Langerhans Cell Histiocytosis: Emerging Insights and Clinical Implications

Langerhans cell histiocytosis is a disorder characterized by lesions that include CD207+ dendritic cells along with an inflammatory infiltrate. Langerhans cell histiocytosis has a highly variable clinical presentation, ranging from a single lesion to potentially fatal disseminated disease. The uncertainty as to whether Langerhans cell histiocytosis is a reactive or a neoplastic disease has resulted in a long-standing debate on this question, and the limited understanding of the pathogenesis of the disease has impeded clinical improvement for patients. The current standard of care for multisystem Langerhans cell histiocytosis, empirically derived chemotherapy with vinblastine and prednisone, cures fewer than 50% of patients, and optimal therapies for relapse and neurodegenerative disease remain uncertain. Recent research advances support a model in which Langerhans cell histiocytosis arises due to pathologic activation of the mitogen-activated protein kinase (MAPK) pathway in myeloid precursors. Redefinition of Langerhans cell histiocytosis as a myeloid neoplastic disorder driven by hyperactive ERK supports the potential of chemotherapy with efficacy against immature myeloid cells, as well as mutation-specific targeted therapy.

Historical Perspective

Langerhans cell histiocytosis is a historically poorly understood hematologic disorder with a wide range of clinical presentations characterized by granulomatous lesions composed of clonal pathologic “histiocytes” (CD207+ cells). Langerhans cell histiocytosis may present with a wide spectrum of symptoms, ranging from self-resolving single-organ lesions to disseminated multi-organ disease, which is associated with 10% to 20% mortality.[1,2] Langerhans cell histiocytosis affects 4 to 8 children per million[3-7] and 1 to 2 adults per million[8] each year.

The first descriptions of patients with symptoms now recognized as Langerhans cell histiocytosis were in historical case reports and series. Around 400 BC, Hippocrates described a patient with a nonfatal disease characterized by painful skull lesions, a presentation that could be consistent with Langerhans cell histiocytosis.[9] In published cases from the late 1800s and early 1900s, patients with rash, lytic bone lesions, and diabetes insipidus were described as having Hand-Schüller-Christian disease, while patients with more widespread disease (including histiocytes infiltrating the liver, spleen, or bone marrow) were said to have Letterer-Siwe disease.[10-14] Farber characterized single lytic bone lesions as “eosinophilic granulomas.”[15] In 1953, Lichtenstein noted that tissues from these clinically diverse patients had a similar histology, and he proposed that they represented a common syndrome, “histiocytosis X”-with the “X” indicating uncertainty as to the cell of origin.[16] With the development of electron microscopy, Nezelof and colleagues reported the common finding of intracytoplasmic Birbeck granules in both Langerhans cell histiocytosis lesions and epidermal Langerhans cells, leading to the hypothesis that Langerhans cell histiocytosis arises from neoplastic or pathologically activated Langerhans cells (Figure 1).[1,17,18]

The uncertainty regarding whether Langerhans cell histiocytosis is a neoplastic or an inflammatory disorder has influenced clinical approaches. Langerhans cell histiocytosis has historically been differentiated from cancers. Relapses are termed “reactivations,” and the goal of therapy in many cases has been symptomatic control rather than cure. Despite a frequency and clinical outcomes similar to those associated with Hodgkin lymphoma, Langerhans cell histiocytosis has been excluded from the cooperative clinical trials and research funding opportunities that have catalyzed improvements for other pediatric cancers.

Clinical Presentation and Natural History of the Disease

The range of potential symptoms in patients with Langerhans cell histiocytosis and the clinical overlap with more common conditions in children and adults make the diagnosis of Langerhans cell histiocytosis a clinical challenge. However, once Langerhans cell histiocytosis rises to consideration in the differential, definitive diagnosis with biopsy is straightforward in most cases. Excisional biopsy is optimal because of the cellular heterogeneity of the lesions and the possible presence of physiologic resident or migrating langerin-positive (CD207+) dendritic cells. Histology shows a mixture of pathologic dendritic cells and recruited inflammatory cells, including lymphocytes, eosinophils, and macrophages. Pathologic histiocytes have abundant pink cytoplasm, a deep groove in the nucleus that gives them a coffee bean–like appearance, and positive immunohistochemical staining for CD1a and CD207 (Figure 2A-C).[19,20]

Initial evaluations

Strategies for evaluation may be driven by specific clinical features.[21] The staging workup should include a thorough physical examination, including a complete evaluation of the skin and oral mucosa, lung exam, and evaluation for hepatosplenomegaly, in addition to a complete blood cell count to evaluate for cytopenias and liver function tests to evaluate for possible liver involvement. A bone marrow biopsy and aspiration can be considered in all young patients (under 2 years), as well as in patients with cytopenias. Radiologic workup includes a skeletal survey or positron emission tomography (PET) scan to determine whether there is bone involvement (Figure 2D, E), computed tomography (CT) of the head to check for bone lesions, and magnetic resonance imaging (MRI) of the brain and spine if central nervous system (CNS) involvement is suspected.

Characteristic clinical presentations

Skin and bone. Bone and skin are the most commonly involved organs, with bone lesions in 75% of patients and skin involvement in 34%.[3,6] The most common location for bone lesions is the skull, but any bone may be involved. Lesions are lytic, and may have an associated soft-tissue mass. They can be painless or painful, and can be mistaken for trauma. The presentation of Langerhans cell histiocytosis of the skin is highly variable, and the appearance can be similar to that of many more common conditions. Dry scaly involvement of the scalp might resemble seborrheic dermatitis; erythematous rashes involving intertriginous regions, such as the groin or axilla, can look similar to candidal dermatitis; or skin may be diffusely involved, with red to purple papules on the limbs, chest, and back (Figure 2F, G). When the skin of the inner ear is involved, patients may develop copious otorrhea. In addition to the skin, Langerhans cell histiocytosis may arise in any mucosal tissue. In the oral mucosa, it may present as recurrent ulcerations of the gingiva, and patients may develop “floating teeth” (Figure 2H).[5,6,22] Langerhans cell histiocytosis lesions may also arise throughout the gastrointestinal tract, and are sometimes associated with chronic diarrhea, hypoalbuminemia, and/or weight loss or failure to thrive.

‘Risk’ organs. A characteristic and severe presentation of Langerhans cell histiocytosis includes diffuse infiltration or focal lesions of the spleen, liver, or bone marrow; this presentation is most often seen in younger patients (less than 2 years of age). These patients are clinically defined as “high-risk” because of their more severe clinical presentation and higher risk of death compared with “low-risk” patients without bone marrow, spleen, or liver involvement. Patients with risk organ involvement have a 5-year survival rate of 84%, whereas the rate in low-risk patients is 99%.[23]

Patients with bone marrow involvement often present with cytopenias. Liver disease is typically associated with dysfunction reflected in hepatomegaly, elevated transaminase levels, hyperbilirubinemia, and hypoalbuminemia. Imaging studies identify discrete lesions and/or abnormalities along portal tracts. Liver biopsy frequently demonstrates a periportal lymphocytic infiltrate but may not include typical CD207+ histiocytes. Cytopenias may be a sign of bone marrow infiltration. Bone marrow biopsy may also lack differentiated CD207+ histiocytes. Lymph nodes are frequently involved in high-risk patients, but infiltrated lymph nodes by themselves do not confer increased clinical risk. Interestingly, despite the physiologic function of activated dendritic cells-to migrate to neighboring lymph nodes-Langerhans cell histiocytosis cells are not typically identified in draining lymph nodes of affected tissue.

Lungs. Patients with Langerhans cell histiocytosis involving the lungs may develop shortness of breath, pleuritic pain, or spontaneous pneumothoraces. On a high-resolution chest CT scan, Langerhans cell histiocytosis of the lungs presents with a nodular/cystic pattern (Figure 2I). While lung involvement may present acute clinical challenges, patients with pulmonary Langerhans cell histiocytosis (without involvement of other high-risk organs) are no longer considered high-risk.[24]

CNS. Langerhans cell histiocytosis may also involve the CNS, presenting with mass lesions, diabetes insipidus, or the development of progressive neurodegenerative symptoms (Figure 2J).[25,26] A classic clinical challenge is the patient who presents with sudden onset of uncontrollable thirst and increased urination and is found to have a pituitary lesion (Figure 2K). An isolated pituitary lesion is difficult to differentiate from germinoma or hypophysitis. Diabetes insipidus has been reported in 10% to 50% of patients with Langerhans cell histiocytosis.[27-29] MRI may show a mass or thickening involving the pituitary stalk, or a lack of the normal enhancement of the posterior pituitary gland, known as the pituitary “bright spot.” Langerhans cell histiocytosis mass lesions at other sites in the brain may also induce neurologic dysfunction as a result of mass effects (Figure 2L, M). A particularly puzzling and devastating consequence of Langerhans cell histiocytosis is an associated neurodegenerative condition that may arise as long as decades after the initial presentation. Symptoms include tremor, ataxia, dysmetria, dysphagia, behavioral changes, and learning disability. MRI identifies characteristic changes in the cerebellum, basal ganglia, and/or pons (Figure 2N).[26] The pathophysiology of Langerhans cell histiocytosis–associated neurodegenerative disease is poorly understood, but has been hypothesized to be an autoimmune or inflammatory reaction to Langerhans cell histiocytosis.[30]

Long-term consequences of Langerhans cell histiocytosis

The permanent consequences of Langerhans cell histiocytosis can be severe, even in patients with low-risk disease. Lesions of the orbit, mastoid, temporal bones, and pituitary are considered to be CNS-risk lesions, and predispose patients to the development of Langerhans cell histiocytosis–associated neurodegenerative disease.[25,29,31] Patients with diabetes insipidus are at risk for the development of permanent anterior pituitary dysfunction. In one study, the 10-year risk of developing growth hormone deficiency was 53% for Langerhans cell histiocytosis patients with diabetes insipidus, and another study reported that the overall risk of growth retardation was 17% following a diagnosis of Langerhans cell histiocytosis.[32,33] Orthopedic problems can include collapsed vertebra, facial or limb asymmetry, and scoliosis. Patients have also experienced ophthalmologic problems, such as persistent proptosis, as well as dental problems and pulmonary fibrosis.[33] Patients with liver disease are at risk for later development of irreversible sclerosing cholangitis and liver failure.[34] Patients with severe or uncontrolled disease are at highest risk for long-term sequelae.[35]

Pathophysiology: Reactive vs Neoplastic

Is Langerhans cell histiocytosis a dysregulated inflammatory disorder?

Whether Langerhans cell histiocytosis is a neoplastic or a reactive disorder is a question that has been debated for decades.[36,37] Langerhans cell histiocytosis lesions are characterized by CD1a+/CD207+ histiocytes (median infiltration, 8%; range, < 1% to 75%). The majority of the lesion is composed of an inflammatory infiltrate of lymphocytes, eosinophils, and macrophages.[20,38] The polymorphous nature of the inflammatory infiltrate led to the initial hypothesis that Langerhans cell histiocytosis is an immune disorder. Langerhans cell histiocytosis has no known viral etiology,[39] although Merkel cell polyomavirus has been identified in some patients.[31] Langerhans cell histiocytosis–associated Langerhans cells exhibit high levels of CD207 and CD1a expression, similar to what is seen in epidermal Langerhans cells; however, “cytokine storm,” resulting from expression of T-cell costimulatory molecules and pro-inflammatory cytokines, is more representative of an activated Langerhans cell phenotype.[40-42] Langerhans cell histiocytosis lesions are enriched in regulatory T cells.[40,43] Interleukin-17A expression has been implicated in the pathogenesis of Langerhans cell histiocytosis, but this has not been widely confirmed by different research groups.[44,45] While Langerhans cell histiocytosis clearly has features of inflammation, infectious or autoimmune causes of the disease have not been proven.

Is Langerhans cell histiocytosis a neoplastic disorder?

It has been proposed that Langerhans cell histiocytosis arises from Langerhans cells or precursors in arrested development, misdirected to the inappropriate sites by aberrant cytokine and chemokine signaling.[41,46,47] The coincidence of Langerhans cell histiocytosis with myelodysplastic syndrome and other malignancies, and evidence that Langerhans cell histiocytosis cells are clonal, have supported a neoplastic origin for Langerhans cell histiocytosis.[48-50] However, clonality alone in immune cells does not indicate malignancy, and a sustained failure to identify gross genetic abnormalities in Langerhans cell histiocytosis lesions has cautioned against the classification of Langerhans cell histiocytosis as a neoplastic disorder.[43,51,52]

Redefining Langerhans cell histiocytosis in the genomic era: MAPK pathway activation

The advent of next-generation sequencing technologies has facilitated genomic amplification and sequencing depth capable of identifying a critical single base mutation in a rare cell population. A historic breakthrough came when Dr. Barrett Rollins’s group reported the first recurrent somatic point mutation, BRAF-V600E, in approximately 60% of Langerhans cell histiocytosis lesions.[53] The high prevalence of the BRAF-V600E mutation was subsequently validated in several independent cohorts.[54-57] In addition to the BRAF-V600E point mutation, single case reports have described additional mutations/polymorphisms within the BRAF gene locus, including the somatic mutations BRAF-V600D and BRAF-600DLAT and the germline mutation/polymorphism BRAF-T599A.[57,58] A complex compound somatic mutation in ARAF with enhanced kinase activity in vitro has also been described in a single patient.[59] We speculate that the actual frequency of BRAF-V600E might be higher than reported, since the percentage of mutated cells in many cases is below the limit of detection of the sequencing methods used in some studies.

BRAF codes for the serine/threonine-protein kinase BRAF, which transduces signals through the mitogen-activated protein kinase (MAPK; or Ras/Raf/ERK) signaling pathway. This pathway regulates numerous essential cellular functions involved in development, cell-cycle regulation, cell proliferation and differentiation, cell survival and apoptosis, and many other physiologic processes, by transmitting extracellular signals to various nuclear, cytoplasmic, and membrane-bound targets (Figure 3).[60] The BRAF-V600E mutation leads to Ras-independent constitutive activation of downstream MEK and ERK.[61] The BRAF-V600E mutation is observed in approximately 7% of human cancers, as well as in several benign neoplastic conditions.[62,63]

Whole-exome sequencing performed on matched Langerhans cell histiocytosis lesions and peripheral blood tissue samples obtained from 41 patients revealed an overall low mutation rate background (0.03 mutations per megabase), which translates to a median of 1 somatic mutation within the exome per patient.[55] This study revealed a second recurrent mutated gene locus in Langerhans cell histiocytosis, MAP2K1 (encoding MAP2K1 or MEK1; 6 in-frame deletions and 1 missense mutation), in 33% of patients with wild-type BRAF, and single cases of somatic mutations of the MAPK pathway genes ARAF and ERBB3 (Figure 3).[55] Functionally, the MAP2K1 gene mutations occurred within mutation hotspots and resulted in constitutive in vitro activation of MEK1 and the downstream targets ERK1 and ERK2,[55] similar to what is observed as a result of the BRAF-V600E mutation.[53,55] Targeted sequencing of the second and third exons of MAP2K1 identified mutations in the MAP2K1 gene locus in 15% to 50% of Langerhans cell histiocytosis patients with wild-type BRAF.[64,65] Importantly, these studies established that BRAF and MAP2K1 mutations are mutually exclusive.[55,64,66]

In vitro analysis using primary CD207+ cells from Langerhans cell histiocytosis lesions revealed robust phosphorylation of MEK1 only in patients with either a BRAF-V600E or MAP2K1 mutation-and not in patients with wild-type BRAF or MAP2K1.[55] However, ERK1/ERK2 was universally phosphorylated in all cases of Langerhans cell histiocytosis, consistent with previously reported immunohistochemistry studies.[53] This indicates a potential critical role of ERK hyperactivation in Langerhans cell histiocytosis pathogenesis, as well as heterogeneous mechanisms of ERK hyperactivation, including a highly unusual pattern of ERK activation, in the absence of MEK activation in some cases.

Recurrent PIK3CA (encoding the phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) mutations have been reported in Erdheim-Chester disease, a histiocytic disorder that also has frequent BRAF-V600E mutations. However, no recurrent PIK3CA mutations were identified in 41 Langerhans cell histiocytosis lesions by whole-exome sequencing; only a PIK3R2 (encoding the phosphatidylinositol-3-kinase, regulatory subunit 2) mutation in a patient harboring MAP2K1 was identified.[55] Just a single case of PIK3CA mutation has been reported in a targeted sequencing study of 86 Langerhans cell histiocytosis patients, indicating the rare occurrence of these mutations in Langerhans cell histiocytosis.[67] Recurrent loss-of-function mutations (not exclusive to BRAF-V600E mutation) in MAP3K1 (encoding MEKK1), which cross-talk with both JNK signaling and the MAPK pathway, were identified by targeted sequencing in 3 out of 30 Langerhans cell histiocytosis cases.[65] While our understanding of the complete genomic landscape of Langerhans cell histiocytosis continues to evolve, a view is taking shape that contends that somatic mutations drive MAPK pathway activation in most, if not all, cases of Langerhans cell histiocytosis.

Functional consequences of MAPK pathway activation

Specific MAPK pathway mutations have not correlated with extent of disease or survival[53-55,68] in reports to date. However, in an institutional series, BRAF-V600E mutations correlated significantly with a twofold increased risk of initial treatment failure.[54] Thus, while they may not have a role in determining the extent of disease (eg, high- vs low-risk classifications), MAPK pathway mutations might have clinical and therapeutic implications. While CD207+ cells with BRAF-V600E or MAP2K1 mutations have had predictable responses to BRAF and MEK inhibition, responses of lesional cells with no identified MAPK pathway mutations have been highly variable,[55] highlighting the possibility that MAPK pathway mutation status might be used in the development of personalized therapeutic regimens.

Cell of Origin: The ‘Misguided Myeloid Differentiation Model’

Why revisit the cell of origin?

If all instances of Langerhans cell histiocytosis arose from a common precursor, the occurrence or lack of somatic mutations could dictate disease severity as in other cancer models. However, specific MAPK pathway mutations are not correlated with either extent of disease (high- vs low-risk) or survival.[53-55,68] In addition, relapse samples have not demonstrated the acquisition of new mutations.[55] The impact of pathologically activated MAPK may therefore depend on the cell in which the mutation arises.

Gene expression analysis in Langerhans cell histiocytosis lesions has revealed that lesions associated with Langerhans cells have a gene expression profile closer to that of a myeloid-derived precursor dendritic cell than to the profile of epidermal Langerhans cells.[40] Gene expression analysis has shown that Langerhans cell histiocytosis cells express relatively less epithelial cell adhesion molecule (EPCAM), E-cadherin (CDH1), and CD36 than do epidermal Langerhans cells.[40] Langerhans cell histiocytosis also shows high expression of CD2, CD11b, CD11c, CD13, CD33, CD66c, and CD300LF-markers associated with myeloid dendritic cells at all stages of maturation. Langerhans cell histiocytosis cells also express high levels of cytokines and chemokines, including osteopontin (SPP1), together with the receptors C-C chemokine receptor type 1 (CCR1) and neuopilin-1 (NRP1), which influence the capacity to recruit and interact with T cells.[40] Moreover, Langerhans cells isolated from lesions are somewhat immature, and lesions are enriched with eosinophils and regulatory T cells-findings suggesting that Langerhans cell accumulation in Langerhans cell histiocytosis results from survival rather than uncontrolled proliferation.[43] These observations support a model in which aberrant differentiation of a myeloid progenitor leads to a series of differentiation steps that may parallel some aspects of Langerhans cell differentiation, including induction of langerin expression.

Cell of origin determines severity and extent of disease

The BRAF-V600E mutation has provided a tool with which to identify and track potential Langerhans cell histiocytosis precursor cells. In order to identify the precursor population, peripheral blood mononuclear cells from patients with active Langerhans cell histiocytosis in whom BRAF-V600E mutations have been identified in Langerhans cell histiocytosis lesion cells need to be tested for the presence of circulating cells that also carry the mutation.[54] In a series of 100 patients, BRAF-V600E mutations were detected in peripheral blood mononuclear cells in all patients with active high-risk Langerhans cell histiocytosis. In comparison, no circulating cells with BRAF-V600E were detected in patients with single-system disease and were detected in only a small number of patients with clinically defined multifocal low-risk disease. Subsequent lineage analysis of the circulating cells in high-risk Langerhans cell histiocytosis patients identified cells with BRAF-V600E mutations in CD14+ monocyte fractions and CD11c+ myeloid dendritic cell fractions (the latter include CD1c+ dendritic cells, CD141+ dendritic cells, and CD16+ nonclassical monocytes) in all cases, suggesting that the somatic mutation arose in a myeloid progenitor. Subsequently, the BRAF-V600E mutation was identified in CD34+ hematopoietic stem and progenitor cells from bone marrow aspirate in some high-risk patients. In half of the cases where BRAF-V600E was detectable in bone marrow aspirate, the associated histology was normal, indicating that the mutation was present in morphologically normal precursor cells, a cautionary note to keep in mind when one is tempted to declare the bone marrow uninvolved on the basis of histology alone.[54] Interestingly, the BRAF-V600E mutation can also be localized to hematopoietic stem cells in hairy cell leukemia, a lymphoid malignancy.[69]

Why does the same mutation lead to two distinct pathologies? It might be because of differential epigenetic alterations, or additional modifying somatic mutations, or the acquisition of the mutations at different stages of hematopoietic development.[70] Similarly, enforced expression of the BRAF-V600E mutation in langerin-positive cells in mice resulted in the formation of localized Langerhans cell histiocytosis–like lesions, with no detectable mutation in the circulatory myeloid cells. In comparison, enforced expression of BRAF-V600E in CD11c+ cells resulted in a more aggressive phenotype, similar to that of disseminated high-risk Langerhans cell histiocytosis.[54]

These findings support the “misguided myeloid differentiation model” of the pathogenesis of Langerhans cell histiocytosis, in which the developmental stage at which an ERK-activating mutation arises determines the clinical manifestations of Langerhans cell histiocytosis (Figure 4). Indeed, many patients with BRAF-V600E mutations showed responses when treated with the BRAF inhibitor vemurafenib.[68,71] Based on these data, MAPK activation in myeloid precursor cells appears to be sufficient to drive Langerhans cell histiocytosis pathogenesis and supports the classification of Langerhans cell histiocytosis as a myeloid neoplasia.

Treatment

Treatment of limited disease

Treatment strategies are currently based on extent and location of disease. Patients with more limited disease, such as single bone lesions or skin-only disease, may not need systemic therapy. However, these patients were not included in prior Langerhans cell histiocytosis international trials, and data on the effectiveness of treatment has not been collected in a prospective manner. If Langerhans cell histiocytosis is really driven by hematopoietic myeloid precursors, local therapy may not make sense as a curative strategy unless the lesion is truly unifocal (and presumably includes a local tissue Langerhans cell histiocytosis “stem cell”). Symptomatic treatment options for disease limited to the skin include topical treatment with corticosteroids, nitrogen mustard, imiquimod, and phototherapy. Systemic therapy regimens with methotrexate, 6-mercaptopurine, vinca alkaloids, thalidomide, cladribine, and cytarabine have also been reported.[21,72] Single skin lesions may be surgically resected, and single bone lesions can be treated with curettage and local corticosteroid injections.[21] Enrollment of all Langerhans cell histiocytosis patients in a registry or clinical trial is highly recommended so as to better define the natural history of the disease and the optimal therapies for these patients.

Treatment of multifocal/multisystem disease

The formation of the Histiocyte Society in the late 1980s led to an international collaborative effort. The most recent trial, Langerhans cell histiocytosis III (LCH-III), demonstrated a decreased frequency of early relapse in patients treated with 12 months-as opposed to 6 months-of vinblastine/prednisone. We therefore consider 1 year of vinblastine/prednisone, with mercaptopurine added for patients with risk organ involvement, to be the current standard of care.[23] Like previous trials, LCH-III also showed that response to therapy is an important prognostic factor. Survival for patients with high-risk disease was 95% in those who had a good response to therapy at 6 weeks, 83% in those with intermediate response, and 57% if disease progressed. While LCH-III may define the current treatment standard, over 50% of patients in this study relapsed or failed to respond to therapy,[23] supporting the need for continued investigation for optimal therapy. In light of the new understanding of Langerhans cell histiocytosis as a myeloid “stem cell” disease, use of agents with activity against acute myeloid leukemia may be a reasonable strategy. Intermediate outpatient-dose cytarabine has been shown to have efficacy in institutional trials.[73,74]

Salvage therapy

Many patients who fail to achieve a durable response to vinblastine/prednisone are ultimately cured with salvage therapies that include agents used in the treatment of acute myeloid leukemia, including cytarabine, cladribine, and clofarabine.[74-78] However, data in Langerhans cell histiocytosis patients are largely limited to case series and pilot studies. Cladribine (5 mg/m²/day × 5 days) has been tested in a prospective clinical trial for patients with high-risk (liver, bone marrow, spleen, and/or lung involvement) Langerhans cell histiocytosis in first or later relapse, and in low-risk patients with second or later relapse. While many patients had an initial response at 6 months (improved, without progression: in 38% of patients with high-risk disease, in 62% of those with low-risk disease), only 20% of high-risk patients and 49% of low-risk patients had sustained responses, and only 4% of all patients had undetectable disease at 6 months.[78] In addition, extended use of cladribine monotherapy is associated with a risk of long-term bone marrow toxicity.[79] Cytarabine has been reported to have efficacy in adults with Langerhans cell histiocytosis, superior to that of cladribine and vinblastine/prednisone, in an institutional retrospective series.[75] In a pediatric series, the estimated 3-year event-free survival (EFS) for patients treated with cytarabine in first or later relapse was 41% (60% at 1 year).[73] Clofarabine monotherapy has been reported to be a promising agent in patients with highly refractory disease.[76,80] In one series (N = 11), 1-year EFS was 73%.[77] Another published strategy for patients with high-risk Langerhans cell histiocytosis is combination therapy with very-high-dose cytarabine (500 mg/m² BID) and cladribine (9 mg/m²/day) for 5 days/cycle, followed by less intense maintenance if there has been no active disease.[81] In this series, 21 of 27 evaluable patients had no evidence of disease at 5 years. However, two died from infection, and all patients experienced extended grade 4 cytopenias. While relatively effective, this strategy has very high toxicity. These salvage strategies are summarized in the Table.

Treatment of neurologic disease

Patients with known Langerhans cell histiocytosis who have new symptoms of diabetes insipidus or who have infiltrating lesions of the pituitary stalk should be started on systemic chemotherapy, with a goal of preventing tissue damage by the infiltrate, preventing hormone loss, and possibly preventing the development of neurodegenerative symptoms. However, reversal of diabetes insipidus is limited to case reports.[26,44,82-87] Vinblastine/prednisone, cytarabine, vincristine/cytarabine, cladribine, and clofarabine have been reported in case reports and case series to effectively treat pituitary and mass lesions, but there have been no prospective trials to determine the optimal treatment regimen.[44,45,77,88,89] Tumorous lesions in the brain also respond to systemic treatment with similar regimens.[31,44,45,81,88] In one case, efficacy was reported using the tyrosine kinase inhibitor imatinib.[90]

Treatment of Langerhans cell histiocytosis–associated neurodegenerative disease is particularly challenging due to its uncertain etiology and indolent course. Radiographic changes on MRI may precede symptoms by several years, and the natural history of patients who are asymptomatic with abnormal brain MRI is not known. In addition to surveillance MRI, regular neurologic examinations using the International Cooperative Ataxia Rating Scale may identify concerning symptoms. Patients with an increase of 5 points in their Ataxia Rating Scale score or in whom MRI shows progressive changes may merit systemic therapy.[21,91] Retinoic acid and intravenous immunoglobulin have been reported to stabilize neurodegenerative Langerhans cell histiocytosis, and cytarabine as monotherapy or in combination with vincristine has been shown to improve clinical and radiographic findings.[31,92,93] Despite the efficacy of cladribine in treating mass lesions in the CNS, current data do not support its ability to reverse clinical or radiographic findings of Langerhans cell histiocytosis–associated neurodegenerative disease.[44] It is likely that damage from longstanding Langerhans cell histiocytosis–associated neurodegenerative disease may be irreversible with any therapy, supporting the importance of long-term surveillance and early initiation of therapy.

Personalized therapy for Langerhans cell histiocytosis

Emerging data suggest that most, if not all, instances of Langerhans cell histiocytosis are driven by pathologic ERK activation, arising from activating somatic mutations in MAPK pathway genes. Inhibition of pathologic ERK activation based on a patient’s specific mutation is therefore a reasonable consideration for therapy. Response to BRAF and MEK inhibitors is variable for individual Langerhans cell histiocytosis–associated mutations.[55] Vemurafenib, which specifically inhibits the BRAF-V600E mutation, has already been used with some success in adult case series of refractory Langerhans cell histiocytosis and Erdheim-Chester disease, a related histiocytic disease.[94,95] MAPK inhibition may also have promise for pediatric patients with refractory Langerhans cell histiocytosis or Langerhans cell histiocytosis–associated neurodegenerative disease. A recent case report described an infant with high-risk Langerhans cell histiocytosis who had a good response to vemurafenib.[96] MAPK inhibitors do have significant side effects. Vemurafenib has been associated with the development of de novo squamous cell carcinoma in 20% to 25% of patients with melanoma who received the drug, believed to be due to paradoxical activation of wild-type BRAF.[97,98] Skin irritation was nearly universal in the Langerhans cell histiocytosis/Erdheim-Chester disease series, including rash (78%), photosensitivity reaction (28%), and cutaneous squamous cell carcinoma (44%). Other toxicities experienced by adults with Erdheim-Chester disease or Langerhans cell histiocytosis treated with vemurafenib have included fatigue (61%), arthralgia (61%), hypertension (44%), diarrhea (33%), alopecia (39%), and nausea (33%).[95] In adult melanoma trials, other BRAF and MEK inhibitors have similar toxicity profiles, with symptoms that include fever, fatigue, arthralgia, nausea, diarrhea, and rash.[99-101]The rates of squamous cell carcinoma and keratoacanthoma were significantly lower in patients treated with a combination of MEK and BRAF inhibitors compared with a BRAF inhibitor alone.[99-101] The proposed mechanism of the decreased toxicity is protection against paradoxical activation of wild-type BRAF from first-generation BRAF inhibitors.[102] As for patients with Langerhans cell histiocytosis, there are limited data about long-term toxicities with combination inhibition or about the use of these agents in the pediatric population. Ongoing collaborative efforts among histiocytosis treatment centers will be valuable as efficacy and toxicity data on children with Langerhans cell histiocytosis in early-phase studies become available.

Concluding Remarks and Perspective

Langerhans cell histiocytosis is a complex disease that can pose a wide array of clinical challenges. In recent decades, great advances have been made in our understanding of Langerhans cell histiocytosis. Historically, Langerhans cell histiocytosis was thought of as multiple syndromes, including Letterer-Siwe disease, Hand-Schüller-Christian disease, and eosinophilic granuloma, but it has been “rebranded” over time, as our understanding of the pathophysiology has grown. “Histiocytosis X” represented an unknown common cell of origin uniting the distinct phenotypes. Advances in technology provided tools to “solve for X” in the equation, and we now know that there may be multiple levels of differentiation that lead to variable clinical manifestations. A proposed model of pathophysiology suggests that the cell of origin is not terminally differentiated Langerhans cells, but rather precursor myeloid cells that acquire somatic mutations that activate the MAPK pathway (Figure 5). The current understanding of Langerhans cell histiocytosis suggests that it is once again time to update classification schema to reflect that the disease is an inflammatory myeloid neoplasia. The “cancer model” of treating patients in prospective collaborative clinical trials with correlative biology is essential if we are to continue to improve outcomes for children and adults with Langerhans cell histiocytosis.

Financial Disclosure:The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

Acknowledgements:The authors would like to acknowledge support of the Texas Children’s Histiocytosis Program by the HistioCure Foundation. Authors also receive funding from the National Institutes of Health (NIH) National Cancer Institute (CA154489) (CA), the NIH Specialized Program of Research Excellence (SPORE) in Lymphoma (P50CA126752, Principal Investigator, Helen Heslop, MD) (CA), Alex’s Lemonade Stand Foundation for Childhood Cancer (RC), and the St. Baldrick’s Foundation (CA), which sponsors the North American Consortium for Histiocytosis Research.

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