References

1. Rodriguez-Galindo C, Allen CE: Langerhans cell histiocytosis. Blood 135 (16): 1319-1331, 2020. [PubMed: 32106306]
2. Emile JF, Abla O, Fraitag S, et al.: Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood 127 (22): 2672-81, 2016. [PMC free article: PMC5161007] [PubMed: 26966089]
3. 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]
4. Allen CE, Merad M, McClain KL: Langerhans-Cell Histiocytosis. N Engl J Med 379 (9): 856-868, 2018. [PMC free article: PMC6334777] [PubMed: 30157397]
5. 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]
6. 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]

Cell of Origin and Biologic Correlates

In accordance with the findings noted above, the pathologic histiocyte or Langerhans cell histiocytosis (LCH) cell has a gene expression profile closely resembling that of a myeloid dendritic cell. Studies have also demonstrated that the BRAF V600E mutation can be identified in mononuclear cells in peripheral blood and cell-free DNA, usually in patients with disseminated disease.[1-3] This shows that multisystem LCH arises from a somatic mutation within the marrow or a circulating precursor cell, while localized disease arises from a mutation occurring in a precursor cell at the local site.[2]

Modern classification of the histiocytic diseases subdivides them into dendritic cell–related, monocyte/macrophage-related, or true malignancies. LCH is a dendritic cell disease.[4,5] Comprehensive gene expression array data analysis on LCH cells is consistent with the concept that the skin Langerhans cell (LC) is not the cell of origin for LCH.[1] Rather, it is likely to be a hematopoietic progenitor cell before being a committed myeloid dendritic cell, which expresses the same antigens (CD1a and CD207) as the skin LC.[6,7] This concept was further supported by reports that the transcription profile of LCH cells was distinct from myeloid and plasmacytoid dendritic cells, as well as epidermal LCs.[1,6,8,9]

LCH is now considered a myeloid neoplasm. However, some controversy remains as to whether it is a true malignancy or a neoplasm with varying clinical behavior. The same BRAF V600E mutation has been found in many cancers; however, V600E-mutated BRAF is also present in benign nevi, possibly indicating the need for additional mutations for malignant transformation.[10] These findings have raised the possibility of treatment with targeted therapies; several trials of BRAF and MEK inhibitors are open for adults and children with LCH.

For more information, see the sections on Cytogenetic and Genomic Studies and Cytokine Analysis.

Histopathology

The Langerhans histiocytosis cells in LCH lesions (LCH cells) are immature dendritic cells making up fewer than 10% of the cells present in the lesion.[9,11] These cells are classically large oval cells with abundant pink cytoplasm and a bean-shaped nucleus on hematoxylin and eosin stain. LCH cells stain positively with antibodies to S100, CD1a, and/or anti-Langerin (CD207). Staining with CD1a or Langerin confirms the diagnosis of LCH, but care should be taken to correlate with clinical presentation in organs in which normal LC cells occur.[12]

Because LCH cells activate other immunologic cells, LCH lesions also contain other histiocytes, lymphocytes, macrophages, neutrophils, eosinophils, and fibroblasts, and they may contain multinucleated giant cells.

In the brain, the following three types of histopathologic findings have been described in LCH:

1. Mass lesions in the meninges or choroid plexus with CD1a-positive LCH cells and predominantly CD8-positive lymphocytes.
2. Mass lesions in connective tissue spaces with CD1a-positive LCH cells and predominantly CD8-positive lymphocytes that cause an inflammatory response and neuronal loss.
3. Neurodegenerative lesions, consisting of cells staining for the mutant BRAF protein with CD14+, CD33+, and CD163+, identifying these as hematopoietic myeloid/monocytic cells. These are the pathologic LCs that have migrated into the brain and do not stain with CD1a or CD207 and have become microglia-like.[13]

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.[14] Antibody staining for the dendritic cell markers, including 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.[11,14,15] Transforming growth factor-beta (TGF-beta) and interleukin (IL)-10 may be responsible for preventing LCH cell maturation in LCH.[11] The expansion of regulatory T cells in patients with LCH has been reported.[15] 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 the peripheral blood of controls and returned to a normal level when patients were in remission.[15]

Cytogenetic and Genomic Studies

Genomics of Langerhans Cell Histiocytosis (LCH)

BRAF, NRAS, and ARAF mutations

Pulmonary LCH in adults was initially reported to be nonclonal in approximately 75% of cases,[16] while an analysis of BRAF mutations showed that 25% to 50% of adult patients with lung LCH had evidence of BRAF V600E mutations.[16,17] Another study of 26 pulmonary LCH cases found that 50% had BRAF V600E mutations and 40% had NRAS mutations.[18] Approximately the same number of mutations are polyclonal as are monoclonal. It has not been determined whether clonality and BRAF pathway mutations are concordant in the same patients, which might suggest a reactive rather than a neoplastic condition in smoker's lung LCH and a clonal neoplasm in other types of LCH.

In a study of 117 patients with LCH, 83 patients with adult pulmonary LCH underwent molecular analysis. Nearly 90% of these patients had mutations in the MAPK pathway.[19][Level of evidence C3] Of the 69 patients who had their biopsy samples further analyzed using a next-generation sequencing panel of 74 genes, 36% had BRAF V600E mutations, 29% had BRAF N486-P490 deletions, 15% had MAP2K1 mutations or deletions, and 4% had NRAS mutations. Only one patient had a KRAS mutation. Additionally, 11 patients had their biopsy samples analyzed using whole-exome sequencing. An average of 14 mutations were found per patient, which is markedly higher than the average of one mutation found per pediatric patient.[20] There were no clinical correlates, including presence of a BRAF V600E mutation and smoking status. Of the 117 patients with LCH, 60% relapsed.

Figure 1. Courtesy of Rikhia Chakraborty, Ph.D. Permission to reuse the figure in any form must be obtained directly from Dr. Chakraborty.

The theory for the genomic basis of LCH was advanced by a 2010 report of an activating mutation of the BRAF oncogene (V600E) that was detected in 35 of 61 cases (57%).[21] Multiple subsequent reports have confirmed the presence of BRAF V600E mutations in 50% or more of LCH cases in children.[2,22,23] Other BRAF mutations that result in signal activation have been described.[22,24] ARAF mutations are infrequent in LCH but, when present, can also lead to RAS-MAPK pathway activation.[25]

The RAS-MAPK signaling pathway (see Figure 1) 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 the 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. Activation of ERK occurs by phosphorylation, and phosphorylated ERK can be detected in virtually all LCH lesions.[21,26]

The presence of the BRAF V600E mutation in blood and bone marrow was studied in a series of 100 patients, 65% of whom tested positive for the BRAF V600E mutation by a sensitive quantitative polymerase chain reaction technique.[2] Circulating cells with the BRAF V600E mutation could be detected in all high-risk patients and in a subset of low-risk multisystem patients. The presence of circulating cells with the mutation conferred a twofold increased risk of relapse. In a similar study that included 48 patients with BRAF V600E–mutated LCH, the BRAF V600E allele was detected in circulating cell-free DNA in 100% of patients with risk-organ–positive multisystem LCH, 42% of patients with risk-organ–negative LCH, and 14% of patients with single-system LCH.[27]

The myeloid dendritic cell origin of LCH was confirmed by finding CD34-positive stem cells with the mutation in the bone marrow of high-risk patients. In those with low-risk disease, the mutation was found in more mature myeloid dendritic cells, suggesting that the stage of cell development at which the somatic mutation occurs is critical in defining the extent of disease in LCH. LCH is now generally considered to represent a myeloid neoplasm.

Other RAS-MAPK pathway alterations

Because RAS-MAPK pathway activation can be detected in all LCH cases, but not all cases have BRAF mutations, the presence of genomic alterations in other components of the pathway was suspected. The following genomic alterations were identified:

• MAP2K1 mutations. Whole-exome sequencing of BRAF-mutated versus BRAF–wild-type LCH biopsy tissue samples revealed that 7 of 21 BRAF–wild-type specimens had MAP2K1 mutations, while no BRAF-mutated specimens had MAP2K1 mutations.[26] The mutations in MAP2K1 (which codes for MEK) were activating, as indicated by their induction of ERK phosphorylation.[26]
  Another study showed MAP2K1 mutations exclusively in 11 of 22 BRAF–wild-type cases.[28]
• In-frame BRAF deletions and FAM73A::BRAF fusions. In-frame BRAF deletions and in-frame FAM73A::BRAF fusions have occurred in the group of BRAF V600E and MAP2K1 mutation–negative cases.[20]

Studies support the universal activation of ERK in LCH; ERK activation in most cases is explained by BRAF and MAP2K1 alterations.[20,21,26] Altogether, these mutations in the MAP kinase pathway account for nearly 90% of the causes of the universal activation of ERK in LCH.[20,21,26]

Clinical implications

Clinical implications of the described genomic findings include the following:

• LCH joins a group of other pediatric entities with activating BRAF mutations, including select nonmalignant conditions (e.g., benign nevi) [29] and low-grade malignancies (e.g., pilocytic astrocytoma).[30,31] 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.[29,32]
• BRAF V600E mutations can be targeted by BRAF inhibitors (e.g., vemurafenib and dabrafenib) or by the combination of BRAF inhibitors plus MEK inhibitors (e.g., dabrafenib/trametinib and vemurafenib/cobimetinib). These agents and combinations are approved for adults with melanoma. Treatment of melanoma in adults with combinations of a BRAF inhibitor and a MEK inhibitor showed significantly improved progression-free survival outcomes compared with treatment using a BRAF inhibitor alone.[33,34]
  Case reports and case series have described the activity of BRAF inhibitors in adult patients with LCH [35-39] and pediatric patients with LCH.[40-44]
  Several case reports and two case series have demonstrated the efficacy of BRAF inhibitors for the treatment of LCH in children.[40-45] However, the long-term role of this therapy is complicated because most patients will relapse when the inhibitors are stopped.
• Circulating BRAF V600E–mutated cells have been found in 59% of patients who developed neurodegenerative-disease LCH, compared with 15% of patients who did not develop neurodegenerative-disease LCH. Detectable mutated circulating cells had a sensitivity of 0.59 and specificity of 0.86 for developing the neurodegenerative disease condition. Even after therapy, some patients with neurodegenerative-disease LCH had circulating BRAF V600E–mutated cells.[13]
• With additional research, the observation of the BRAF V600E mutation (or potentially MAP2K1 mutations) in circulating cells or cell-free DNA may become a useful diagnostic tool to define high-risk versus low-risk disease.[2] Additionally, for patients who have a somatic mutation, persistence of circulating cells with the mutation may be useful as a marker of residual disease.[2]

Cytokine Analysis

Immunohistochemical staining has shown upregulation of many different cytokines/chemokines, both in LCH lesions and in the serum/plasma of patients with LCH.[46,47] 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-positive and CD3-positive cells was SPP1 (encoding the osteopontin protein); other genes that activate and recruit T cells to sites of inflammation are also upregulated.[1] The expression profile of the T cells was that of an activated regulatory T-cell phenotype with increased expression of FOXP3, CTLA4, and SPP1. These findings support a previous report on the expansion of regulatory T cells in LCH.[1] There was pronounced expression of genes associated with early myeloid progenitors such as CD33 and CD44, which is consistent with an earlier report of elevated myeloid dendritic cells in the blood of patients with LCH.[48] 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.[1]

A study to evaluate possible biomarkers for central nervous system LCH examined 121 unique proteins in the cerebrospinal fluid (CSF) of 40 pediatric patients with LCH and compared them with controls, which included 29 patients with acute lymphoblastic leukemia, 25 patients with brain tumors, 28 patients with neurodegenerative diseases, and 9 patients with hemophagocytic lymphohistiocytosis. Only osteopontin proved to be significantly increased in the CSF of LCH patients with either neurodegeneration or mass lesions (pituitary), compared with all of the control groups. Analysis of osteopontin expression in these tissues confirmed an upregulation of the SPP1 gene.[13]

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.[1] 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.[49]

References

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2. 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]
3. Hyman DM, Diamond EL, Vibat CR, et al.: Prospective blinded study of BRAFV600E mutation detection in cell-free DNA of patients with systemic histiocytic disorders. Cancer Discov 5 (1): 64-71, 2015. [PMC free article: PMC5705028] [PubMed: 25324352]
4. Emile JF, Abla O, Fraitag S, et al.: Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood 127 (22): 2672-81, 2016. [PMC free article: PMC5161007] [PubMed: 26966089]
5. Picarsic J, Jaffe R: Nosology and Pathology of Langerhans Cell Histiocytosis. Hematol Oncol Clin North Am 29 (5): 799-823, 2015. [PubMed: 26461144]
6. Ginhoux F, Merad M: Ontogeny and homeostasis of Langerhans cells. Immunol Cell Biol 88 (4): 387-92, 2010 May-Jun. [PubMed: 20309014]
7. Durham BH, Roos-Weil D, Baillou C, et al.: Functional evidence for derivation of systemic histiocytic neoplasms from hematopoietic stem/progenitor cells. Blood 130 (2): 176-180, 2017. [PMC free article: PMC5510787] [PubMed: 28566492]
8. 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]
9. 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]
10. Badalian-Very G, Vergilio JA, Fleming M, et al.: Pathogenesis of Langerhans cell histiocytosis. Annu Rev Pathol 8: 1-20, 2013. [PubMed: 22906202]
11. Geissmann F, Lepelletier Y, Fraitag S, et al.: Differentiation of Langerhans cells in Langerhans cell histiocytosis. Blood 97 (5): 1241-8, 2001. [PubMed: 11222366]
12. 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]
13. McClain KL, Picarsic J, Chakraborty R, et al.: CNS Langerhans cell histiocytosis: Common hematopoietic origin for LCH-associated neurodegeneration and mass lesions. Cancer 124 (12): 2607-2620, 2018. [PMC free article: PMC6289302] [PubMed: 29624648]
14. 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]
15. 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]
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. Mourah S, How-Kit A, Meignin V, et al.: Recurrent NRAS mutations in pulmonary Langerhans cell histiocytosis. Eur Respir J 47 (6): 1785-96, 2016. [PubMed: 27076591]
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23. Sahm F, Capper D, Preusser M, et al.: BRAFV600E mutant protein is expressed in cells of variable maturation in Langerhans cell histiocytosis. Blood 120 (12): e28-34, 2012. [PubMed: 22859608]
24. Héritier S, Hélias-Rodzewicz Z, Chakraborty R, et al.: New somatic BRAF splicing mutation in Langerhans cell histiocytosis. Mol Cancer 16 (1): 115, 2017. [PMC free article: PMC5498996] [PubMed: 28679432]
25. Nelson DS, Quispel W, Badalian-Very G, et al.: Somatic activating ARAF mutations in Langerhans cell histiocytosis. Blood 123 (20): 3152-5, 2014. [PubMed: 24652991]
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. Héritier S, Hélias-Rodzewicz Z, Lapillonne H, et al.: Circulating cell-free BRAF(V600E) as a biomarker in children with Langerhans cell histiocytosis. Br J Haematol 178 (3): 457-467, 2017. [PubMed: 28444728]
28. 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]
29. 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]
30. 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]
31. 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]
32. 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]
33. Larkin J, Ascierto PA, Dréno B, et al.: Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med 371 (20): 1867-76, 2014. [PubMed: 25265494]
34. Long GV, Stroyakovskiy D, Gogas H, et al.: Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet 386 (9992): 444-51, 2015. [PubMed: 26037941]
35. Haroche J, Cohen-Aubart F, Emile JF, et al.: Reproducible and sustained efficacy of targeted therapy with vemurafenib in patients with BRAF(V600E)-mutated Erdheim-Chester disease. J Clin Oncol 33 (5): 411-8, 2015. [PubMed: 25422482]
36. 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]
37. Gandolfi L, Adamo S, Pileri A, et al.: Multisystemic and Multiresistant Langerhans Cell Histiocytosis: A Case Treated With BRAF Inhibitor. J Natl Compr Canc Netw 13 (6): 715-8, 2015. [PubMed: 26085387]
38. Euskirchen P, Haroche J, Emile JF, et al.: Complete remission of critical neurohistiocytosis by vemurafenib. Neurol Neuroimmunol Neuroinflamm 2 (2): e78, 2015. [PMC free article: PMC4345630] [PubMed: 25745636]
39. Hyman DM, Puzanov I, Subbiah V, et al.: Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations. N Engl J Med 373 (8): 726-36, 2015. [PMC free article: PMC4971773] [PubMed: 26287849]
40. Héritier S, Jehanne M, Leverger G, et al.: Vemurafenib Use in an Infant for High-Risk Langerhans Cell Histiocytosis. JAMA Oncol 1 (6): 836-8, 2015. [PubMed: 26180941]
41. Donadieu J, Larabi IA, Tardieu M, et al.: Vemurafenib for Refractory Multisystem Langerhans Cell Histiocytosis in Children: An International Observational Study. J Clin Oncol 37 (31): 2857-2865, 2019. [PMC free article: PMC6823889] [PubMed: 31513482]
42. Eckstein OS, Visser J, Rodriguez-Galindo C, et al.: Clinical responses and persistent BRAF V600E+ blood cells in children with LCH treated with MAPK pathway inhibition. Blood 133 (15): 1691-1694, 2019. [PMC free article: PMC6460419] [PubMed: 30718231]
43. Kolenová A, Schwentner R, Jug G, et al.: Targeted inhibition of the MAPK pathway: emerging salvage option for progressive life-threatening multisystem LCH. Blood Adv 1 (6): 352-356, 2017. [PMC free article: PMC5738993] [PubMed: 29296950]
44. Lee LH, Gasilina A, Roychoudhury J, et al.: Real-time genomic profiling of histiocytoses identifies early-kinase domain BRAF alterations while improving treatment outcomes. JCI Insight 2 (3): e89473, 2017. [PMC free article: PMC5291734] [PubMed: 28194436]
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49. 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]

General Information About Childhood LCH

Special Considerations for the Treatment of Children With Cancer

Cancer in children and adolescents is rare, although the overall incidence has been slowly increasing since 1975.[38] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:

• Primary care physicians.
• Pediatric surgical subspecialists.
• Pathologists.
• Radiation oncologists.
• Pediatric medical oncologists/hematologists.
• Rehabilitation specialists.
• Pediatric nurse specialists.
• Social workers.

For information about supportive care for children and adolescents with cancer, see the summaries on Supportive and Palliative Care.

The American Academy of Pediatrics has outlined guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer.[39] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate is offered to most patients and families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with current standard therapy. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.

Low-Risk Disease: Single-System or Multisystem LCH

High-Risk Disease: Multisystem LCH

Recurrent, Refractory, or Progressive Childhood LCH

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 ultrasonography, CT, or MRI scans, 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 are not particularly helpful in assessing the response of lytic bone lesions. Technetium Tc 99m bone scans remain positive in healing bone. PET scans may be helpful in following the response to therapy because the intensity of the PET image diminishes with the response of lesions and healing of bone.[18]

For children or adults with lung LCH, pulmonary function testing and high-resolution CT scans are sensitive methods for detecting disease progression.[21] Residual interstitial changes reflecting residual fibrosis or residual inactive cysts must be distinguished from active disease; somatostatin analog scintigraphy may be useful in this regard.[162]

Treatment Options No Longer Considered Effective for Childhood LCH

Treatments that have been used in the past but are no longer recommended for pediatric patients with LCH include cyclosporine [163] and interferon-alpha.[164]

Extensive surgery is also not indicated. For lesions of the mandible, extensive surgery may destroy any possibility of secondary tooth development. Surgical resection of groin or genital lesions is contraindicated because 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 or are painful and not amenable to other therapy.[90,97,165]

Late Disease and Treatment Effects of Childhood LCH

The reported overall frequency of long-term consequences of LCH has ranged from 20% to 70%. Children with low-risk organ involvement (skin, bones, lymph nodes, or pituitary gland) have an approximately 20% chance of developing long-term sequelae.[29,166]; [167][Level of evidence B4] Patients with multisystem involvement have an approximately 70% incidence of long-term complications.[29,97,168,169]

This wide variation in frequency results from case definition, sample size, therapy used, method of data collection, and follow-up duration. Quality-of-life studies have reported the following:

• In one quality-of-life study of long-term survivors of skeletal LCH, the quality-of-life scores were not significantly different from those of healthy control children and adults.[100] In addition, the quality-of-life scores were very similar between those with and without permanent sequelae.
• In another study of 40 patients who were carefully screened for late effects, adverse quality-of-life scores were found in more than 50% of patients.[37] Seventy-five percent of patients had detectable long-term sequelae; hypothalamic/pituitary dysfunction (50%), cognitive dysfunction (20%), and cerebellar involvement (17.5%) were the most common side effects.

The late effects of LCH may occur in the following body systems:

• Endocrine. Patients with diabetes insipidus are at risk of panhypopituitarism and should be monitored carefully for adequacy of growth and development. In a retrospective review of 141 patients with LCH and diabetes insipidus, 43% developed growth hormone (GH) deficiency.[97,168,169] The 5-year risk of GH deficiency among children with LCH and diabetes insipidus was 35%, and the 10-year risk was 54%. There was no increased reactivation of LCH in patients who received GH compared with those who did not.[168] Growth and development problems are more frequent because of the young age at presentation and the more toxic effects of long-term prednisone therapy in the very young child.
• Special senses (hearing loss). Hearing loss has been found in 38% of children who were treated for LCH.[97] Seventy percent of patients with LCH in this study had ear involvement, which included aural discharge, mastoid swelling, and hearing loss. Of those with CT or MRI abnormalities in the mastoid, 59% had hearing loss.[170][Level of evidence C1]
• Neurologic. Neurologic symptoms secondary to vertebral compression of cervical lesions have been reported in 3 of 26 patients with LCH and spinal lesions.[97] CNS LCH occurs most often in children with LCH of the pituitary or CNS-risk skull bones (mastoid, orbit, or temporal bone). Significant cognitive defects and MRI abnormalities may develop in some long-term survivors with CNS-risk skull lesions.[171] Some patients have markedly abnormal cerebellar function and behavior abnormalities, while others have subtle deficits in short-term memory and brain stem–evoked potentials.[81]
• Skeletal. Orthopedic problems from lesions of the spine, femur, tibia, or humerus may be seen in 20% of patients. These problems include vertebral collapse or instability of the spine that may lead to scoliosis and facial or limb asymmetry.
• Respiratory. Diffuse pulmonary disease may result in poor lung function with higher risk of infections and decreased exercise tolerance. These patients should be monitored with pulmonary function testing, including the diffusing capacity of carbon monoxide and ratio of residual volume to total lung capacity.[36]
• Digestive. Liver disease may lead to sclerosing cholangitis, which rarely responds to any treatment other than liver transplant.[126] Dental problems characterized by loss of teeth have been significant for some patients, usually related to overly aggressive dental surgery.[172]
• Subsequent neoplasms. Bone marrow failure secondary to LCH or from therapy is rare and is associated with a higher risk of malignancy. Patients with LCH have a higher-than-normal risk of developing secondary cancers.[173,174]
  Leukemia (usually acute myeloid leukemia) occurs after treatment, as does lymphoblastic lymphoma. Concurrent LCH and malignancy has been reported in a few patients, and some patients had their malignancy first, followed by development of LCH. Three patients with T-cell acute lymphoblastic leukemia (ALL) and aggressive LCH were reported and, as with all histiocytic disorders associated with or following lymphoblastic malignancies, the same genetic changes were found in both diseases, suggesting a shared clonal origin.[175-177] One study reported two cases in which clonality with the same T-cell receptor gamma genotype was found.[176] The authors of this study emphasized the plasticity of lymphocytes developing into Langerhans cells. The second study described one patient with LCH after T-cell ALL who had the same T-cell receptor gene rearrangements and activating mutations of the NOTCH1 gene.[177]
  An association between solid tumors and LCH has also been reported. Solid tumors associated with LCH include retinoblastoma, brain tumors, hepatocellular carcinoma, and Ewing sarcoma.

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Incidence

The incidence of LCH in adults is estimated to be one to two cases per 1 million people.[7] The true incidence of this disease is not known, however, because most published studies are not population based, and the disorder is likely to be underdiagnosed. A survey from Germany reported that 66% of the patients with LCH were women, with an average age at diagnosis of 43.5 years for all patients.[8]

More than 90% of adult pulmonary LCH cases occur in young adults who smoke, often more than 20 cigarettes per day.[9,10]

Clinical Presentation

Adult patients may have signs and symptoms of LCH for many months before receiving a definitive diagnosis and treatment. LCH in adults is often similar to that in children and appears to involve the same organs, although the incidence in each organ may be different. There is a predominance of lung disease in adults, usually occurring as single-system disease and closely associated with smoking and some unique biologic characteristics. Most adult isolated lung LCH cases are polyclonal and possibly reactive, while fewer lung LCH cases are monoclonal.[11,12]

A German registry with 121 registrants showed that 62% had single-organ involvement and 38% had multisystem involvement, while 34% of the total study population had lung involvement. The median age at diagnosis was 44 years (±12.8 years). The most common organ involved was lung, followed by bone and skin. All organ systems found in childhood LCH were seen in these adults, including endocrine and central nervous system (CNS), liver, spleen, bone marrow, and gastrointestinal tract. The major difference is the much higher incidence of isolated pulmonary LCH in adults, particularly in young adults who smoke. Other differences appear to be the more frequent involvement of genital and oral mucosa. There may be a difference in the distribution of bone lesions, but both groups suffer reactivations of bone lesions and progression to diabetes insipidus, although the exact incidence in adults is unknown.[7]

Presenting signs and symptoms from published studies include the following:

• Dyspnea or tachypnea.
• Polydipsia and polyuria.
• Bone pain.
• Lymphadenopathy.
• Weight loss.
• Fever.
• Gingival hypertrophy.
• Ataxia.
• Memory problems.
• Skin rash or scalp nodules.
• Soft tissue swelling near bone lesions.
• Hepatosplenomegaly.

Patients who present with isolated diabetes insipidus should be carefully observed for the onset of other signs or symptoms characteristic of LCH. At least 80% of patients with diabetes insipidus had involvement of other organ systems, including bone (68%), skin (57%), lung (39%), and lymph nodes (18%).[13] However, isolated diabetes insipidus in adults is similar to that in pediatric patients, with progression from posterior to anterior pituitary/hypothalamus and to cerebellar involvement. For more information, see the Endocrine system section.

Treatment of Adult LCH

References

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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 in the care of their 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:

PDQ® Pediatric Treatment Editorial Board. PDQ Langerhans Cell Histiocytosis Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/langerhans/hp/langerhans-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389240]

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