VOLUME 56ㆍNUMBER S1 REVIEW

BLOOD RESEARCH April 2021 ARTICLE

Recent advances in the understanding of the molecular pathogenesis

and targeted therapy options in Langerhans cell histiocytosis
Jin Kyung Suh, Sunghan Kang, Hyery Kim, Ho Joon Im, Kyung-Nam Koh
Division of Pediatric Hematology/Oncology, Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan
College of Medicine, Seoul, Korea

p-ISSN 2287-979X / e-ISSN 2288-0011 Abstract

https://doi.org/10.5045/br.2021.2021013 Langerhans cell histiocytosis (LCH) is the most common histiocytic disorder caused by
Blood Res 2021;56:S65-S69.
the clonal expansion of myeloid precursors that differentiate into CD1a+/CD207+ cells
in the lesion. Advances in genomic sequencing techniques have improved our under-
Received on January 21, 2021 standing of the pathophysiology of LCH. Activation of the mitogen-activated protein kin-
Revised on April 2, 2021 ase (MAPK) pathway is a key molecular mechanism involved in the development of LCH.
Accepted on April 2, 2021 Recurrent BRAF mutations and MAP2K1 mutations are the major molecular alterations
involved in the activation of the MAPK pathway. Recent studies have supported the
*This study was supported by a grant from
the Korea Disease Control and Prevention “misguided myeloid differentiation model” of LCH, where the extent of disease is defined
Agency (2019ER690301). by the differentiation stage of the cell in which the activating somatic MAPK mutation
occurs, suggesting LCH. Several studies have advocated the efficacy of targeted therapy
Correspondence to using BRAF inhibitors with a high response rate, especially in patients with high-risk or
Kyung-Nam Koh, M.D., Ph.D.
Ho Joon Im, M.D., Ph.D.
refractory LCH. However, the optimal treatment scheme for children remains unclear.
Division of Pediatric This review outlines recent advances in LCH, focusing on understanding the molecular
Hematology/Oncology, Department of pathophysiology, emerging targeted therapy options, and their clinical implications.
Pediatrics, Asan Medical Center Children’s
Hospital, University of Ulsan College of Key Words Langerhans cell histiocytosis, Therapeutics, Pathology
Medicine, 88, Olympic-ro, 43-gil,
Songpa-gu, Seoul 05505, Korea (K.N.K. and
H.J.I.)
E-mail: K.N.K, pedkkn@amc.seoul.kr
H.J.I., hojim@amc.seoul.kr
Ⓒ 2021 Korean Society of Hematology

ing have highlighted the activation of the mitogen-activated

INTRODUCTION
protein kinase (MAPK) pathway at critical stages in myeloid
differentiation as an essential driver of LCH pathology [4].
Langerhans cell histiocytosis (LCH) is a myeloproliferative In this review, we overview the recently growing under-
disorder characterized by inflammatory lesions with the ac- standing of LCH pathogenesis and a novel therapeutic option
cumulation of CD1a+/CD207+ histiocytes, leading to the de- to optimize and personalize therapy through improved risk
struction of affected tissues [1, 2]. While LCH invades bones stratification, targeted therapy, and the assessment of therapy
and skin commonly, it can involve any organ, including responses based on specific molecular features.
the liver, spleen, lungs, lymph nodes, central nervous system,
and hematopoietic system. The clinical course varies greatly Pathological considerations of LCH
from a single bone lesion to a fatal multi-organ disease [3]. Diagnosis and clinical overview of LCH: Histiocytic disorders
Although the precise origin of the pathological histiocytes are diseases associated with cells of the mononuclear phag-
in LCH is unclear, the current hypothesis is that these patho- ocyte system, which include hematopoietic cells with mono-
logical cells are more likely to arise from dysregulated differ- nuclear morphology and phagocytic activity. LCH is the
entiation or the recruitment of bone marrow-derived pre- most common histiocytic disorder, and its clinical pre-
cursor cells or yolk sac progenitors than from epidermal sentation varies from limited, indolent, and self-regressive
Langerhans cells [4, 5]. Recent advances in genomic sequenc- to life-threatening disseminated disease. The diagnosis of

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0)
which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
66 Jin Kyung Suh, et al.

LCH is based on clinical and radiological findings in combina- blood mononuclear cells (PBMCs) identified the presence
tion with histopathological analysis, identifying the infiltra- of a small (＜1%) but consistent proportion of BRAF-V600E
tion of tissue by histiocytes using the ultrastructural or im- mutations in myeloid cells (CD11c+ myeloid dendritic cell
munophenotypic characteristics of Langerhans cells, which precursors and CD14+ monocytes) in patients with high-risk
include the surface expression of CD207 (Langerin) and LCH. Similarly, in bone marrow samples, BRAF-V600E was
CD1a, as well as the detection of Birbeck granules using identified in CD34+ hematopoietic stem cells from many
electron microscopy [6]. In routine clinical practice, the iden- patients with high-risk LCH, of which up to 50% were re-
tification of Birbeck granules has recently been replaced ported to have normal histology. In contrast, BRAF-V600E
with positive immunohistochemical staining for CD1a and was generally absent in PBMCs from patients with single
CD207. lesion LCH and rare in the PBMCs of patients with multifocal
LCH as an immunoreactive disorder versus as a neoplastic dis- low-risk LCH [4, 7, 10]. These observations support the
order: In LCH lesions, pathological CD1a+CD207+ histio- “misguided myeloid differentiation model” of LCH, where
cytes are present in a small proportion, from less than 1% the extent of disease is defined by the differentiation stage
to more than 70% (median 8%), and are mixed with a variety of the cell in which the activating somatic MAPK mutation
of inflammatory cells, including eosinophils, macrophages, occurs (Fig. 1) [4]. According to this model, the high-risk
multinucleated giant cells, and lymphocytes (enriched with multisystem LCH is caused by somatic activating mutations
regulatory T cells) [7, 8]. In addition, these pathological in the MAPK gene of hematopoietic stem/progenitor cells
histiocytes have a benign morphology and low mitotic from bone marrow; the low-risk multisystem LCH is caused
activity. In this regard, LCH is considered an immune dis- by somatic MAPK mutations of committed dendritic cell
order in which normal cells proliferate in response to envi- (DC) precursor cells in the blood, and the low-risk single-sys-
ronmental stimuli. tem LCH is caused by somatic MAPK mutations of more
The findings of Badalian-Very et al. [9], in 2010, showed differentiated DC precursors from blood residing in a single
that 57% of patients with LCH had recurrent BRAF-V600E lesion [4, 7, 10].
mutations, and subsequent studies have identified recurrent
somatic mutations in pathological LCH cells, revealing the Recent progress in molecular pathogenesis of LCH
neoplastic nature of LCH and leading to the definition of Activation of MAPK pathway in LCH: The improvement of
LCH as an inflammatory myeloid neoplasm [1]. sequencing techniques that amplify the sequencing depth
Misguided myeloid differentiation model of LCH pathogenesis: has enabled simultaneous studies of multiple target genomic
The identification of the BRAF-V600E mutation provided regions per sample, which has led to the identification of
a molecular tag for lineage tracking to test the hypothesis the recurrent oncogenic somatic mutations in LCH that acti-
that LCH originated from early myeloid progenitors rather vate the MAPK pathway. The MAPK pathway comprising
than epidermal Langerhans cells. An analysis of peripheral RAS/RAF/MEK/ERK, which regulates cell differentiation,

Fig. 1. Misguided myeloid differ-

entiation model for LCH ontogeny
according to different risk groups.
According to this model, the extent
of disease is defined by the differ-
entiation stage of the cell in which
the activating somatic MAPK mutation
occurs.
Abbreviations: DC, dendritic cell;
LCH, Langerhans cell histiocytosis.

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Langerhans cell histiocytosis advances 67

proliferation, and apoptosis, plays a vital role in myeloid in a pediatric LCH case and in an adult non-LCH disease
cell differentiation and maturation (Fig. 2). Previous reports (Erdheim-Chester disease) [18, 19]. No genetic alterations
have shown evidence of activation of the MAPK pathway were found in approximately 20% of the patients with LCH.
in all the LCH samples [9, 11]. Mutations in the MAPK In these cases, copy number changes or epigenetic alterations
pathway proteins are associated with the differentiation of may be additional mechanisms for MAPK pathway activation
DC progenitors and inhibit the maturation of DCs. This [1].
role of activation of the MAPK pathway in myeloid cell
differentiation and maturation may have implications regard- Targeted therapy in LCH
ing the origin and functional alterations of histiocytes in BRAF kinase inhibitors: vemurafenib and dabrafenib: Identification
LCH [4]. of BRAF and MAP2K1 mutations in LCH led to targeted
Somatic mutations associated with LCH: Badalian-Very et therapies acting on the MAPK pathway. First-generation
al. [9] identified the BRAF-V600E mutation in pathological BRAF inhibitors, vemurafenib and dabrafenib, for the treat-
LCH cells and subsequent studies explored the genomic land- ment of high-risk or refractory LCH, have been studied.
scape of childhood LCH using targeted and whole-exome The efficacy of BRAF inhibitors in the treatment of LCH
next-generation sequencing (NGS) approaches. The hetero- was first reported in the off-label clinical use of vemurafenib
zygous BRAF-V600E mutation is a predominant genomic in three patients with multisystem and refractory ECD carry-
alteration in LCH, estimated in 38–64% of patients with ing the BRAF-V600E mutation, two of whom also had com-
LCH [7, 9, 12, 13]. Recurrent mutations in exons 2 and bined LCH, and the other being a young infant with re-
3 of the MAP2K1 gene, which encodes MEK1, a downstream fractory, multisystem LCH. In these reports, patients receiv-
signaling protein of BRAF in the MAPK pathway, were ing vemurafenib showed a dramatic response and good
reported in 15–20% of LCH cases [14, 15]. In addition, small short-term tolerability [20, 21]. A recent international study
in-frame BRAF deletions or insertions localized to exon 12, of vemurafenib in 54 pediatric patients with refractory multi-
which encodes the small N-terminal lobe of the BRAF kinase system LCH showed a 100% overall response rate (complete
domain, have been reported in 5–10% of LCH cases [14, response in 70% and partial response in 30%) after at least
16]. In addition, rare cases of mutations of other genes encod- eight weeks of vemurafenib (20 mg/kg/day) monotherapy.
ing MAPK pathway proteins have been reported, such as However, 80% of the patients experienced LCH reactivation
FAM73A-BRAF fusion [14], MAP3K1 mutation [15], and after the discontinuation of vemurafenib. The re-in-
ARAF mutation [17]. A somatic oncogenic PIK3CA mutation troduction of vemurafenib was effective in 75% of the re-
associated with the PIK3-AKT pathway has been reported activated patients [22]. Previous studies on vemurafenib have

Fig. 2. MAPK pathway mutations

in LCH. Activating MAPK pathway
mutations in LCH drive pathologic
ERK activation.
Abbreviations: A-Raf, rapidly acc-
elerated fibrosarcoma isoform A;
B-Raf, rapidly accelerated fibrosarcoma
isoform B; C-Raf, rapidly accelerated
fibrosarcoma isoform C; ERK,
extracellular signal-regulated kinase;
GPCR, G-protein-coupled receptor;
LCH, Langerhans cell histiocytosis;
MAPK, mitogen-activated protein
kinase; MEK, mitogen-activated
protein kinase kinase; Ras, rat
sarcoma.

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68 Jin Kyung Suh, et al.

found that while patients achieved excellent response rates, Circulating cell-free BRAF-V600E as a biomarker in LCH:
frequent recurrences were observed after the discontinuation Héritier et al. [30] quantified the BRAF-V600E allele in
of vemurafenib [23, 24]. Dabrafenib is another treatment the circulating cell-free DNA from plasma samples from
option for high-risk and refractory LCH. Dabrafenib is a pediatric patients with LCH. This study reported a higher
selective BRAF kinase inhibitor that has been reported to BRAF ccf load in patients with risk organ involvement and
have fewer adverse effects [25]. In a recently reported a sequential decrease in the BRAF ccf load after treatment
Chinese pediatric study, with 20 enrolled patients with re- [30]. Recent studies of BRAF inhibitors in patients with
fractory LCH that were treated with dabrafenib mono- LCH included follow-up tests of BRAF ccf load and showed
therapy, the overall objective response rate was 65%, and that BRAF ccf load reduced rapidly after BRAF inhibitor
the overall disease control rate was 75% [26]. treatment [22, 26]. These results indicated that the BRAF
Drawbacks of BRAF kinase inhibitors and future perspectives ccf load was associated with high-risk features and was re-
of target therapy: Although BRAF-V600E targeted therapy sponsive to chemotherapy. In this regard, the ccf BRAF
is an important advance, especially for refractory or high-risk load should be considered as a blood biomarker of LCH
LCH, the use of BRAF kinase inhibitors has several drawbacks in future clinical trials.
that need to be overcome. BRAF inhibitors were initially
used in the treatment of metastatic melanoma and other
CONCLUSION
adult BRAF-mutated cancers. According to the adult experi-
ence of BRAF inhibitors, BRAF inhibitors were ineffective
for many other BRAF mutations, such as BRAF fusion with LCH has long been an enigma with respect to its origin
a partner gene, insertion/deletion of exon 12, and ineffective and pathogenesis. Recent advances in molecular genomic
in activating mutations of genes that encode proteins acting analysis techniques have revealed the pathogenic molecular
upstream of RAF (such as RAS) [27]. This ineffectiveness mechanism of LCH. The understanding of the origin and
can trigger a paradoxical transactivation mechanism, which biology of LCH has increased rapidly in the last decade,
is responsible for serious cutaneous adverse effects, including leading to the introduction of promising targeted therapies
keratoacanthomas and squamous-cell carcinomas [28]. In pe- for high-risk patients. However, high-risk patients still have
diatric cases, rapid LCH reactivation has been observed after suboptimal outcomes, and targeted therapy for such patients
the discontinuation of BRAF inhibitors, and it has been found cannot eradicate the malignant clone and provide long-last-
to be ineffective in sclerosing cholangitis and advanced neu- ing remission after discontinuation. Future research should
rodegenerative disease [1, 22, 29]. In this regard, prospective focus on improving outcomes and reducing permanent seque-
trials should be performed to determine an optimal duration lae in high-risk LCH patients based on the recent under-
of use and potential combinations with other targeted or standing of LCH.
cytotoxic therapies. An approach combining a BRAF in-
hibitor with a MEK inhibitor that is used in adult malig-
ACKNOWLEDGMENTS
nancies can be effective in LCH. There is currently an on-
going international clinical trial to evaluate the efficacy of
a combination of dabrafenib and the MEK inhibitor, trameti- We thank Lee Changik, Park Yerang, and Lee Sangmin
nib, for adults and children with refractory or relapsed LCH for their generous support for this research.
(MEK inhibitor±BRAF inhibitor, NCT02124772).
AuthorsÊ Disclosures of Potential Conflicts of Interest
Clinical considerations according to molecular pathogenesis
BRAF-V600E mutation as a risk factor of LCH: Several pre-
vious studies have shown that the BRAF-V600E mutation No potential conflicts of interest relevant to this article
is associated with the severity of LCH and with treatment were reported.
failure. Berres et al [7]. reported that patients with a
BRAF-V600E mutation had an approximately two-fold risk
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