The histiocytic diseases in children and adults are caused by an abnormal accumulation of cells of the mononuclear phagocytic system. Only Langerhans cell histiocytosis (LCH), a myeloid-derived dendritic cell disorder, is discussed in detail in this summary.
The histiocytic diseases have been reclassified into five categories, with LCH in the L group. LCH results from the clonal proliferation of immunophenotypically and functionally immature, morphologically rounded LCH cells found in relevant lesions along with eosinophils, macrophages, lymphocytes, and, occasionally, multinucleated giant cells.[2,3] The term LCH cells is used because there are clear morphologic, phenotypic, and gene expression differences between normal Langerhans cells of the epidermis (LCs) and the pathologic variant of the LCH lesions (LCH cells), despite the pathologic histiocyte having the identical immunophenotypic characteristics of normal epidermal LCs, including the presence of Birbeck granules identified by electron microscopy.
LCH cells, known for many years to be a clonal proliferation, have now been shown to likely derive from a myeloid precursor whose proliferation is uniformly associated with activation of the MAPK/ERK signaling pathway.[4,5]
In accordance with these findings, the pathologic histiocyte or 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.[2,6,7] This shows that multisystem LCH arises from a somatic mutation within a marrow or circulating precursor cell, while localized disease arises from the mutation occurring in a precursor cell at the local site.
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. 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.
(Refer to the Cytogenetic and Genomic Studies and Cytokine Analysis sections of this summary for more information.)
LCH may involve a single organ (single-system LCH), which may be a single site (unifocal) or involve multiple sites (multifocal); or LCH may involve multiple organs (multisystem LCH), which may involve a limited number of organs or be disseminated. Involvement of specific organs such as the liver, spleen, and hematopoietic system separates multisystem LCH into high-risk and low-risk groups, where risk indicates the risk of death from disease.
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] 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. 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.[4,5] 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.[3,4,6,7]
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.[7,8] 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 confirm the diagnosis of LCH, but care should be taken to correlate with clinical presentation in organs in which normal LC cells occur.
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:
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. 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.[8,11,12] Transforming growth factor-beta (TGF-beta) and interleukin (IL)-10 may be responsible for preventing LCH cell maturation in LCH. The expansion of regulatory T cells in patients with LCH has been reported. 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.
Cytogenetic and Genomic Studies
Genomics of Langerhans Cell Histiocytosis
Studies published in 1994 showed clonality in Langerhans cell histiocytosis (LCH) using polymorphisms of methylation-specific restriction enzyme sites on the X-chromosome regions coding for the human androgen receptor, DXS255, PGK, and HPRT.[13,14] Analysis of lesions with single-system or multisystem disease showed a proliferation of LCH cells from a single clone. The discovery of recurring genomic alterations (primarily BRAF V600E) in LCH (see below) confirmed the clonality of LCH in children.
Pulmonary LCH in adults was initially reported to be nonclonal in approximately 75% of cases, while an analysis of BRAF mutations showed that 25% to 50% of adult lung LCH patients had evidence of BRAF V600E mutations.[15,16] Another study of 26 pulmonary LCH cases found that 50% had BRAF V600E mutations and 40% had NRAS mutations. Approximately the same number of mutations are polyclonal as are monoclonal. It has not yet 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.
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%). Multiple subsequent reports have confirmed the presence of BRAF V600E mutations in 50% or more of LCH cases in children.[19,20,21] Other BRAF mutations that result in signal activation have been described.[20,22]ARAF mutations are infrequent in LCH but, when present, can also lead to RAS-MAPK pathway activation.
The RAS-MAPK signaling pathway (refer to 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.[18,24]
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:
Studies support the universal activation of ERK in LCH; ERK activation in most cases is explained by BRAF and MAP2K1 alterations.[18,24,26] Altogether, these mutations in the MAP kinase pathway account for nearly 90% of the causes of the universal activation of ERK in LCH.[18,24,26]
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. 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.
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.
Clinical implications of the described genomic findings include the following:
Several case reports and two case series have demonstrated the efficacy of BRAF inhibitors for the treatment of LCH in children.[39,40,41,42,43,44] However, the long-term role of this therapy is complicated because most patients will relapse when the inhibitors are stopped.
Immunohistochemical staining has shown upregulation of many different cytokines/chemokines, both in LCH lesional tissue and in the serum/plasma of patients with LCH.[45,46] 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. 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. 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. 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.
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.
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. 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.
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 the HLA-DRB1*03 type than did those with multisystem disease. In 29 patients and 37 family members in the United States, the Cw7 and DR4 types were significantly more prevalent in whites with single-bone lesions.
The annual incidence of Langerhans cell histiocytosis (LCH) has been estimated to be between 2 and 10 cases per 1 million children aged 15 years or younger.[1,2,3] The male-to-female ratio (M:F) is close to one, and the median age of presentation is 30 months. 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). A survey of LCH in northwest England (Manchester) revealed an overall incidence of 2.6 cases per 1 million child-years.
Surveillance, Epidemiology, and End Results registry data from 2000 to 2009 were reviewed to identify high-risk LCH cases and assess demographic variables. On the basis of 145 cases, the age-standardized incidence for disseminated disease 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. Crowded living conditions and lower socioeconomic circumstances were associated with a higher risk of LCH, possibly because of the correlation with maternal and neonatal infections. In a population-based, case-control study, Hispanic mothers were more likely to have children who developed LCH compared with non-Hispanic whites; this risk increased when both parents were Hispanic. Non-Hispanic black mothers were less likely to give birth to children who developed LCH compared with non-Hispanic whites. In addition, a family-based genome-wide association study found that a polymorphism of the SMAD6 gene was highly associated with LCH, especially in Hispanic patients.
Identical twins and non-twin siblings with LCH, as well as LCH in multiple generations in one family, have been reported.
The etiology of LCH is unknown.
Although the following risk factors have been identified for LCH, strong and consistent associations have not been confirmed:
LCH most commonly presents with a painful bone lesion, with skin being the second most commonly involved organ. Systemic symptoms of fever, weight loss, diarrhea, edema, dyspnea, polydipsia, and polyuria relate to specific organ involvement and single-system or multisystem disease presentation, as noted below.
Specific organs are considered high risk or low risk when involved with disease presentation. Risk refers to the risk of mortality in high-risk patients. Chronic recurrent involvement of low-risk organs, while usually not life-threatening, can result in potentially devastating long-term consequences.
Patients may present with single-organ involvement (single-system LCH), which may involve a single site (unifocal) or multiple sites (multifocal). Bone is the most common single-organ site. Less commonly, LCH may involve multiple organs (multisystem LCH), which may involve a limited number of organs, or it may be disseminated. Patients can have LCH of the skin, bone, lymph nodes, and pituitary gland in any combination and still be considered at low risk of death, although there may be a relatively high risk of developing long-term consequences of the disease.
Treatment decisions for patients are based on whether high-risk or low-risk organs are involved and whether LCH presents as unifocal, multifocal, or multisystem disease.
Single-system low-risk disease presentation
In single-system low-risk 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 gland.
Skin and nails
Skin LCH in infants may be limited to skin (skin-only disease) or may be part of multisystem LCH. In a report of 61 neonatal cases from 1,069 patients in the Histiocyte Society database, nearly 60% (36 of 61 patients) had multisystem disease, and 72% of the patients with multisystem disease had risk-organ involvement. A retrospective analysis of 71 infants and children with apparent skin-only LCH found that those older than 18 months were more likely to have multisystem involvement and often relapsed after treatment with vinblastine and prednisone. Eight of 11 patients in this category had circulating cells with the BRAF V600E mutation, compared with only 1 of 13 patients in the skin-only group. Patients younger than 1 year with skin-only disease who were completely evaluated to exclude any other site of disease had a 3-year progression-free survival rate of 89% with initial therapy.
Skin-only LCH may be self-limited because the lesions may disappear without therapy during the first year of life. Therapy is used only for very extensive rashes, pain, ulceration, or bleeding. These patients must be monitored closely because skin-only LCH in neonates and very young infants may progress within weeks or months to high-risk multisystem disease, which may be life-threatening.[18,19,20]
Hashimoto-Pritzker disease or congenital spontaneous regressing skin histiocytosis is a self-limited disease that has the same immunohistochemical staining as LCH but, on electron microscopy, shows dense bodies thought to be senescent mitochondria. Careful review of the original cases revealed that some patients progressed to multisystem LCH; the distinction between skin-only LCH and Hashimoto-Pritzker disease is felt to be without clinical value because all of these infants should be carefully observed after diagnosis.
In a review of patients presenting in the first 3 months of life with skin-only LCH, the clinical and histopathologic findings of 21 children whose skin LCH regressed were compared with those of 10 children who did not regress. Patients with regressing disease had distal lesions that appeared in the first 3 months of life and were necrotic papules or hypopigmented macules. Patients with nonregressing disease who required systemic therapy were more often intertriginous. Immunohistochemical studies showed no difference in interleukin (IL)-10, Ki-67, E-cadherin expression, or T-reg number between the two clinical groups.
Fingernail involvement is an unusual finding that may present as a single site or with other sites of LCH involvement; in this scenario, there are longitudinal, discolored grooves and loss of nail tissue. This condition often responds to the usual LCH therapies.
In the mouth, presenting symptoms include gingival hypertrophy and ulcers on the soft or hard palate, buccal mucosa, or tongue and lips. Hypermobile teeth (floating teeth) and tooth loss usually indicate involvement of underlying bone.[23,24] Lesions of the oral cavity may precede evidence of LCH elsewhere.
Bone is the most commonly affected system, estimated to be affected in 80% of patients with LCH. LCH can occur in any bone of the body, although the hands and feet are often spared.
Sites of LCH bone lesions in children include the following:
Lymph nodes and thymus
The cervical nodes are most frequently involved and may be soft-matted or hard-matted groups with accompanying lymphedema. An enlarged thymus or mediastinal node involvement can mimic an infectious process and may cause asthma-like symptoms. Accordingly, biopsy with culture is indicated for these presentations. Mediastinal involvement is rare (<5%) and usually presents with respiratory distress, superior vena cava syndrome, or cough and tachypnea. The 5-year survival rate for these patients is 87%, with deaths mostly attributable to hematologic involvement.
The posterior part of the pituitary gland and pituitary stalk can be affected in patients with LCH, causing central diabetes insipidus. (Refer to the Endocrine system subsection in the Multisystem disease presentation section of this summary for more information.) Anterior pituitary involvement often results in growth failure and delayed or precocious puberty. Rarely, hypothalamic involvement may cause morbid obesity.
Thyroid involvement has been reported in LCH. Symptoms include massive thyroid enlargement, hypothyroidism, and respiratory symptoms.
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; these are divided into high-risk sites (liver, spleen, bone marrow) and low-risk sites (all other sites).
Multisystem low-risk disease
Bone and other organ systems
Patients with LCH may present with multiple bone lesions as a single site (single-system multifocal bone) or bone lesions with other organ systems involved (multisystem including bone). A review of patients with single-system multifocal bone presentation and patients with multisystem-including-bone presentation who were treated on the Japanese LCH study (JLSG-02) found that patients in the multisystem including bone group were more likely to have lesions in the temporal bone, mastoid/petrous bone, orbit, and zygomatic bone (CNS risk). These patients also had a higher incidence of diabetes insipidus, correlating with the higher frequency of risk-bone lesions. By contrast, a study from members of the Histiocyte Society found decreased mortality in high-risk multisystem LCH patients who had bone involvement, suggesting that those with bone LCH may have more indolent disease.
Abdominal organs and gastrointestinal system
In LCH, the liver and spleen are considered high-risk organs, and involvement of these organs affects prognosis. Involvement in this context means the liver and spleen are enlarged from direct infiltration of LCH cells or as a secondary phenomenon of excess cytokines, which cause macrophage activation or infiltration of lymphocytes around bile ducts. LCH cells have a portal (bile duct) tropism that may lead to biliary damage and ductal sclerosis. A percutaneous (peripheral) liver biopsy may not be diagnostic of the infiltrate that tends to be more central in the liver but will show the upstream obstructive effects of distal biliary occlusion. Hepatic enlargement can be accompanied by dysfunction, leading to hypoalbuminemia with ascites, hyperbilirubinemia, and clotting factor deficiencies. Sonography, computed tomography (CT), or MRI of the liver will show hypoechoic or low-signal intensity along the portal veins or biliary tracts when the liver is involved with LCH.
Patients with diarrhea, hematochezia, perianal fistulas, or malabsorption have been reported.[34,35] Diagnosing gastrointestinal involvement with LCH is difficult because of patchy involvement. Careful endoscopic examination that includes multiple biopsies is usually needed.
In LCH, the lung is less frequently involved in children than in adults because smoking in adults is a key etiologic factor. The cystic/nodular pattern of disease reflects the cytokine-induced destruction of lung tissue. Classically, the disease is symmetrical and predominates in the upper and middle lung fields, sparing the costophrenic angle and giving a very characteristic picture on high-resolution CT scan. Confluence of cysts may lead to bullous formation, and spontaneous pneumothorax can be the first sign of LCH in the lung, although patients may present with tachypnea or dyspnea. Ultimately, widespread fibrosis and destruction of lung tissue may lead to severe pulmonary insufficiency. Declining diffusion capacity may also herald the onset of pulmonary hypertension. Widespread fibrosis and declining diffusion capacity are much less common in children. In young children with diffuse disease, therapy can halt the progress of the tissue destruction, and normal repair mechanisms may restore some function, although scarring or even residual nonactive cysts may continue to be visible on radiologic studies.
Pulmonary involvement is present in approximately 25% of children with multisystem low-risk and high-risk LCH. However, a multivariate analysis of pulmonary disease in multisystem LCH did not show pulmonary disease to be an independent prognostic factor, with 5-year overall survival rates of 94% for those with pulmonary involvement and 96% for those without pulmonary involvement. Isolated pulmonary involvement is rarely seen in children.
Diabetes insipidus, caused by LCH-induced damage to the antidiuretic hormone-secreting cells of the posterior pituitary, is the most frequent endocrine manifestation in LCH. MRI scans usually show nodularity and/or thickening of the pituitary stalk and loss of the pituitary bright spot on T2-weighted images. Pituitary biopsies are rarely done. A biopsy of the pituitary gland may be indicated when the pituitary gland is the only site of disease and the stalk is greater than 6.5 mm or there is a hypothalamic mass. If the pituitary disease is associated with other sites of involvement, these sites can be biopsied to establish the diagnosis.
Approximately 4% of LCH patients present with an apparently idiopathic form of diabetes insipidus before other lesions of LCH are identified. A review of pediatric patients presenting with idiopathic central diabetes insipidus showed that 19% eventually developed manifestations of LCH, while 18% were diagnosed with craniopharyngioma and 10% with germinoma. A prospective study of the etiology of central diabetes insipidus in children and young adults found that 15% of patients had LCH, 11% had a germinoma, and 7% had a craniopharyngioma. The other diagnoses were related to trauma, familial association, or midline defects, and 50% remained idiopathic. When the pituitary stalk is thickened or is very large, there is a 50% chance the patient will have a germinoma, LCH, or lymphoma. Decisions about when to treat or whether to treat a patient with apparent isolated central diabetes insipidus as LCH without a biopsy remain controversial. These patients should be monitored closely for signs of any of the possible diagnoses.
Approximately 50% of patients who present with isolated diabetes insipidus as the initial manifestation of LCH either have anterior pituitary deficits at the time of diagnosis or develop them within 10 years of diabetes insipidus onset.[46,47] Anterior pituitary deficits include secondary amenorrhea, panhypopituitarism, growth hormone deficiency, hypoadrenalism, and abnormalities of gonadotropins. This incidence appears to be higher in patients with LCH than in those with true idiopathic central diabetes insipidus.
Patients with diabetes insipidus caused by LCH are 50% to 80% more likely to develop other lesions that are diagnostic of LCH (including bone, lung, and skin lesions) within 1 year of diabetes insipidus onset.[42,46] More commonly, patients with LCH present with diabetes insipidus later in the course of the disease, as noted in the following studies:
Using longer therapy and more chemotherapeutic agents, the German-Austrian-Dutch (Deutsche Arbeitsgemeinschaft für Leukäemieforschung und -Behandlung im Kindesalter [DAL]) group found a 20% cumulative incidence of diabetes insipidus at 15 years after LCH diagnosis. The incidence of diabetes insipidus was also lower in patients treated with more-intensive chemotherapy regimens on the HISTSOC-LCH-III (NCT00276757), JLSG-96, and JLSG-02 studies in Japan (8.9% for multisystem patients) compared with the HISTSOC-LCH-I and HISTSOC-LCH-II studies (14.2%).[49,50,51,52,53] Overall, diabetes insipidus occurred in 11% of patients treated with multiagent chemotherapy and in up to 50% of patients treated less aggressively.[47,54]
Patients with multisystem disease and craniofacial involvement (particularly of the orbit, mastoid, and temporal bones) at the time of diagnosis carried a significantly increased risk of developing diabetes insipidus during the disease course (relative risk, 4.6), with 75% of patients with diabetes insipidus having these CNS-risk bone lesions. The risk increased when the disease remained active for a longer period of time or reactivated.
Although rare, ocular LCH, sometimes leading to blindness, has been reported. Other organ systems may be involved, and the ocular LCH may not respond well to conventional chemotherapy.
CNS disease manifestations
Patients with LCH may develop mass lesions in the hypothalamic-pituitary region, the choroid plexus, the grey matter, or the white matter. These lesions contain CD1a-positive LCH cells and CD8-positive lymphocytes and are, therefore, active LCH lesions.
Patients with large pituitary tumors (>6.5 mm) have a higher risk of anterior pituitary dysfunction and neurodegenerative CNS LCH. A retrospective study of 22 patients found that all had radiologic signs of neurodegenerative CNS LCH detected at a median time of 3 years and 4 months after LCH diagnosis; it worsened in 19 patients. Five patients had neurologic dysfunction. Eighteen of 22 patients had anterior pituitary dysfunction, and 20 had diabetes insipidus. Growth hormone deficiency occurred in 21 patients; luteinizing hormone/follicle-stimulating hormone deficiency occurred in 10 patients; and thyroid hormone deficiency occurred in 10 patients.
LCH CNS neurodegenerative syndrome
A chronic neurodegenerative syndrome occurs in 1% to 4% of patients with LCH. These patients may develop tremors, gait disturbances, ataxia, dysarthria, headaches, visual disturbances, cognitive and behavioral problems, and psychosis.
Brain MRI scans from these patients show hyperintensity of the dentate nucleus and white matter of the cerebellum on T2-weighted images or hyperintense lesions of the basal ganglia on T1-weighted images and/or atrophy of the cerebellum. The radiologic findings may precede the onset of symptoms by many years or be found coincidently. A study of 83 patients with LCH who had at least two MRI studies of the brain for evaluation of craniofacial lesions, diabetes insipidus, and/or other endocrine deficiencies of neuropsychological symptoms has been published. Forty-seven of 83 patients (57%) had radiological neurodegenerative changes at a median time of 34 months from diagnosis. Of the 47 patients, 12 (25%) developed clinical neurological deficits that presented 3 to 15 years after the LCH diagnosis. Fourteen of the 47 patients had subtle deficits in short-term auditory memory.
Among 1,897 patients with LCH, 36 patients were diagnosed with clinical neurodegenerative LCH (cND-LCH). The incidence of cND-LCH was 4.1% at 10 years of follow-up. cND-LCH was more frequent in patients with pituitary involvement (86.1% vs. 12.2% without pituitary lesions), skin involvement (75% vs. 34.2% without skin lesions), and base skull bone involvement (63.9% vs. 28.4% without skull lesions). Patients with the BRAF mutation were more likely to have cND-LCH (93.7%) than those without the mutation (54.1%). In the multivariable analysis, the overall risk of developing cND-LCH was 2.13 for patients with base skull lesions, 9.8 for patients with the BRAF V600E mutation, and 30.88 for patients with pituitary involvement. The risk of cND-LCH had not plateaued up to 20 years after LCH diagnosis.
A study of CNS-related permanent consequences (neuropsychologic deficits) in 14 of 25 patients with LCH who were monitored for a median of 10 years has been published. Seven of these patients had diabetes insipidus, and five patients had radiographic evidence of LCH CNS neurodegenerative changes. Patients with craniofacial lesions had lower performance and verbal intelligence quotient scores than did those with other LCH lesions.
The first histological evaluation of neurodegenerative lesions reported prominent T-cell infiltration, usually in the absence of the CD1a-positive dendritic cells along with microglial activation and gliosis. However, in a report from 2018, analysis of brain tissue from patients with neurodegenerative-disease LCH showed perivascular infiltration of CD207-negative cells staining with the BRAF V600E mutant protein in the pons, cerebellum, and basal ganglia. These are areas identified by the characteristic abnormal MRI findings on T2 fluid-attenuated inversion recovery (FLAIR) images. Quantitative PCR analysis of these areas showed increased numbers of BRAF-mutated cells and elevated expression of osteopontin. Brain tissue in these areas showed active demyelination, correlating with the radiologic findings and clinical deficits.
Multisystem high-risk disease
Liver (sclerosing cholangitis)
Patients with hepatic LCH present with hepatomegaly or hepatosplenomegaly, and elevated alkaline phosphatase, liver transaminases, and gamma glutamyl transpeptidase levels. One of the most serious complications of hepatic LCH is cholestasis and sclerosing cholangitis. This usually occurs months after initial presentation, but occasionally may be present at diagnosis. The median age of children with this form of hepatic LCH is 23 months. While ultrasonography and/or MRI-cholangiogram can be helpful in the diagnosis of this complication, liver biopsy is the only definitive way to determine whether active LCH or residual hepatic fibrosis is present. Biopsy results often show lymphocytes and biliary obstructive effects without LCH cells. Peribiliary LCH cells and, rarely, nodular masses of LCH may also be present. It is thought that cytokines such as transforming growth factor-beta (TGF-beta), elaborated by lymphocytes during the active phase of the disease, lead to fibrosis and sclerosis around the bile ducts.
Massive splenomegaly, resulting from either primary involvement by LCH or from portal hypertension secondary to biliary cirrhosis, may lead to cytopenias because of hypersplenism and may cause respiratory compromise. Splenectomy typically provides only transient relief of cytopenias, as increased liver size and reticuloendothelial activation result in peripheral blood cell sequestration and destruction. Although rare, LCH infiltration of the pancreas and kidneys has been reported. Splenectomy is performed only as a life-saving measure.
Most patients with bone marrow involvement are young children who have diffuse disease in the liver, spleen, lymph nodes, and skin and who present with significant thrombocytopenia and anemia with or without neutropenia. Others have only mild cytopenias and are found to have bone marrow involvement with LCH by sensitive immunohistochemistry, flow cytometry, or PCR for analysis of BRAF-mutated cells in the bone marrow.[67,68] A high content of bone marrow macrophages can obscure LCH cells. Patients with LCH who are considered at very high risk sometimes present with hemophagocytosis in the bone marrow. The cytokine milieu driving LCH is probably responsible for the epiphenomenon of macrophage activation which, in the most severe cases, presents with typical manifestations of hemophagocytic lymphohistiocytosis such as cytopenias and hyperferritinemia.
The complete evaluation of any patient, presenting with either single-system or multisystem disease, should include the following:
Other tests and procedures include the following:
In severe multisystem LCH, additional tests for secondary hemophagocytic lymphohistiocytosis such as ferritin, triglycerides, fibrinogen, d-dimers, and lactate dehydrogenase may be indicated.
CT scan of the lungs may be indicated for patients with abnormal chest X-rays or pulmonary symptoms. High-resolution CT scans may show evidence of pulmonary LCH when the chest X-ray is normal; thus, in infants and toddlers with normal chest X-rays, a CT scan may be considered. Patients with pulmonary LCH may also have normal chest X-rays and abnormal pulmonary function tests.
LCH causes fatty changes in the liver or hypodense areas along the portal tract, which can be identified by CT scan, if indicated.
All patients with vertebral body involvement need careful assessment of associated soft tissue, which may impinge on the spinal cord.
MRI findings of CNS LCH include T2 FLAIR enhancement in the pons, basal ganglia, white matter of the cerebellum, and mass lesions or meningeal enhancement. In a report of 163 patients, meningeal lesions were found in 29% and choroid plexus involvement in 6%. Paranasal sinus or mastoid lesions were found in 55% of patients versus 20% of controls, and accentuated Virchow-Robin spaces were found in 70% of patients versus 27% of controls.
A pathologic diagnosis is always required to make a definitive diagnosis. However, this may sometimes be difficult or contraindicated, such as in isolated pituitary stalk disease or vertebra plana without a soft tissue mass, when the risk outweighs the benefit of a firm diagnosis.
Survival is closely linked to the extent of disease at presentation when high-risk organs (liver, spleen, and/or bone marrow) are involved, as well as the response to initial treatment. Many studies have confirmed the high mortality rate (35%) in high-risk multisystem patients who do not respond well to therapy in the first 6 weeks. For many years, the 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. Because of treatment advances, including early implementation of additional therapy for poor responders, the outcome for children with LCH involving high-risk organs has improved.[50,51] Data from HISTSOC-LCH-III (NCT00276757) showed an overall survival (OS) rate of 84% for patients treated for 12 months with systemic chemotherapy.
Patients with single-system disease and low-risk multisystem disease do not usually die of LCH, but recurrent disease may result in considerable morbidity and significant late effects. Overall, recurrences have been found in 10% of patients with single-system unifocal disease, 25% of patients with single-system multifocal bone LCH, and 50% of both low-risk multisystem patients and high-risk multisystem patients who achieve nonactive disease status with chemotherapy. HISTSOC-LCH-III data showed a significant difference in reactivation rate for low-risk organ patients randomly assigned to receive 6 months of treatment (54%) versus 12 months of treatment (37%). Similarly, the nonrandomized high-risk group who were all treated for 12 months had a reactivation rate of 30% compared with more than 50% in previous studies with 6 months of the same therapy.
Most good-responder, high-risk patients who have a reactivation (30%) do so in low-risk organs such as bone and then have the same risk of late effects as the low-risk multisystem patients. The major current treatment challenge is to reduce this overall 20% to 30% incidence of reactivations and the significant incidence of serious permanent consequences in this group of patients.
Apart from disease extent, prognostic factors for children with LCH include the following:
An earlier study of 100 patients did not find these clinical correlations with the BRAF V600E mutation.
Follow-up Considerations in Childhood LCH
Because of the risk of reactivation (which ranges from 10% in single-system unifocal bone lesions to close to 50% in low-risk and high-risk multisystem LCH) and the risk of permanent long-term effects, LCH patients need to be monitored for many years.
Patients with diabetes insipidus and/or skull lesions in the orbit, mastoid, or temporal bones appear to be at higher risk of LCH CNS involvement and LCH CNS neurodegenerative syndrome. These patients should have MRI scans with gadolinium contrast at the time of LCH diagnosis and every 1 to 2 years thereafter for 10 years to detect evidence of CNS disease. The Histiocyte Society CNS LCH Committee does not recommend any treatment for radiologic CNS LCH of the neurodegenerative type if there is no associated clinical neurodegeneration and the MRI findings remain stable. However, careful neurologic examinations and appropriate imaging with MRI are suggested at regular intervals. Brain stem auditory evoked responses should also be done at regular intervals to define the onset of clinical CNS LCH as early as possible, as this may affect response to therapy. When clinical signs are present, intervention may be indicated in patients with radiologic evidence of LCH-associated changes in the cerebellum. Available studies of different forms of therapy for CNS neurodegeneration suggest that the neurodegenerative changes may be stabilized or improved, but only if therapy is started early. (Refer to the LCH CNS neurodegenerative syndrome section of this summary for more information.) Careful follow-up of patients at risk is critical.
For children with LCH in the lung, pulmonary function testing and chest CT scans are sensitive methods for detecting disease progression.
A 16-year follow-up study of patients from one institution suggested that children with LCH have an increased risk of developing adult smoker's lung LCH compared with the normal young adult who smokes. Ongoing re-education regarding this risk should be part of the routine follow-up of children with LCH at any site.
In summary, many patients with multisystem disease will experience long-term sequelae caused by their underlying disease and/or treatment. Endocrine and CNS sequelae are the most common. These long-term sequelae significantly affect health quality of life in many of these patients.[Level of evidence: 3iiiC] Specific long-term follow-up guidelines after treatment of childhood cancer or in those who have received chemotherapy have been published by the Children's Oncology Group and are available on their website.
Special Considerations for the Treatment of Children With Cancer
Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. 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:
Refer to the PDQ summaries on Supportive and Palliative Care for specific information about supportive care for children and adolescents with cancer.
Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics. 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 in these trials is offered to most patients and families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. 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.
Over many years, national and international study groups have defined risk groups for allocation of Langerhans cell histiocytosis (LCH) patients to risk-based therapy on the basis of mortality risk and risk of late effects of the disease.
Depending on the site and extent of disease, treatment of LCH may include observation alone (after biopsy or curettage), surgery, radiation therapy, or oral, topical, and intravenous medication. The recommended duration of therapy is 12 months for patients who require chemotherapy for single-system bone, skin, or lymph node involvement.
For patients with high-risk and low-risk multisystem disease, the reactivation rate after 6 months of therapy was as high as 50% on the HISTSOC-LCH-I and HISTSOC-LCH-II trials.[1,2] On the basis of data from the German-Austrian-Dutch (Deutsche Arbeitsgemeinschaft für Leukäemieforschung und -Behandlung im Kindesalter [DAL]) group trials, which treated patients for 1 year and had fewer relapses (29%),[1,3] the HISTSOC-LCH-III trial was designed to administer 12 months of chemotherapy for all high-risk multisystem patients and to randomly assign low-risk multisystem patients to either 6 months or 12 months of therapy. In patients with low-risk or high-risk disease who received 12 months of therapy, the reactivation rate was significantly reduced to approximately 30%.
The standard treatment for LCH is chosen on the basis of 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 these cases, therapy recommendations are based on case series that lack the evidence-based strength of the trials.
Clinical trials organized by the Histiocyte Society have been accruing patients on childhood treatment studies since the 1980s. Information about centers enrolling patients on these trials can be found on the ClinicalTrials.gov website.
Treatment of Low-Risk Single-System or Multisystem Disease
Treatment options for patients with low-risk single-system or multisystem disease depend on the site of involvement, as follows:
Isolated skin involvement
Treatment options for patients with asymptomatic isolated skin involvement include the following:
For patients who require therapy, treatment options for symptomatic isolated skin lesions include the following:
Single skull lesions of the frontal, parietal, or occipital regions, or single lesions of any other bone
Treatment options for patients with single skull lesions of the frontal, parietal, or occipital regions, or single lesions of any other bone, include the following:
Skull lesions in the mastoid, temporal, or orbital bones
The mastoid, temporal, and orbital bones are referred to as CNS-risk bones. Risk refers to the increased risk of progression to diabetes insipidus followed by brain (CNS) involvement.
The purpose of treating patients with isolated CNS-risk lesions is to decrease the chance of developing diabetes insipidus and other long-term neurologic problems.
Treatment options for patients with skull lesions in the mastoid, temporal, or orbital bones include the following:
There is some controversy about whether systemic therapy is required for the first presentation of unifocal bone LCH, even in the CNS-risk bones. Orbital and ear, nose, and throat surgeons have reported a series of patients with orbital or mastoid lesions who received only surgical curettage. None of these patients developed diabetes insipidus. However, when comparing the incidence rates of diabetes insipidus in patients who received little or no chemotherapy (20%–50% incidence) with the incidence rates reported by the German-Austrian-Dutch group DAL-HX 83 trial (10% incidence in patients treated for LCH), it appears that the weight of evidence from the DAL-HX 83 trial supports chemotherapy treatment to prevent diabetes insipidus in patients with LCH of the mastoid, temporal, or orbital bones.[3,26] It should be noted, however, that the DAL-HX studies administered more drugs and treated patients for 12 months.
Vertebral or femoral bone lesions at risk of collapse
Treatment options for patients with vertebral or femoral bone lesions at risk of collapse include the following:
Multiple bone lesions (single-system multifocal bone lesions)
Treatment options for patients with multiple bone lesions (single-system multifocal bone lesions) at risk of collapse include the following:
(Refer to the Multiple bone lesions in combination with skin, lymph node, or diabetes insipidus [low-risk multisystem LCH] section of this summary for information about additional agents used to treat multifocal bone LCH.)
Multiple bone lesions in combination with skin, lymph node, or diabetes insipidus (low-risk multisystem LCH)
Treatment options for patients with multiple bone lesions in combination with skin, lymph node, or diabetes insipidus (low-risk multisystem LCH) include the following:
Patients with low-risk multisystem LCH have a survival rate of almost 100%, but reactivations were shown to be major risk factors for significant late effects on the DAL and Histiocyte Society trials.[3,4]
The three types of LCH CNS lesions are as follows:
Drugs that cross the blood-brain barrier, such as cladribine, or other nucleoside analogs, such as cytarabine, are used for active CNS LCH lesions.
Treatment options for patients with CNS lesions include the following:
CNS neurodegenerative syndrome
There is no established optimal therapy for CNS neurodegenerative LCH, and assessment of response can be difficult.
It is not clear whether LCH changes in the cerebellum, pons, and basal ganglia diagnosed by magnetic resonance imaging (MRI) and without clinical neurologic findings should be treated. Early studies suggested that not all LCH-related radiologic changes progressed to clinical neurodegenerative disease. However, treatment in the early stages of clinical disease before permanent damage occurs appears to be important. The current recommendation is ongoing neurologic evaluation both clinically and with MRI scanning; therapy is started as soon as clinical neurodegenerative disease progression is noted. It is unclear whether progressive radiologic changes should be an indication for treatment. In this regard, studies of cerebrospinal fluid (CSF) and serum biomarkers in an attempt to predict and prevent neurodegenerative disease are ongoing.
Drugs used in active LCH, such as dexamethasone and cladribine, along with other agents, such as tretinoin, intravenous immunoglobulin (IVIG), infliximab, and cytarabine with or without vincristine, have been used in small numbers of patients with mixed results. Many of these agents may result in the complete or partial resolution of radiographic findings, but definitive clinical response rates have not been rigorously defined.[44,45,46,47,48]; [Level of evidence: 3iiiDiii]
In the Japan LCH Study Group (JLSG)-96 Protocol, cytarabine failed to prevent the onset of neurodegenerative syndrome. Patients received cytarabine 100 mg/m2 daily on days 1 to 5 during induction and 150 mg/m2 on day 1 of each maintenance cycle (every 2 weeks for 6 months). Three of 91 patients developed neurodegenerative disease, which is similar to the rate reported for patients on the Histiocyte Society studies.
Early recognition of clinical neurodegeneration and early institution of therapy appear to be vital for success of therapy. Studies combining MRI findings together with CSF markers of demyelination, to identify patients who require therapy even before onset of clinical symptoms, are under way in several countries.
Treatment of High-Risk Multisystem Disease
Treatment options for patients with high-risk multisystem disease (spleen, liver, and bone marrow involving one or more sites) include the following:
Evidence (targeted therapy):
The most serious side effect of BRAF inhibitor therapies in melanoma patients is the induction of cutaneous squamous cell carcinomas,[58,59] with the incidence of these second cancers increasing with age; this effect can be reduced by concurrent treatment with both BRAF and MEK inhibitors.[58,59] In a long-term study of adult patients with Erdheim-Chester disease and LCH who received vemurafenib, 85% of patients had arthralgias; 62% of patients had maculopapular rashes; and more than 40% of patients had other skin disorders, including hyperkeratosis, seborrheic keratosis, and pruritus.
Seventy-five percent of children with sclerosing cholangitis will not respond to chemotherapy because the LCH is no longer active, but the fibrosis and sclerosis remain. Despite the limitations, liver biopsy may be the only way to distinguish active LCH from end-stage fibrosis. Liver transplant is the only alternate treatment when hepatic function worsens. In one series of 28 children undergoing liver transplant, 78% survived and 29% had recurrence of LCH, but only two cases of recurrent LCH occurred in the transplanted liver, although other cases have been reported since publication of the initial data. If possible, active LCH should be under control before transplant. Patients who undergo liver transplant for LCH may have a higher incidence of posttransplant lymphoproliferative disease.
Some patients develop a macrophage activation of their marrow. This may be confusing to clinicians, who may think the patient has hemophagocytic lymphohistiocytosis and LCH. The best therapy for this life-threatening manifestation is not clear because it tends not to respond well to standard hemophagocytic lymphohistiocytosis therapy. Clofarabine, anti-CD52 antibody alemtuzumab, or reduced-intensity allogeneic stem cell transplant could be considered.
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  and interferon-alpha. Extensive surgery is also not indicated. Curettage of a circumscribed skull lesion may be sufficient if the lesion is 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 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.[16,22,67]
Treatment Options Under Clinical Evaluation
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following are examples of national and/or institutional clinical trials that are currently being conducted:
It is preferable that patients with LCH be enrolled in a clinical trial whenever possible so that advances in therapy can be achieved more quickly, utilizing evidence-based recommendations, and to ensure optimal care. Information about clinical trials for LCH in children is available from the NCI website, Histiocyte Society website and the North American Consortium for Histiocytosis (NACHO) website.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
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, computed tomography (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. Positron emission tomography (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.
For children or adults with lung LCH, pulmonary function testing and high-resolution CT scans are sensitive methods for detecting disease progression. 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.
Reactivation of Single-System and Multisystem LCH
Reactivation of Langerhans cell histiocytosis (LCH) after complete response is common. In a large study, the percentage of patients with reactivations was 9% to 17.4% for single-site disease; 37% for single-system, multifocal disease; 46% for multisystem (nonrisk organ) disease; and 54% for risk-organ involvement. Forty-three percent of reactivations were in bone, 11% in ears, 9% in skin, and 7% developed diabetes insipidus; a lower percentage of patients had lymph node, bone marrow, or risk-organ relapses. The median time to reactivation was 12 to 15 months in nonrisk patients and 9 months in risk patients. One-third of patients had more than one reactivation, varying from 9 to 14 months after the initial reactivation. Patients with reactivations were more likely to have long-term sequelae in the bones, diabetes insipidus, or other endocrine, ear, or lung problems.
A comprehensive review of the German-Austrian-Dutch (Deutsche Arbeitsgemeinschaft für Leukäemieforschung und -Behandlung im Kindesalter [DAL]) and Histiocyte Society clinical trials revealed a reactivation rate of 46% at 5 years for patients with multisystem LCH, with most reactivations occurring within 2 years of first remission. A second reactivation occurred in 44% of patients, again within 2 years of the second remission. Involvement of the risk organs in these reactivations occurred only in those who were initially in the high-risk group (meaning they had liver, spleen, or bone marrow involvement at the time of original diagnosis).[Level of evidence: 3iiiDiii] Most reactivations, even in patients with high-risk disease who initially responded to therapy, were in bone, skin, or other nonrisk locations.
Consistent with these findings, the percentage of reactivations in multisystem disease was 45% in the Japanese trial [Level of evidence: 1iiA] and 46% in the HISTSOC-LCH-II trial. There was no statistically significant difference in reactivations between the high-risk and low-risk groups. Both the DAL-HX and Japanese studies concluded that intensified treatment increased the rapidity of response, particularly in young children and infants younger than 2 years, and together with rapid switch to salvage therapy for nonresponders, mortality was reduced for patients with high-risk multisystem LCH. Based on the HISTSOC-LCH-III (NCT00276757) randomized trial, prolongation of therapy also significantly reduced the rate of reactivation, although the exact duration of therapy (12 vs. 24 months) is being addressed in the HISTSOC-LCH-IV (NCT02205762) trial.
Treatment of Low-Risk Single-System or Multisystem LCH
The optimal therapy for patients with recurrent, refractory, or progressive LCH has not been determined.
Treatment options for patients with recurrent, refractory, or progressive low-risk single-system or multisystem disease include the following:
Several chemotherapy regimens exist for the treatment of recurrent, refractory, or progressive low-risk disease.
Bisphosphonate therapy is also effective for treating recurrent LCH bone lesions.
Evidence (bisphosphonate therapy):
Treatment of High-Risk Multisystem LCH
Data from the DAL group studies showed that patients with multisystem high-risk LCH who had progressive disease by week 6 of standard induction treatment or who did not achieve at least a partial response by week 12 had only a 10% chance of survival. These results were consistent with those of the less-intensive HISTSOC-LCH-II trial in which patients treated with vinblastine/prednisone who did not respond well by week 6 had a 27% chance of survival, compared with 52% for good responders.[Level of evidence: 1iiA] To improve on these results, patients with poorly responsive disease need to move to salvage strategies by week 6 for progressive disease and no later than week 12 for those without at least a good response.
Treatment options for patients with recurrent, refractory, or progressive high-risk multisystem disease include the following:
Evidence (targeted therapy):
HSCT has been used in patients with multisystem high-risk organ involvement that is refractory to chemotherapy.[14,27,28,29,30] Early results showing very high treatment-related mortality in these very ill young infants led to the development of reduced-intensity conditioning.
Treatment Options Under Clinical Evaluation
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following are examples of national and/or institutional clinical trials that are currently being conducted:
Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.
The reported overall frequency of long-term consequences of Langerhans cell histiocytosis (LCH) has ranged from 20% to 70%. 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:
Children with low-risk organ involvement (skin, bones, lymph nodes, or pituitary gland) have an approximately 20% chance of developing long-term sequelae.[3,4] Patients with multisystem involvement have an approximately 70% incidence of long-term complications.[3,5,6,7]
The late effects of LCH may occur in the following body systems:
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.[16,17,18] One study reported two cases in which clonality with the same T-cell receptor gamma genotype was found. 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.
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.
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 high-risk LCH is less aggressive than childhood high-risk disease. The risk of reactivations is unknown, but may be higher than in pediatric LCH patients. A reactivation rate of 62.5% has been reported in adults, compared with 36.8% in pediatric patients.. Sixty-four percent of adults with diabetes insipidus monitored for an average of 6 years developed other endocrine problems.[2,3]
A consensus group reported on the evaluation and treatment of adult patients with LCH. However, discussion continues, particularly regarding optimal first-line therapy.
It is estimated that one to two adult cases of LCH occur per 1 million population. 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.
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 an 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.[9,10]
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, including endocrine and central nervous system, 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 possibly 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.
Presenting symptoms from published studies are (in order of decreasing frequency) dyspnea or tachypnea, polydipsia and polyuria, bone pain, lymphadenopathy, weight loss, fever, gingival hypertrophy, ataxia, and memory problems. The signs of LCH are skin rash, scalp nodules, soft tissue swelling near bone lesions, lymphadenopathy, gingival hypertrophy, and hepatosplenomegaly. Patients who present with isolated diabetes insipidus should be carefully observed for the onset of other symptoms or signs 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%). 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 (refer to the Endocrine system subsection in the Childhood LCH section of this summary for more information ).
Skin and oral cavity
Thirty-seven percent of adults with LCH have skin involvement, usually as part of multisystem disease. Skin-only LCH occurs but it is less common in adults than in children. The prognosis for adults with skin-only LCH is excellent, with 100% probability of 5-year survival. The cutaneous involvement is clinically similar to that seen in children and may take many forms. Infra-mammary and vulvar involvement may be seen in adult women with skin LCH.
Many patients have a papular rash with brown, red, or crusted areas ranging from the size of a pinhead to a dime. In the scalp, the rash is similar to that of seborrhea. Skin in the inguinal region, genitalia, or around the anus may have open ulcers that do not heal after antibacterial or antifungal therapy. The lesions are usually asymptomatic but may be pruritic or painful. In the mouth, swollen gums or ulcers along the cheeks, roof of the mouth, or tongue may be signs of LCH.
Diagnosis of LCH is usually made by skin biopsy performed for persistent skin lesions.
The relative frequency of bone involvement in adults differs from that in children; the frequency of mandible involvement is 30% in adults and 7% in children, and the frequency of skull involvement is 21% in adults and 40% in children.[5,6,11,13] The frequencies of lesions in the vertebrae (13%), pelvis (13%), extremities (17%), and ribs (6%) in adults are similar to those found in children.
Pulmonary LCH in adults is usually single-system disease; however, in some patients, other organs may be involved, including bone , skin, and hypothalamus/pituitary.
Pulmonary LCH is more prevalent in smokers than in nonsmokers, and the male-to-female ratio is nearly 1:1, depending on the incidence of smoking in the population studied.[14,15] Patients with pulmonary LCH usually present with a dry cough, dyspnea, or chest pain, although nearly 20% of adults with lung involvement have no symptoms.[16,17] Chest pain may indicate a spontaneous pneumothorax (10%–20% of adult pulmonary LCH cases).
Pulmonary LCH can be diagnosed by bronchoscopy in about 50% of adult patients, as defined by characteristic CD1a immunostaining cells of at least 5% of cells observed. High-resolution lung computed tomography (CT) shows characteristic changes with cysts and nodules, more prevalent at the mid and upper zones. These changes have been characterized as pathognomonic for lung LCH.
The LCH cells in adult lung lesions were shown to be mature dendritic cells expressing high levels of the accessory molecules CD80 and CD86, unlike Langerhans cells (LCs) found in other lung disorders. Pulmonary LCH in adults has been considered a primarily reactive process, rather than a clonal proliferation, as seen in childhood LCH. However, ERK pathway mutations have been demonstrated in up to two-thirds of pulmonary LCH lesions in adults, suggesting a clonal process in a significant proportion of patients.[10,19]
The course of pulmonary LCH in adults is variable and unpredictable.
Favorable prognostic factors for adult LCH of the lung include the following:
Unfavorable prognostic factors for adult LCH of the lung include the following:
The remaining patients have a variable course, with stable disease in some patients and relapses and progression of respiratory dysfunction in others, some after many years. A natural history study of 58 patients with LCH who had pulmonary involvement found that 38% of patients had deterioration of lung function after 2 years. The most significant adverse prognostic variables were positive smoking statuses and low PaO2 levels at the time of inclusion.
The following results may be noted on diagnostic tests:
Liver involvement was reported in 27% of adult patients with LCH and multiorgan disease. Hepatomegaly (48%) and liver enzyme abnormalities (61%) were present. CT and ultrasonography imaging abnormalities are often found.
The early histopathologic stage of liver LCH includes infiltration of CD1a-positive cells and periductal fibrosis with inflammatory infiltrates with or without steatosis. The late stage is biliary tree sclerosis; treatment with ursodeoxycholic acid is suggested.
In a large series of patients from the Mayo Clinic, 31% had multisystem LCH compared with 69% registered on the Histiocyte Society adult registry; this likely reflects referral bias.[12,31] In the adult multisystem patients, the sites of disease included the following:
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 for the treatment of childhood LCH (refer to the Treatment of Childhood LCH section of this summary for more information). 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. Discussion continues, 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 cytarabine or cladribine.[Level of evidence: 3iiiC]
Treatment of pulmonary LCH
It is difficult to judge the effectiveness of various treatments for pulmonary LCH because patients can recover spontaneously or have stable disease without treatment.
Treatment options for adult patients with pulmonary LCH include the following:
The best strategy for follow-up of pulmonary LCH includes physical examination, chest radiographs, lung function tests, and high-resolution computed tomography (CT) scans.
Treatment of bone LCH
Treatment options for adult patients with bone LCH include the following:
Treatment of single-system skin disease
Treatment options for adult patients with single-system skin disease include the following:
Oral isotretinoin has induced remissions in some refractory cases of skin LCH in adults.
Chemotherapy is generally used for skin LCH associated with multisystem disease in adults.
Chemotherapy for the treatment of other single-system disease and multisystem disease
Evidence (chemotherapy for the treatment of other single-system disease [not mentioned above] and multisystem disease):
Targeted therapies for the treatment of single-system and multisystem disease
Early reports on the use of targeted therapies for LCH patients with low-risk or high-risk LCH sites include the following:
Of four patients with LCH who were treated with vemurafenib on the VE-BASKET (NCT01524978) trial, one patient had a complete response and three patients had partial responses. Early results of targeted inhibitor therapy are encouraging, but many questions remain, particularly the optimal duration of therapy and the reactivation rate after therapy is discontinued. A BRAF inhibitor in combination with a MEK inhibitor have been shown to be effective in patients with melanoma who have BRAF mutations (with reduced toxicity), and this combination may be effective in patients with LCH. A number of clinical trials of BRAF and other RAS pathway inhibitors in adults and children with LCH are ongoing.
Current Clinical Trials
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The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Histopathologic, Immunologic, and Cytogenetic Characteristics of Langerhans Cell Histiocytosis (LCH)
Added Váradi et al. as reference 44.
Treatment of Childhood LCH
Revised text to include specific radiation therapy doses used in the treatment of patients with single skull lesions of the frontal, parietal, or occipital regions, or single lesions of any other bone (cited Greenberger et al. as reference 18).
Treatment of Recurrent, Refractory, or Progressive Childhood LCH
Added Kudo et al. as reference 30.
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
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:
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:
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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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Last Revised: 2020-10-05
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