital lesions is contraindicated as these lesions can be healed by chemotherapy.

Radiation therapy use in LCH has been significantly reduced in pediatric patients, and even low-dose radiation therapy should be limited to single-bone vertebral body lesions or other single-bone lesions compressing the spinal cord or optic nerve that do not respond to chemotherapy.[42]

Assessment of Response to Treatment

Response assessment remains one of the most difficult areas in LCH therapy unless there is a specific area that can be followed clinically or with sonography, computed tomography (CT), or MRI scans of areas such as the skin, hepato/splenomegaly, and other mass lesions. Clinical judgment including evaluation of pain and other symptoms remains important.

Bone lesions may take many months to heal and are difficult to evaluate on plain radiographs, although sclerosis around the periphery of a bone lesion suggests healing. CT or MRI scans are useful in assessing response of a soft tissue mass associated with a bone lesion, but is not particularly helpful in lytic bone lesions. Technetium bone scans remain positive in healing bone. Positron emission tomography (PET) scans may be helpful in following the response to therapy since intensity of the PET image diminishes with response of lesions and healing of bone.[43]

For children or adults with lung LCH, pulmonary function testing and high resolution CT scans are sensitive methods for detecting disease progression.[44] Residual interstitial changes reflecting residual fibrosis or residual inactive cysts must be distinguished from active disease and somatostatin analogue scintigraphy may be useful in this regard.[45]

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with childhood Langerhans cell histiocytosis. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

References

1. 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 32 (4): e122-5, 2010. [PubMed: 20418784]
2. Gadner H, Minkov M, Grois N, et al.: Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis. Blood 121 (25): 5006-14, 2013. [PubMed: 23589673]
3. Lau L, Krafchik B, Trebo MM, et al.: Cutaneous Langerhans cell histiocytosis in children under one year. Pediatr Blood Cancer 46 (1): 66-71, 2006. [PubMed: 16261594]
4. Steen AE, Steen KH, Bauer R, et al.: Successful treatment of cutaneous Langerhans cell histiocytosis with low-dose methotrexate. Br J Dermatol 145 (1): 137-40, 2001. [PubMed: 11453923]
5. McClain KL, Kozinetz CA: A phase II trial using thalidomide for Langerhans cell histiocytosis. Pediatr Blood Cancer 48 (1): 44-9, 2007. [PubMed: 16333818]
6. Hoeger PH, Nanduri VR, Harper JI, et al.: Long term follow up of topical mustine treatment for cutaneous langerhans cell histiocytosis. Arch Dis Child 82 (6): 483-7, 2000. [PMC free article: PMC1718363] [PubMed: 10833183]
7. Lindahl LM, Fenger-Grøn M, Iversen L: Topical nitrogen mustard therapy in patients with Langerhans cell histiocytosis. Br J Dermatol 166 (3): 642-5, 2012. [PubMed: 21967132]
8. Kwon OS, Cho KH, Song KY: Primary cutaneous Langerhans cell histiocytosis treated with photochemotherapy. J Dermatol 24 (1): 54-6, 1997. [PubMed: 9046743]
9. Vogel CA, Aughenbaugh W, Sharata H: Excimer laser as adjuvant therapy for adult cutaneous Langerhans cell histiocytosis. Arch Dermatol 144 (10): 1287-90, 2008. [PubMed: 18936391]
10. Nauert C, Zornoza J, Ayala A, et al.: Eosinophilic granuloma of bone: diagnosis and management. Skeletal Radiol 10 (4): 227-35, 1983. [PubMed: 6359441]
11. Gramatovici R, D'Angio GJ: Radiation therapy in soft-tissue lesions in histiocytosis X (Langerhans' cell histiocytosis). Med Pediatr Oncol 16 (4): 259-62, 1988. [PubMed: 3262194]
12. Baptista AM, Camargo AF, de Camargo OP, et al.: Does adjunctive chemotherapy reduce remission rates compared to cortisone alone in unifocal or multifocal histiocytosis of bone? Clin Orthop Relat Res 470 (3): 663-9, 2012. [PMC free article: PMC3270175] [PubMed: 22052526]
13. Gadner H, Grois N, Arico M, et al.: A randomized trial of treatment for multisystem Langerhans' cell histiocytosis. J Pediatr 138 (5): 728-34, 2001. [PubMed: 11343051]
14. Grois N, Pötschger U, Prosch H, et al.: Risk factors for diabetes insipidus in langerhans cell histiocytosis. Pediatr Blood Cancer 46 (2): 228-33, 2006. [PubMed: 16047354]
15. Woo KI, Harris GJ: Eosinophilic granuloma of the orbit: understanding the paradox of aggressive destruction responsive to minimal intervention. Ophthal Plast Reconstr Surg 19 (6): 429-39, 2003. [PubMed: 14625488]
16. Dunger 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 321 (17): 1157-62, 1989. [PubMed: 2797079]
17. Gadner H, Heitger A, Grois N, et al.: Treatment strategy for disseminated Langerhans cell histiocytosis. DAL HX-83 Study Group. Med Pediatr Oncol 23 (2): 72-80, 1994. [PubMed: 8202045]
18. Kotecha R, Venkatramani R, Jubran RF, et al.: Clinical outcomes of radiation therapy in the management of Langerhans cell histiocytosis. Am J Clin Oncol 37 (6): 592-6, 2014. [PubMed: 23466581]
19. Peng XS, Pan T, Chen LY, et al.: Langerhans' cell histiocytosis of the spine in children with soft tissue extension and chemotherapy. Int Orthop 33 (3): 731-6, 2009. [PMC free article: PMC2903089] [PubMed: 18338168]
20. Lau LM, Stuurman K, Weitzman S: Skeletal Langerhans cell histiocytosis in children: permanent consequences and health-related quality of life in long-term survivors. Pediatr Blood Cancer 50 (3): 607-12, 2008. [PubMed: 17973322]
21. Mammano S, Candiotto S, Balsano M: Cast and brace treatment of eosinophilic granuloma of the spine: long-term follow-up. J Pediatr Orthop 17 (6): 821-7, 1997 Nov-Dec. [PubMed: 9591990]
22. Titgemeyer C, Grois N, Minkov M, et al.: Pattern and course of single-system disease in Langerhans cell histiocytosis data from the DAL-HX 83- and 90-study. Med Pediatr Oncol 37 (2): 108-14, 2001. [PubMed: 11496348]
23. Egeler RM, de Kraker J, Voûte PA: Cytosine-arabinoside, vincristine, and prednisolone in the treatment of children with disseminated Langerhans cell histiocytosis with organ dysfunction: experience at a single institution. Med Pediatr Oncol 21 (4): 265-70, 1993. [PubMed: 8469221]
24. Farran RP, Zaretski E, Egeler RM: Treatment of Langerhans cell histiocytosis with pamidronate. J Pediatr Hematol Oncol 23 (1): 54-6, 2001. [PubMed: 11196272]
25. Morimoto A, Shioda Y, Imamura T, et al.: Nationwide survey of bisphosphonate therapy for children with reactivated Langerhans cell histiocytosis in Japan. Pediatr Blood Cancer 56 (1): 110-5, 2011. [PubMed: 21108445]
26. Gadner H, Grois N, Pötschger U, et al.: Improved outcome in multisystem Langerhans cell histiocytosis is associated with therapy intensification. Blood 111 (5): 2556-62, 2008. [PubMed: 18089850]
27. Ronceray L, Pötschger U, Janka G, et al.: Pulmonary involvement in pediatric-onset multisystem Langerhans cell histiocytosis: effect on course and outcome. J Pediatr 161 (1): 129-33.e1-3, 2012. [PubMed: 22284564]
28. Morimoto A, Ikushima S, Kinugawa N, et al.: Improved outcome in the treatment of pediatric multifocal Langerhans cell histiocytosis: Results from the Japan Langerhans Cell Histiocytosis Study Group-96 protocol study. Cancer 107 (3): 613-9, 2006. [PubMed: 16804933]
29. Jordan MB, McClain KL, Yan X, et al.: Anti-CD52 antibody, alemtuzumab, binds to Langerhans cells in Langerhans cell histiocytosis. Pediatr Blood Cancer 44 (3): 251-4, 2005. [PubMed: 15390358]
30. Büchler T, Cervinek L, Belohlavek O, et al.: Langerhans cell histiocytosis with central nervous system involvement: follow-up by FDG-PET during treatment with cladribine. Pediatr Blood Cancer 44 (3): 286-8, 2005. [PubMed: 15481071]
31. Watts J, Files B: Langerhans cell histiocytosis: central nervous system involvement treated successfully with 2-chlorodeoxyadenosine. Pediatr Hematol Oncol 18 (3): 199-204, 2001 Apr-May. [PubMed: 11293288]
32. Dhall G, Finlay JL, Dunkel IJ, et al.: Analysis of outcome for patients with mass lesions of the central nervous system due to Langerhans cell histiocytosis treated with 2-chlorodeoxyadenosine. Pediatr Blood Cancer 50 (1): 72-9, 2008. [PubMed: 17455311]
33. Grois N, Fahrner B, Arceci RJ, et al.: Central nervous system disease in Langerhans cell histiocytosis. J Pediatr 156 (6): 873-81, 881.e1, 2010. [PubMed: 20434166]
34. Ng Wing Tin S, Martin-Duverneuil N, Idbaih A, et al.: Efficacy of vinblastine in central nervous system Langerhans cell histiocytosis: a nationwide retrospective study. Orphanet J Rare Dis 6 (1): 83, 2011. [PMC free article: PMC3287163] [PubMed: 22151964]
35. Idbaih A, Donadieu J, Barthez MA, et al.: Retinoic acid therapy in "degenerative-like" neuro-langerhans cell histiocytosis: a prospective pilot study. Pediatr Blood Cancer 43 (1): 55-8, 2004. [PubMed: 15170890]
36. Imashuku S, Ishida S, Koike K, et al.: Cerebellar ataxia in pediatric patients with Langerhans cell histiocytosis. J Pediatr Hematol Oncol 26 (11): 735-9, 2004. [PubMed: 15543008]
37. Imashuku S, Okazaki NA, Nakayama M, et al.: Treatment of neurodegenerative CNS disease in Langerhans cell histiocytosis with a combination of intravenous immunoglobulin and chemotherapy. Pediatr Blood Cancer 50 (2): 308-11, 2008. [PubMed: 17458874]
38. Allen CE, Flores R, Rauch R, et al.: Neurodegenerative central nervous system Langerhans cell histiocytosis and coincident hydrocephalus treated with vincristine/cytosine arabinoside. Pediatr Blood Cancer 54 (3): 416-23, 2010. [PMC free article: PMC3444163] [PubMed: 19908293]
39. Chohan G, Barnett Y, Gibson J, et al.: Langerhans cell histiocytosis with refractory central nervous system involvement responsive to infliximab. J Neurol Neurosurg Psychiatry 83 (5): 573-5, 2012. [PubMed: 21856693]
40. Minkov M, Grois N, Broadbent V, et al.: Cyclosporine A therapy for multisystem langerhans cell histiocytosis. Med Pediatr Oncol 33 (5): 482-5, 1999. [PubMed: 10531573]
41. Lukina EA, Kuznetsov VP, Beliaev DL, et al.: [The treatment of histiocytosis X (Langerhans-cell histiocytosis) with alpha-interferon preparations] Ter Arkh 65 (11): 67-70, 1993. [PubMed: 8108804]
42. Gadner H, Ladisch S: The treatment of Langerhans cell histiocytosis. In: Weitzman S, Egeler R M, eds.: Histiocytic Disorders of Children and Adults. Cambridge, United Kingdom: Cambridge University Press, 2005, pp 229-53.
43. Phillips M, Allen C, Gerson P, et al.: Comparison of FDG-PET scans to conventional radiography and bone scans in management of Langerhans cell histiocytosis. Pediatr Blood Cancer 52 (1): 97-101, 2009. [PubMed: 18951435]
44. Ha SY, Helms P, Fletcher M, et al.: Lung involvement in Langerhans' cell histiocytosis: prevalence, clinical features, and outcome. Pediatrics 89 (3): 466-9, 1992. [PubMed: 1741222]
45. Tazi A, Hiltermann J, Vassallo R: Adult lung histiocytosis. In: Weitzman S, Egeler R M, eds.: Histiocytic Disorders of Children and Adults. Cambridge, United Kingdom: Cambridge University Press, 2005, pp 187-207.

Recurrent Low-Risk Organ Involvement

Refractory High-Risk Organ Involvement

A new treatment plan is indicated when a patient with multisystem involvement shows progressive disease after 6 weeks of standard treatment, or has not had a partial response by 12 weeks. Data from the DAL Group studies have shown that these children have only a 10% chance of surviving.[14] Results from the LCH-II trial revealed that patients treated with vinblastine/prednisone who did not respond well by 6 weeks had a 27% chance of survival, compared with 52% for good responders.[4][Level of evidence: 1iiA] All studies suggest that patients with poorly responsive disease need to be changed early to salvage strategies at 6 weeks for progressive disease and no later than 12 weeks for those without at least a good response.

Cladribine and 2’-deoxycoformycin have been tested as salvage therapies for LCH.[11,15]; [16][Level of evidence: 3iiiDiv] A case series reported that patients with multiple reactivations or high-risk disease could be effectively treated with continuous-infusion cladribine for 3 days. Seven of ten patients on this trial required no more therapy.[17][Level of evidence: 3iiiDii]

Ten patients with refractory high-risk organ (liver, spleen, or bone marrow) involvement and resistant multisystem low-risk organ involvement have been treated with an intensive acute myeloid leukemia–like protocol. Prompt change of therapy to cladribine and cytosine arabinoside appeared to provide an improvement in overall survival (OS).[18]; [19][Level of evidence: 3iiiDii]; [20][Level of evidence: 3iiiDiv] A prospective trial of the cladribine and cytosine arabinoside protocol (N = 27) showed a progression-free survival rate of 63% and an overall 5-year survival rate of 85%.[21]

Six patients with multiorgan LCH resistant to other agents, including cladribine, were reported to respond to treatment with clofarabine.[22]; [23][Level of evidence: 3iiiDii] An additional 11 patients with recurrent multisystem high-risk and low-risk disease had a 90% OS.[13] If confirmed in prospective trials, the reduced toxicity of this regimen, compared with the cladribine/cytarabine combination, could be advantageous despite the cost of the drug.

Hematopoietic stem cell transplantation (HSCT) has been used in patients with multisystem high-risk organ involvement that is refractory to chemotherapy.[7,24-26] The use of reduced-intensity conditioning, especially for patients that have received intensive chemotherapy just before HSCT, may reduce toxic deaths and improve outcome.[27]

Treatment Options Under Clinical Evaluation

New targeted therapies under investigation include the following:

• RAS pathway inhibitors: The discovery that most patients with LCH have BRAF V600E or other mutations that result in activation of the RAS pathway, suggests that new therapies that target molecules within this pathway will become an important part of LCH therapy in the near future. NCT01677741 is currently open in the United States and Canada for adults with LCH and children with recurrent LCH. Although three adults with LCH and Erdheim-Chester disease had favorable responses to vemurafinib,[28] the 30% incidence of squamous cell carcinoma in melanoma patients receiving this drug needs to be taken into account with moderate- to long-term use in children.
• Tyrosine kinase inhibitors: Several reports suggested that LCH, including central nervous system LCH, could be successfully treated with the tyrosine kinase inhibitor imatinib,[29] while other reports failed to show an effect.[30,31]

References

1. Pollono D, Rey G, Latella A, et al.: Reactivation and risk of sequelae in Langerhans cell histiocytosis. Pediatr Blood Cancer 48 (7): 696-9, 2007. [PubMed: 17252574]
2. Minkov M, Steiner M, Pötschger U, et al.: Reactivations in multisystem Langerhans cell histiocytosis: data of the international LCH registry. J Pediatr 153 (5): 700-5, 705.e1-2, 2008. [PubMed: 18589441]
3. Morimoto A, Ikushima S, Kinugawa N, et al.: Improved outcome in the treatment of pediatric multifocal Langerhans cell histiocytosis: Results from the Japan Langerhans Cell Histiocytosis Study Group-96 protocol study. Cancer 107 (3): 613-9, 2006. [PubMed: 16804933]
4. Gadner H, Grois N, Pötschger U, et al.: Improved outcome in multisystem Langerhans cell histiocytosis is associated with therapy intensification. Blood 111 (5): 2556-62, 2008. [PubMed: 18089850]
5. Titgemeyer C, Grois N, Minkov M, et al.: Pattern and course of single-system disease in Langerhans cell histiocytosis data from the DAL-HX 83- and 90-study. Med Pediatr Oncol 37 (2): 108-14, 2001. [PubMed: 11496348]
6. Egeler RM, de Kraker J, Voûte PA: Cytosine-arabinoside, vincristine, and prednisolone in the treatment of children with disseminated Langerhans cell histiocytosis with organ dysfunction: experience at a single institution. Med Pediatr Oncol 21 (4): 265-70, 1993. [PubMed: 8469221]
7. Kudo K, Ohga S, Morimoto A, et al.: Improved outcome of refractory Langerhans cell histiocytosis in children with hematopoietic stem cell transplantation in Japan. Bone Marrow Transplant 45 (5): 901-6, 2010. [PubMed: 19767778]
8. Farran RP, Zaretski E, Egeler RM: Treatment of Langerhans cell histiocytosis with pamidronate. J Pediatr Hematol Oncol 23 (1): 54-6, 2001. [PubMed: 11196272]
9. Morimoto A, Shioda Y, Imamura T, et al.: Nationwide survey of bisphosphonate therapy for children with reactivated Langerhans cell histiocytosis in Japan. Pediatr Blood Cancer 56 (1): 110-5, 2011. [PubMed: 21108445]
10. Sivendran S, Harvey H, Lipton A, et al.: Treatment of Langerhans cell histiocytosis bone lesions with zoledronic acid: a case series. Int J Hematol 93 (6): 782-6, 2011. [PubMed: 21519845]
11. Weitzman S, Braier J, Donadieu J, et al.: 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 53 (7): 1271-6, 2009. [PubMed: 19731321]
12. McClain KL, Kozinetz CA: A phase II trial using thalidomide for Langerhans cell histiocytosis. Pediatr Blood Cancer 48 (1): 44-9, 2007. [PubMed: 16333818]
13. Simko SJ, Tran HD, Jones J, et al.: Clofarabine salvage therapy in refractory multifocal histiocytic disorders, including Langerhans cell histiocytosis, juvenile xanthogranuloma and Rosai-Dorfman disease. Pediatr Blood Cancer 61 (3): 479-87, 2014. [PMC free article: PMC4474604] [PubMed: 24106153]
14. Gadner H, Grois N, Arico M, et al.: A randomized trial of treatment for multisystem Langerhans' cell histiocytosis. J Pediatr 138 (5): 728-34, 2001. [PubMed: 11343051]
15. Weitzman S, Wayne AS, Arceci R, et al.: Nucleoside analogues in the therapy of Langerhans cell histiocytosis: a survey of members of the histiocyte society and review of the literature. Med Pediatr Oncol 33 (5): 476-81, 1999. [PubMed: 10531572]
16. Mottl H, Starý J, Chánová M, et al.: Treatment of recurrent Langerhans cell histiocytosis in children with 2-chlorodeoxyadenosine. Leuk Lymphoma 47 (9): 1881-4, 2006. [PubMed: 17065001]
17. Stine KC, Saylors RL, Saccente S, et al.: Efficacy of continuous infusion 2-CDA (cladribine) in pediatric patients with Langerhans cell histiocytosis. Pediatr Blood Cancer 43 (1): 81-4, 2004. [PubMed: 15170896]
18. Bernard F, Thomas C, Bertrand Y, et al.: Multi-centre pilot study of 2-chlorodeoxyadenosine and cytosine arabinoside combined chemotherapy in refractory Langerhans cell histiocytosis with haematological dysfunction. Eur J Cancer 41 (17): 2682-9, 2005. [PubMed: 16291085]
19. Apollonsky N, Lipton JM: Treatment of refractory Langerhans cell histiocytosis (LCH) with a combination of 2-chlorodeoxyadenosine and cytosine arabinoside. J Pediatr Hematol Oncol 31 (1): 53-6, 2009. [PubMed: 19125089]
20. Imamura 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 91 (4): 646-51, 2010. [PubMed: 20361277]
21. Donadieu J, Bernard F, van Noesel M, et al.: Cladribine and cytarabine in refractory multisystem Langerhans cell histiocytosis: results of an international phase 2 study. Blood 126 (12): 1415-23, 2015. [PMC free article: PMC4624454] [PubMed: 26194764]
22. Rodriguez-Galindo C, Jeng M, Khuu P, et al.: Clofarabine in refractory Langerhans cell histiocytosis. Pediatr Blood Cancer 51 (5): 703-6, 2008. [PubMed: 18623218]
23. Abraham A, Alsultan A, Jeng M, et al.: Clofarabine salvage therapy for refractory high-risk langerhans cell histiocytosis. Pediatr Blood Cancer 60 (6): E19-22, 2013. [PubMed: 23255383]
24. Akkari V, Donadieu J, Piguet C, et al.: Hematopoietic stem cell transplantation in patients with severe Langerhans cell histiocytosis and hematological dysfunction: experience of the French Langerhans Cell Study Group. Bone Marrow Transplant 31 (12): 1097-103, 2003. [PubMed: 12796789]
25. Nagarajan R, Neglia J, Ramsay N, et al.: Successful treatment of refractory Langerhans cell histiocytosis with unrelated cord blood transplantation. J Pediatr Hematol Oncol 23 (9): 629-32, 2001. [PubMed: 11902312]
26. Caselli D, Aricò M; EBMT Paediatric Working Party: The role of BMT in childhood histiocytoses. Bone Marrow Transplant 41 (Suppl 2): S8-S13, 2008. [PubMed: 18545250]
27. Steiner 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 36 (3): 215-25, 2005. [PubMed: 15937510]
28. 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 121 (9): 1495-500, 2013. [PubMed: 23258922]
29. Janku F, Amin HM, Yang D, et al.: Response of histiocytoses to imatinib mesylate: fire to ashes. J Clin Oncol 28 (31): e633-6, 2010. [PubMed: 20733125]
30. Wagner C, Mohme H, Krömer-Olbrisch T, et al.: Langerhans cell histiocytosis: treatment failure with imatinib. Arch Dermatol 145 (8): 949-50, 2009. [PubMed: 19687437]
31. Baumann M, Cerny T, Sommacal A, et al.: Langerhans cell histiocytosis with central nervous system involvement--complete response to 2-chlorodeoxyadenosine after failure of tyrosine kinase inhibitor therapies with sorafenib and imatinib. Hematol Oncol 30 (2): 101-4, 2012. [PubMed: 21732400]

References

1. Lau LM, Stuurman K, Weitzman S: Skeletal Langerhans cell histiocytosis in children: permanent consequences and health-related quality of life in long-term survivors. Pediatr Blood Cancer 50 (3): 607-12, 2008. [PubMed: 17973322]
2. Nanduri VR, Pritchard J, Levitt G, et al.: Long term morbidity and health related quality of life after multi-system Langerhans cell histiocytosis. Eur J Cancer 42 (15): 2563-9, 2006. [PubMed: 16959486]
3. Haupt 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 42 (5): 438-44, 2004. [PubMed: 15049016]
4. Donadieu J, Rolon MA, Pion I, et al.: Incidence of growth hormone deficiency in pediatric-onset Langerhans cell histiocytosis: efficacy and safety of growth hormone treatment. J Clin Endocrinol Metab 89 (2): 604-9, 2004. [PubMed: 14764769]
5. Komp DM: Long-term sequelae of histiocytosis X. Am J Pediatr Hematol Oncol 3 (2): 163-8, 1981. [PubMed: 6975581]
6. Willis B, Ablin A, Weinberg V, et al.: Disease course and late sequelae of Langerhans' cell histiocytosis: 25-year experience at the University of California, San Francisco. J Clin Oncol 14 (7): 2073-82, 1996. [PubMed: 8683239]
7. Nanduri V, Tatevossian R, Sirimanna T: High incidence of hearing loss in long-term survivors of multisystem Langerhans cell histiocytosis. Pediatr Blood Cancer 54 (3): 449-53, 2010. [PubMed: 19813249]
8. Nanduri VR, Lillywhite L, Chapman C, et al.: Cognitive outcome of long-term survivors of multisystem langerhans cell histiocytosis: a single-institution, cross-sectional study. J Clin Oncol 21 (15): 2961-7, 2003. [PubMed: 12885816]
9. Mittheisz E, Seidl R, Prayer D, et al.: Central nervous system-related permanent consequences in patients with Langerhans cell histiocytosis. Pediatr Blood Cancer 48 (1): 50-6, 2007. [PubMed: 16470521]
10. Bernstrand C, Cederlund K, Henter JI: Pulmonary function testing and pulmonary Langerhans cell histiocytosis. Pediatr Blood Cancer 49 (3): 323-8, 2007. [PubMed: 16317743]
11. Braier J, Ciocca M, Latella A, et al.: Cholestasis, sclerosing cholangitis, and liver transplantation in Langerhans cell Histiocytosis. Med Pediatr Oncol 38 (3): 178-82, 2002. [PubMed: 11836717]
12. Guimarães LF, Dias PF, Janini ME, et al.: Langerhans cell histiocytosis: impact on the permanent dentition after an 8-year follow-up. J Dent Child (Chic) 75 (1): 64-8, 2008 Jan-Apr. [PubMed: 18505651]
13. Egeler RM, Neglia JP, Puccetti DM, et al.: Association of Langerhans cell histiocytosis with malignant neoplasms. Cancer 71 (3): 865-73, 1993. [PubMed: 8431870]
14. Egeler RM, Neglia JP, Aricò M, et al.: The relation of Langerhans cell histiocytosis to acute leukemia, lymphomas, and other solid tumors. The LCH-Malignancy Study Group of the Histiocyte Society. Hematol Oncol Clin North Am 12 (2): 369-78, 1998. [PubMed: 9561906]
15. Castro EC, Blazquez C, Boyd J, et al.: Clinicopathologic features of histiocytic lesions following ALL, with a review of the literature. Pediatr Dev Pathol 13 (3): 225-37, 2010 May-Jun. [PubMed: 19642834]
16. Feldman AL, Berthold F, Arceci RJ, et al.: Clonal relationship between precursor T-lymphoblastic leukaemia/lymphoma and Langerhans-cell histiocytosis. Lancet Oncol 6 (6): 435-7, 2005. [PubMed: 15925822]
17. Rodig SJ, Payne EG, Degar BA, et al.: Aggressive Langerhans cell histiocytosis following T-ALL: clonally related neoplasms with persistent expression of constitutively active NOTCH1. Am J Hematol 83 (2): 116-21, 2008. [PubMed: 17874453]

General Information

The natural history of disease in adult Langerhans cell histiocytosis (LCH), with the exception of pulmonary LCH, is unknown. It is unclear whether there are significant differences from childhood LCH, although it appears that multisystem-risk LCH is less aggressive than childhood high-risk disease. The risk of reactivations is unknown.

A consensus group reported on the evaluation and treatment of adult patients with LCH.[1] However, discussion continues, particularly regarding optimal first-line therapy.

References

1. 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 8: 72, 2013. [PMC free article: PMC3667012] [PubMed: 23672541]
2. Baumgartner I, von Hochstetter A, Baumert B, et al.: Langerhans'-cell histiocytosis in adults. Med Pediatr Oncol 28 (1): 9-14, 1997. [PubMed: 8950330]
3. Götz G, Fichter J: Langerhans'-cell histiocytosis in 58 adults. Eur J Med Res 9 (11): 510-4, 2004. [PubMed: 15649860]
4. Slater JM, Swarm OJ: Eosinophilic granuloma of bone. Med Pediatr Oncol 8 (2): 151-64, 1980. [PubMed: 6999317]
5. 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 85 (4): 1370-6, 2000. [PubMed: 10770168]
6. 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 39 (16): 2341-8, 2003. [PubMed: 14556926]
7. Vassallo R, Ryu JH, Schroeder DR, et al.: Clinical outcomes of pulmonary Langerhans'-cell histiocytosis in adults. N Engl J Med 346 (7): 484-90, 2002. [PubMed: 11844849]
8. Schönfeld N, Frank W, Wenig S, et al.: Clinical and radiologic features, lung function and therapeutic results in pulmonary histiocytosis X. Respiration 60 (1): 38-44, 1993. [PubMed: 8469818]
9. Travis WD, Borok Z, Roum JH, et al.: Pulmonary Langerhans cell granulomatosis (histiocytosis X). A clinicopathologic study of 48 cases. Am J Surg Pathol 17 (10): 971-86, 1993. [PubMed: 8372949]
10. 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 163 (6): 3511-5, 1999. [PubMed: 10477625]
11. Baqir M, Vassallo R, Maldonado F, et al.: Utility of bronchoscopy in pulmonary Langerhans cell histiocytosis. J Bronchology Interv Pulmonol 20 (4): 309-12, 2013. [PubMed: 24162113]
12. Yousem SA, Colby TV, Chen YY, et al.: Pulmonary Langerhans' cell histiocytosis: molecular analysis of clonality. Am J Surg Pathol 25 (5): 630-6, 2001. [PubMed: 11342775]
13. 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 38 (4): 548-51, 2014. [PubMed: 24625419]
14. Vassallo R, Ryu JH, Colby TV, et al.: Pulmonary Langerhans'-cell histiocytosis. N Engl J Med 342 (26): 1969-78, 2000. [PubMed: 10877650]
15. Delobbe A, Durieu J, Duhamel A, et al.: 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 9 (10): 2002-6, 1996. [PubMed: 8902457]
16. Chaulagain CP: Pulmonary langerhans' cell histiocytosis. Am J Med 122 (11): e5-6, 2009. [PubMed: 19854315]
17. Lin MW, Chang YL, Lee YC, et al.: Pulmonary Langerhans cell histiocytosis. Lung 187 (4): 261-2, 2009. [PubMed: 19440787]
18. Tazi A, Hiltermann J, Vassallo R: Adult lung histiocytosis. In: Weitzman S, Egeler R M, eds.: Histiocytic Disorders of Children and Adults. Cambridge, United Kingdom: Cambridge University Press, 2005, pp 187-207.
19. Dauriat G, Mal H, Thabut G, et al.: Lung transplantation for pulmonary langerhans' cell histiocytosis: a multicenter analysis. Transplantation 81 (5): 746-50, 2006. [PubMed: 16534477]
20. Crausman RS, Jennings CA, Tuder RM, et al.: Pulmonary histiocytosis X: pulmonary function and exercise pathophysiology. Am J Respir Crit Care Med 153 (1): 426-35, 1996. [PubMed: 8542154]
21. Diette GB, Scatarige JC, Haponik EF, et al.: Do high-resolution CT findings of usual interstitial pneumonitis obviate lung biopsy? Views of pulmonologists. Respiration 72 (2): 134-41, 2005 Mar-Apr. [PubMed: 15824522]
22. Soler P, Bergeron A, Kambouchner M, et al.: Is high-resolution computed tomography a reliable tool to predict the histopathological activity of pulmonary Langerhans cell histiocytosis? Am J Respir Crit Care Med 162 (1): 264-70, 2000. [PubMed: 10903252]
23. 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 21 (7): 1406-15, 2011. [PubMed: 21311888]
24. Abdallah M, Généreau T, Donadieu J, et al.: Langerhans' cell histiocytosis of the liver in adults. Clin Res Hepatol Gastroenterol 35 (6-7): 475-81, 2011. [PubMed: 21550330]
25. Howarth DM, Gilchrist GS, Mullan BP, et al.: Langerhans cell histiocytosis: diagnosis, natural history, management, and outcome. Cancer 85 (10): 2278-90, 1999. [PubMed: 10326709]

Standard Treatment Options

The lack of clinical trials limits the ability to make evidence-based recommendations for adult patients with Langerhans cell histiocytosis (LCH).

Most investigators have previously recommended treatment according to the guidelines given above for standard treatment of children with Langerhans cell histiocytosis. It is unclear, however, whether adult LCH responds as well as the childhood form of the disease. In addition, the drugs used in the treatment of children are not as well-tolerated when used in adults. Excessive neurologic toxicity from vinblastine, for example, prompted closure of the LCH-A1 trial.

A consensus opinion reported on the evaluation and treatment of adult patients with LCH.[1] Discussion continues, however, particularly with regard to optimal first-line therapy with some experienced clinicians preferring to start with vinblastine and prednisone and others with alternative therapy, such as single-agent cytosine arabinoside or cladribine.

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with adult Langerhans cell histiocytosis. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

References

1. 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 8: 72, 2013. [PMC free article: PMC3667012] [PubMed: 23672541]
2. Tazi A: Adult pulmonary Langerhans' cell histiocytosis. Eur Respir J 27 (6): 1272-85, 2006. [PubMed: 16772390]
3. Mogulkoc N, Veral A, Bishop PW, et al.: Pulmonary Langerhans' cell histiocytosis: radiologic resolution following smoking cessation. Chest 115 (5): 1452-5, 1999. [PubMed: 10334170]
4. Dauriat G, Mal H, Thabut G, et al.: Lung transplantation for pulmonary langerhans' cell histiocytosis: a multicenter analysis. Transplantation 81 (5): 746-50, 2006. [PubMed: 16534477]
5. 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 142 (5): 1150-1157, 2012. [PubMed: 22459770]
6. Abbritti M, Mazzei MA, Bargagli E, et al.: Utility of spiral CAT scan in the follow-up of patients with pulmonary Langerhans cell histiocytosis. Eur J Radiol 81 (8): 1907-12, 2012. [PubMed: 21549535]
7. Olschewski T, Seegenschmiedt MH: Radiotherapy of Langerhans' Cell Histiocytosis : Results and Implications of a National Patterns-of-Care Study. Strahlenther Onkol 182 (11): 629-34, 2006. [PubMed: 17072519]
8. Kriz J, Eich HT, Bruns F, et al.: Radiotherapy in langerhans cell histiocytosis - a rare indication in a rare disease. Radiat Oncol 8: 233, 2013. [PMC free article: PMC3852286] [PubMed: 24103738]
9. Arzoo K, Sadeghi S, Pullarkat V: Pamidronate for bone pain from osteolytic lesions in Langerhans'-cell histiocytosis. N Engl J Med 345 (3): 225, 2001. [PubMed: 11463032]
10. Farran RP, Zaretski E, Egeler RM: Treatment of Langerhans cell histiocytosis with pamidronate. J Pediatr Hematol Oncol 23 (1): 54-6, 2001. [PubMed: 11196272]
11. Brown RE: Bisphosphonates as antialveolar macrophage therapy in pulmonary langerhans cell histiocytosis? Med Pediatr Oncol 36 (6): 641-3, 2001. [PubMed: 11344496]
12. Kamizono J, Okada Y, Shirahata A, et al.: Bisphosphonate induces remission of refractory osteolysis in langerhans cell histiocytosis. J Bone Miner Res 17 (11): 1926-8, 2002. [PubMed: 12412797]
13. Morimoto A, Shioda Y, Imamura T, et al.: Nationwide survey of bisphosphonate therapy for children with reactivated Langerhans cell histiocytosis in Japan. Pediatr Blood Cancer 56 (1): 110-5, 2011. [PubMed: 21108445]
14. Reichle A, Vogt T, Kunz-Schughart L, et al.: Anti-inflammatory and angiostatic therapy in chemorefractory multisystem Langerhans' cell histiocytosis of adults. Br J Haematol 128 (5): 730-2, 2005. [PubMed: 15725096]
15. Vogel CA, Aughenbaugh W, Sharata H: Excimer laser as adjuvant therapy for adult cutaneous Langerhans cell histiocytosis. Arch Dermatol 144 (10): 1287-90, 2008. [PubMed: 18936391]
16. Rieker J, Hengge U, Ruzicka T, et al.: [Multifocal facial eosinophilic granuloma: successful treatment with topical tacrolimus]. Hautarzt 57 (4): 324-6, 2006. [PubMed: 16523273]
17. O'Kane D, Jenkinson H, Carson J: Langerhans cell histiocytosis associated with breast carcinoma successfully treated with topical imiquimod. Clin Exp Dermatol 34 (8): e829-32, 2009. [PubMed: 19843082]
18. Taverna JA, Stefanato CM, Wax FD, et al.: Adult cutaneous Langerhans cell histiocytosis responsive to topical imiquimod. J Am Acad Dermatol 54 (5): 911-3, 2006. [PubMed: 16635684]
19. McClain KL, Kozinetz CA: A phase II trial using thalidomide for Langerhans cell histiocytosis. Pediatr Blood Cancer 48 (1): 44-9, 2007. [PubMed: 16333818]
20. Steen AE, Steen KH, Bauer R, et al.: Successful treatment of cutaneous Langerhans cell histiocytosis with low-dose methotrexate. Br J Dermatol 145 (1): 137-40, 2001. [PubMed: 11453923]
21. Tsambaos D, Georgiou S, Kapranos N, et al.: Langerhans' cell histiocytosis: complete remission after oral isotretinoin therapy. Acta Derm Venereol 75 (1): 62-4, 1995. [PubMed: 7747539]
22. Cantu MA, Lupo PJ, Bilgi M, et al.: Optimal therapy for adults with Langerhans cell histiocytosis bone lesions. PLoS One 7 (8): e43257, 2012. [PMC free article: PMC3419729] [PubMed: 22916233]
23. Tsele E, Thomas DM, Chu AC: Treatment of adult Langerhans cell histiocytosis with etoposide. J Am Acad Dermatol 27 (1): 61-4, 1992. [PubMed: 1619078]
24. Munn SE, Olliver L, Broadbent V, et al.: Use of indomethacin in Langerhans cell histiocytosis. Med Pediatr Oncol 32 (4): 247-9, 1999. [PubMed: 10102016]
25. Saven A, Foon KA, Piro LD: 2-Chlorodeoxyadenosine-induced complete remissions in Langerhans-cell histiocytosis. Ann Intern Med 121 (6): 430-2, 1994. [PubMed: 7914398]
26. Pardanani A, Phyliky RL, Li CY, et al.: 2-Chlorodeoxyadenosine therapy for disseminated Langerhans cell histiocytosis. Mayo Clin Proc 78 (3): 301-6, 2003. [PubMed: 12630583]
27. 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 21 (6): 1173-8, 2010. [PubMed: 19861578]
28. Gadner H: Treatment of adult-onset Langerhans cell histiocytosis--is it different from the pediatric approach? Ann Oncol 21 (6): 1141-2, 2010. [PubMed: 19940006]
29. Chohan G, Barnett Y, Gibson J, et al.: Langerhans cell histiocytosis with refractory central nervous system involvement responsive to infliximab. J Neurol Neurosurg Psychiatry 83 (5): 573-5, 2012. [PubMed: 21856693]
30. Hong WC, Murovic JA, Gibbs I, et al.: Pituitary stalk Langerhans cell histiocytosis treated with CyberKnife radiosurgery. Clin Neurol Neurosurg 115 (5): 573-7, 2013. [PubMed: 22835714]
31. Dhall G, Finlay JL, Dunkel IJ, et al.: Analysis of outcome for patients with mass lesions of the central nervous system due to Langerhans cell histiocytosis treated with 2-chlorodeoxyadenosine. Pediatr Blood Cancer 50 (1): 72-9, 2008. [PubMed: 17455311]
32. Egeler RM, de Kraker J, Voûte PA: Cytosine-arabinoside, vincristine, and prednisolone in the treatment of children with disseminated Langerhans cell histiocytosis with organ dysfunction: experience at a single institution. Med Pediatr Oncol 21 (4): 265-70, 1993. [PubMed: 8469221]
33. Montella L, Insabato L, Palmieri G: Imatinib mesylate for cerebral Langerhans'-cell histiocytosis. N Engl J Med 351 (10): 1034-5, 2004. [PubMed: 15342818]
34. Janku F, Amin HM, Yang D, et al.: Response of histiocytoses to imatinib mesylate: fire to ashes. J Clin Oncol 28 (31): e633-6, 2010. [PubMed: 20733125]
35. Wagner C, Mohme H, Krömer-Olbrisch T, et al.: Langerhans cell histiocytosis: treatment failure with imatinib. Arch Dermatol 145 (8): 949-50, 2009. [PubMed: 19687437]
36. 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 121 (9): 1495-500, 2013. [PubMed: 23258922]
37. Charles J, Beani JC, Fiandrino G, et al.: Major response to vemurafenib in patient with severe cutaneous Langerhans cell histiocytosis harboring BRAF V600E mutation. J Am Acad Dermatol 71 (3): e97-9, 2014. [PubMed: 25128147]

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood and adult Langerhans cell histiocytosis. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Langerhans Cell Histiocytosis Treatment are:

• Louis S. Constine, MD (James P. Wilmot Cancer Center at University of Rochester Medical Center)
• Thomas G. Gross, MD, PhD (National Cancer Institute)
• Kenneth L. McClain, MD, PhD (Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital)
• Carlos Rodriguez-Galindo, MD (St. Jude Children's Research Hospital)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

National Cancer Institute: PDQ® Langerhans Cell Histiocytosis Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://www.cancer.gov/types/langerhans/hp/langerhans-treatment-pdq. Accessed <MM/DD/YYYY>.

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