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Pediatrics International (2014) 56, 451–461 doi: 10.1111/ped.12380

Review Article

Recent advances in Langerhans cell histiocytosis

Akira Morimoto,1 Yukiko Oh,1 Yoko Shioda,2 Kazuko Kudo3 and Toshihiko Imamura4
1
Department of Pediatrics, Jichi Medical University of Medicine, Shimotsuke, 2Division of Hematology/Oncology, National
Center for Child Health and Development, Tokyo, 3Division of Hematology and Oncology, Shizuoka Children’s Hospital,
Shizuoka, and 4Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan

Abstract The purpose of this review is to provide an updated overview of the pathogenesis and treatment of Langerhans cell
histiocytosis (LCH). The pathogenesis of LCH remains obscure and the optimal treatment for LCH has not been
established, although incremental progress has been made. Proinflammatory cytokines and chemokines are known to
play a role in LCH, which suggests that LCH is an immune disorder. However, the oncogenic BRAF mutation is also
detected in more than half of LCH patients, which suggests that LCH is a neoplastic disorder. Remaining major issues
in the treatment of LCH are how to rescue patients who have risk-organ involvement but do not respond to first-line
therapy, the optimal treatment for the orphan disease of multifocal adult LCH, and how to reduce and treat central
nervous system-related consequences, such as central diabetes insipidus and neurodegeneration. More research is needed
to better understand the pathogenesis of this disease and to resolve the treatment issues.

Key words BRAF, chemokine, cytokine, diabetes insipidus, Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH), which was previously
termed “histiocytosis X,” is a rare clonal disorder characterized
by the proliferation of clonal CD1a-positive immature dendritic
cells (LCH cells) in the skin, bone, lymph nodes and other
organs. The clinical manifestations of LCH vary from a self-
limiting single bone disease to rapidly fatal disseminated disease.
However, LCH usually follows a chronic course and reactivations
often occur. This can result in permanent consequences, such as
orthopedic abnormalities, the development of central diabetes
insipidus (CDI), and neurodegenerative central nervous system
(ND-CNS) disease. LCH was originally described as three dif-
ferent entities, namely, eosinophilic granuloma, Hand–Schüller–
Christian disease, and Letterer–Siwe disease. However, at
present, LCH is classified as single-system (SS) vs multisystem
(MS) and unifocal vs multifocal disease. MS disease is classified
into two groups depending on whether risk organs (RO), namely,
the liver, lung, spleen and bone marrow, are involved. SS disease,
RO-negative MS disease, and RO-positive MS disease are almost
equivalent to eosinophilic granuloma, Hand–Schüller–Christian
disease, and Letterer–Siwe disease, respectively. This review
largely describes the new insights into the pathogenesis and treat-
ment of LCH.
Epidemiology
The incidence of LCH in children aged less than 15 years is 4–5
cases per million per year and LCH is diagnosed most often in
Correspondence: Akira Morimoto, MD PhD, Department of Pediatrics,
Jichi Medical University School of Medicine, 3311-1, Yakushiji,
Shimotsuke, Tochigi 329-0498, Japan. Email: akira@jichi.ac.jp
Received 19 January 2014; revised 27 March 2014; accepted 1 May
2014.
this age group between 0 and 3 years of age.1–3 It is estimated that
70 children are diagnosed with LCH newly on an annual basis in
Japan.3 MS disease, especially RO-positive MS disease, is quite
common in infants. SS disease accounts for about 70% of cases,
while nearly 10% of cases have RO-positive MS disease. LCH
appears to be more common in boys than in girls (1.2–2:1). In
adults, the incidence is about one-third of the childhood inci-
dence (i.e., 1–2 cases per million per year)4 and it occurs more
frequently in young adults than in older adults.5 The development
of the disease is usually sporadic. However, genetic predisposi-
tion may play a role in the development of LCH because about
1% of patients have relatives with LCH, monozygotic twin pairs
are concordant for LCH,6 and patients with LCH are more likely
to develop malignant disorders than the normal population.7
Pathology and diagnosis
To diagnose LCH, it is essential to perform a pathological exami-
nation. After hematoxylin–eosin staining, LCH cells have a dis-
tinctive homogeneously stained pink cytoplasm. The nuclei
appear twisted with a longitudinal groove and the small nucleolus
has a “coffee bean” appearance. Immunohistochemical staining
of S-100 protein is helpful for detecting LCH cells. LCH cells do
express CD14, CD68 and intracellular major histocompatibility
complex (MHC) class II antigen, but do not express Fascin,
CD83 or CD86. A definitive diagnosis can be made when the
accumulating histiocytes are positive for CD1a or langerin
(CD207) on immunohistochemistry.8 The Birbeck granule is a
Langerhans cell-specific tennis racquet-shaped organelle that can
be detected by electron microscopy. In terms of diagnostic value,
the Birbeck granule has been replaced by langerin, which is a
cell-surface receptor that induces the formation of the Birbeck

© 2014 Japan Pediatric Society

452 A Morimoto et al.

granule. Active LCH lesions contain granulomas caused by the Pathogenesis

aggregation of LCH cells as well as a number of various inflam-
matory cells. In the later stages of LCH, macrophages are more
predominant than LCH cells in the lesions, and xanthomatous
and fibrotic changes are often observed. In cases where the aggre-
gating histiocytes are negative for CD1a staining, juvenile
xanthogranuloma, Erdheim–Chester disease or Rosai–Dorfman
disease may be considered. When the CD1a-positive cells exhibit
prominent dysmorphic features and mitotic figure, Langerhans
cell sarcoma should be ruled out.9,10 Characteristics of these types
of non-Langerhans cell histiocytosis are summarized in
Table 1.
Etiology
It has been debated for many years whether LCH is a neoplasm
or is reactive in nature. Several lines of evidence suggest that
LCH is reactive: LCH lesions sometimes regress sponta-
neously,11 some virus DNA sequences have been detected in
peripheral blood and tissues from LCH patients,12 and there is
no evidence that LCH cells are immortalized. However, the fact
that LCH cells are monoclonal13,14 and sometimes show chro-
mosomal deletion or gain15 suggests the opposite conclusion.
Further supporting this is that an oncogenic BRAF V600E
mutation was recently discovered in LCH cells;16 this mutation
is detected in more than half of LCH patients.17 However, the
clinical significance of this mutation has not been settled
because it occurs equally as frequently in MS and SS LCH,
although it was reported recently that BRAF V600E mutation-
positive patients may have a higher reactivation rate than nega-
tive patients.18
The putative cell interaction and cytokine /chemokine network
are illustrated in Figure 1.
LCH cell characteristics
Compared to normal Langerhans cells, LCH cells are more
proliferative and have a lower antigen-presenting capability.
This suggests that during their maturation, LCH cells
become arrested at an activated state.19 A recent study using
an expression array revealed that LCH cells exhibit a unique
transcription profile that separates them not only from
plasmacytoid but also from epidermal Langerhans cells.20,21
In particular, LCH cells are the only dendritic cells that
co-express Notch1 and its Jagged-1 and -2 ligands.21 Interest-
ingly, when hematopoietic progenitor cells are cultured with
granulocyte-macrophage colony-stimulating factor (GM-CSF),
the presence of fibroblasts expressing Jagged-1 stimulates
the accumulation of dendritic cell precursors, not mature
dendritic cells, because their transition to terminally differenti-
ated dendritic cells is blocked.22 Further supporting the possi-
bility that Notch1 may contribute to LCH pathogenesis is
a report of a patient who first developed T-cell acute
lymphoblastic leukemia and then LCH: the leukemic cells and
LCH cells of this patient harbored the same activating Notch1
mutation.23
In summary, LCH cells are distinctive immature dendritic
cells and the JAG-mediated Notch signaling pathway may play
an important role in maintaining LCH cells in an immature
state.

Table 1 Characteristics of non-Langerhans cell histiocytoses

Disease Subtype Susceptible age Character of lesions Pathology

Juvenile Cutaneous type (75%) <2 years old Multiple nodular small papules
xanthogranuloma Soft tissue type (15%) <2 years old Soft tissue mass lesions in
subcutaneous fat or muscle
Systemic type (10%) <6 months old Mass lesions in visceral organ –
subcutis, central nervous system,
bone, liver, spleen, lung and
others
Erdheim–Chester >40 years old Symmetrical sclerotic lesions in the
disease long bones.
Non-osseous lesions – ureteral
stricture associated with
retroperitoneal fibrosis,
xanthomatous skin lesion, central
diabetes insipidus and pulmonary
fibrosis (50%).
Rosai–Dorfman Children and Painless bilateral cervical
disease young adults lymphadenopathy (80%)
Extranodal lesions – osteolytic bone
lesions, maculopapular skin rash,
orbital masses and others (50%).
Langerhans cell Any age Multiple organ involvement – lymph
sarcoma nodes, liver, spleen, bone, lung
and others
CD1a (–), Langerin (–), S100
(–), Fascin (+), Factor XIIa
(+), CD163 (+)
Touton giant cells (cutaneous
type)
Similar to juvenile
xanthogranuloma
CD1a (–), Langerin (–), S100
(+), CD163 (+)
Intracytoplasmic emperipolesis of
lymphocytes, neutrophils,
plasma cells and red blood
cells to the histiocytes
CD1a (+), Langerin (+), S100 (+)
Prominent nuclear pleomorphism
and mitoses

© 2014 Japan Pediatric Society


Fig. 1 Putative cell interaction and
cytokine/chemokine network in
Langerhans cell histiocytosis (LCH)
lesions. GM-CSF, granulocyte-macro-
phage colony-stimulating factor; HLA-
DR, human leukocyte antigen-DR;
IL, interleukin; M-CSF, macrophage
colony-stimulating factor; OPG, oste-
oprotegerin; RANKL, receptor activator
for nuclear factor κ B ligand; TNF,
tumor necrosis factor.
Interaction of LCH cells with other cells that infiltrate
LCH lesions
LCH lesions not only contain LCH cells, they also bear inflam-
matory cells, including T lymphocytes, macrophages, plasma
cells, eosinophils, osteoclast-like multinucleated giant cells, and
neutrophils. LCH cells also express the immature dendritic cell
marker CCR6 and produce its ligand (CCL20/MIP-3α) as well
as CCL5/RANTES (CCR1/3/5 ligand) and CXCL11/I-TAC
(CXCR3 ligand).24 Recently, it was reported that LCH cells from
patients with multifocal lesions express CXCR4 and its ligand
(CXCL12/SDF-1).25 These chemokine receptors and their ligand
interactions may play a role in the hematogenous migration of
not only LCH cells but also eosinophils and CD4-positive T cells
into the lesions. These infiltrating cells and LCH cells in turn
stimulate each other to produce abundant cytokines, such as
GM-CSF, interferon (IFN)-γ, tumor necrosis factor (TNF)-α,
interleukin (IL)-1α, IL-2, IL-3, IL-4, IL-5, IL-7, and IL-10.26
Moreover, in LCH lesions, LCH cells express CD40 at high
levels while T cells express CD154 (the CD40 ligand): interac-
tions between CD40 and CD154 are essential for the activation of
both the antigen-presenting cells and the T cells.27 We also found
that the serum levels of lesional inflammatory cytokines/
chemokines and dendritic cell/macrophage-activating factors,
such as IL-2R, IL-12p40, IL-18 and CXCL9, are markers of
disease dissemination and severity.28 Recently, it was reported
that LCH cells also abundantly express the pleiotropic cytokine
osteopontin (OPN).20 Moreover, bronchoalveolar lavage cells in
patients with pulmonary LCH have upregulated OPN expression
and overexpression of OPN in rat lungs induces lesions similar to
pulmonary LCH.29 OPN has a variety of functions that include
promoting the generation of T helper (Th)1 and Th17 cells,
recruiting histiocytes/monocytes, and activating osteoclasts.30 We
found that patients with MS LCH have much higher serum OPN
levels than patients with SS LCH.31 Finally, a recent study sug-
gests that the accumulation of LCH cells is due to their survival
Recent advances in LCH 453
rather than to their uncontrolled proliferation, and that because
LCH cells bear immature dendritic cell characteristics, they may
promote the expansion of regulatory T cells, which in turn results
in the failure of the host immune system to eliminate LCH cells.32
In summary, LCH lesions are characterized by a cytokine/
chemokine storm and interactions between infiltrating cells that
play a role in the accumulation of LCH cells and other infiltrating
cells and are responsible for various clinical features of LCH.
Osteoclastogenesis in LCH
Receptor activator for nuclear factor κ B ligand (RANKL) is
expressed by osteoblast/stromal cells and promotes bone resorp-
tion by binding to RANK on osteoclast (OC) precursors, which
activates these cells. Osteoprotegerin (OPG), which is also
secreted by osteoblast/stromal cells, is a decoy receptor of
RANKL. Thus, the balance between RANKL and OPG dictates
OC formation and thereby regulates bone resorption. In LCH,
OC-like multinucleated giant cells (MGC) are present not only in
the bone but also the skin and lymph node lesions. Moreover,
both the LCH cells and T cells in these lesions produce the
OC-inducing cytokines of RANKL and macrophage colony-
stimulating factor (M-CSF).33 Enzymes derived from OC-like
MGC may play a major role in the chronic tissue destruction that
is seen in LCH lesions.33 We found that patients with SS LCH and
multiple bone lesions had significantly higher soluble RANKL/
OPG ratios than patients with MS LCH; moreover, the soluble
RANKL/OPG ratios correlated positively with the number of
bone lesions.34
Coury et al. showed that patients with active LCH have high
serum levels of IL-17A, which is mainly produced by LCH
cells.35 In vitro, the serum IL-17A leads to a fusion between
immature dendritic cells that results in the formation of OC-like
MGC. This IL-17A-dependent fusion activity of the serum cor-
relates with LCH activity. An IL-17A autocrine model for LCH
was suggested. We also found that patients with LCH have higher
© 2014 Japan Pediatric Society
454 A Morimoto et al.
serum levels of IL-17A than controls, but that the serum IL-17A
levels of patients with MS LCH and SS LCH did not differ
significantly. However, we also observed that LCH cells in MS
disease had higher levels of IL-17A receptor (IL-17RA) protein
expression than those in SS disease and that IL-17RA expression
levels helped to distinguish between LCH subclasses.36 In addi-
tion, we found that the cleaved form of OPN plays a critical role
in driving immature dendritic cell differentiation into OC-like
MGC in an autocrine and/or paracrine fashion.37
These data suggest that the T cells and LCH cells in LCH
lesions interact and produce abundant amounts of cytokines that
induces the differentiation and activation of OC, which in turn
produces large amounts of tissue-destructive enzymes.
Clinical manifestations
As LCH affects a number of different organs, its clinical signs
and symptoms can be extremely variable. In most pediatric
patients with SS LCH, lesions occur in the bone with single-site
or multifocal involvement, although the lesions can also occur in
the skin.38 By contrast, in adults with SS LCH, the lung is the
most common site of lesions.5 In patients with MS LCH,
the organs involved are mainly the bone and skin, followed by the
hematopoietic system, lymph node, liver, spleen, soft tissue,
lung, thymus, pituitary gland, and other organs.39 The most
common initial manifestations are the development of a soft
tissue mass, bone pain, skin rash, fever, otorrhea, and lymphad-
enopathy. There are no specific laboratory markers for LCH. In
many cases, LCH presents with nonspecific inflammatory signs
that arise from chronic inflammation. A diagnostic approach is
summarized in Figure 2.
© 2014 Japan Pediatric Society
Bone lesions
The bone is involved in about 80% of patients with LCH.40 In
pediatric patients, the skull (Fig. 3a) is the most often affected
location followed by the spine (Fig. 3b), extremities, pelvic
bone, and ribs.41 In adult patients, the most affected bone is the
jaw.5 X-rays typically demonstrate osteolytic “punched out”
lesions with sharp margins. Fluorodeoxyglucose-positron emis-
sion tomography42 and whole-body magnetic resonance
imaging (MRI)43 are also useful for detecting bone lesions and
evaluating their response to treatment. Bone lesions may be
asymptomatic or accompanied with pain and soft tissue
swelling. When LCH is localized solely to the bone, the clinical
course is generally benign and it sometimes resolves sponta-
neously over a period of months to years. However, it can
also result in critical or irreversible symptoms, such as visual
loss or exophthalmos (due to orbital involvement), conductive
hearing loss (due to mastoid antrum lesions), loss of teeth
(due to jaw diseases), and spinal paralysis (due to vertebral
lesions).
Skin lesions
Skin involvement is seen in approximately half of all patients and
particularly frequent in infants. These patients present with
various lesions, including erythema, papules, nodules, petechiae,
vesicles, crusted plaques and seborrhea-like eruptions. Ulcerative
lesions in the genital or inguinal region may also be present.44 It
is essential that patients with skin lesions undergo evaluations of
other viscera because most of these patients have MS disease. In
neonatal infants, isolated skin lesions can regress spontaneously
Fig. 2 Diagnosis approach of
Langerhans cell histiocytosis (LCH).
CDI, central diabetes insipidus; CNS,
central nervous system; CT, computed
tomography; MRI, magnetic resonance
imaging; MS, multisystem.
 Recent advances in LCH 455

Fig. 3 Radiological findings of

Langerhans cell histiocytosis patients.
(a) Computed tomography (CT) of a
skull lesion. Both inner and outer plates
are affected. (b) Magnetic resonance
imaging (MRI) (T1-weighted image) of
a vertebral lesion (kindly provided by
Dr A. Mababe, St Luke’s International
Hospital). Vertebra body of Th9 is
collapsed and extensive paravertebral
soft tissue is present. (c) CT of
pulmonary lesions (kindly provided by
Dr M. Hiwatari, University of Tokyo).
Multiple cysts show honeycomb appear-
ance. (d) MRI (T1-weighted image) of a
pituitary lesion. White arrow indicates
thickened pituitary stalk and black
arrow indicates loss of bright spot in
posterior pituitary.

over weeks to months.45 However, some infants with isolated skin
lesions at diagnosis can develop MS disease followed by a fatal
clinical course.46
Lung lesions
In children, pulmonary involvement is usually part of MS
disease. It has been shown that pulmonary LCH in adults gener-
ally occurs in cigarette smokers and frequently regresses after the
cessation of smoking.47 The lung pathology is associated with
cough, dyspnea, pleural effusion, and recurring pneumothorax.
High resolution-computed tomography may reveal reticular or
micronodular opacities as well as large nodules and honeycomb-
ing (Fig. 3c). KL-6 may be a useful marker for pulmonary
involvement.48 In children with MS LCH, pulmonary involve-
ment is not an independent prognostic variable.49
Hematopoietic involvement
Hematopoietic involvement is seen in disseminated LCH. In
severe cases, serious anemia and thrombocytopenia may
develop and are often associated with a secondary
hemophagocytic syndrome followed by a fatal course. Anemia
with thrombocytopenia, with or without leukopenia and
hypoalbuminemia, are associated with a worse prognosis in
children with MS LCH.50 It is considered to constitute risk-
organ involvement51 (Table 2).
Liver and spleen lesions
Liver and/or spleen involvement occurs in 20% of patients39 and
is characterized by organomegaly and/or liver dysfunction
(Table 2).51 Histological examination of the liver indicates portal
infiltrates that can induce bile duct destruction and periportal
fibrosis (sclerosing cholangitis), leading to biliary cirrhosis with
portal hypertension and ultimately secondary hypersplenism.
Other lesions
Oral mucosa infiltration may appear as ulcerations or swelling of
gingiva.52 Infiltration of the gastrointestinal tracts sometimes
occurs and can cause vomiting, abdominal pain, constipation,
intractable diarrhea with blood and/or mucus53 and malabsorption
of nutrients.54 The lymph nodes that are most commonly affected
are those in the cervical, axillary and inguinal areas.55 Rarely, the
nodes can become massive and cause upper airway obstruction.

© 2014 Japan Pediatric Society

456 A Morimoto et al.
Table 2 Definition of risk-organ involvement†
Hematopoietic involvement (with or without bone-marrow
involvement)
At least two of the following:
• Anemia: hemoglobin <10 g/dL, infants <9 g/dL (not due to other
causes, e.g. iron deficiency)
• Leukocytopenia: leukocytes <4 000 /mm3
• Thrombocytopenia: platelets <100 000 /mm3
Liver involvement
• Enlargement >3 cm below the costal margin in the midclavicular
line
and/or
• Liver dysfunction (i.e. hypoproteinemia <5.5 g/dL,
hypoalbuminemia <2.5 g/dL, not due to other causes)
and/or
• Histopathological diagnosis
Spleen involvement
• Enlargement >2 cm below the costal margin at the midclavicular
line
Lung involvement
• Typical changes on HR-CT (low dose multidetector CT if
available)
and/or
• Histopathological / cytological diagnosis
†
Definition by the Histiocyte Society in 2009.51
Thymic involvement mainly occurs in young children and is
diagnosed when CT indicates thymus enlargement and calcifica-
tions.56 The thyroid gland,57 pancreas, and kidney58 are also occa-
sionally involved.
Hypothalamic-pituitary disease
In 25% of all patients with LCH and 50% of patients with MS
disease, infiltration and dysfunction of the pituitary gland and/or
adjacent hypothalamus is observed.59 The most frequent manifes-
tation is CDI, which may precede, co-occur, or follow other
symptoms and signs of the disease. The cumulative incidence of
CDI continues to increase, even 10 years after the diagnosis of
LCH.60 CDI occurs more often in patients with craniofacial bone
lesions (with the exception of vault), ear, eye and/or oral lesions61
and thus these lesions are known as CNS-risk lesions (Table 3).
Systemic chemotherapy rarely cures CDI but appropriate sys-
Table 3 Definition of CNS-risk lesions†
Craniofacial bone involvement
Lesions in the orbital, temporal, mastoid, sphenoidal, zygomatic, or
ethmoidal bones; the maxilla or paranasal sinuses; or cranial
fossa; with intracranial soft tissue extension
Ear involvement
External otitis, otitis media, otorrhea; or lesions in the temporal
bone, mastoid, or petrous bone
Eye involvement
Proptosis, exophthalmos, or lesions in the orbits; zygomatic or
sphenoidal bone
Oral involvement
Lesions in the oral mucosa, gums, palatal bone, maxilla, and
mandible
†
Definition by the Histiocyte Society in 2009.51
© 2014 Japan Pediatric Society
temic chemotherapy effectively reduces its development.60 About
half of the patients with CDI develop anterior pituitary hormone
deficiencies and/or ND-CNS disease during follow up, usually
after a disease course of several years.62 LCH involvement of the
pituitary gland can be shown by MRI findings, namely, pituitary
stalk thickening and loss of the physiological high-intensity
signal of the posterior pituitary lobe on T1-weighted images
(Fig. 3d). Patients with hypothalamic-pituitary lesions may
present with non-endocrine hypothalamic dysfunction, such as
eating disorder, thirst, fatigue, autonomic disturbance, tempera-
ture instability, memory deficit, and disturbed consciousness.63
The hypothalamic lesions can be indicated by MRI as
gadolinium-enhanced masses.64
Neurodegenerative central nervous system disease
ND-CNS disease may develop over the years after the onset of
the disease, often when the disease is considered quiescent.65,66
Three years after the diagnosis of LCH, more than half of patients
with CNS-risk lesions and/or CDI demonstrate bilateral symmet-
rical lesions in the cerebellar white matter and basal ganglia
(radiological ND-CNS disease) in MRI studies using
T2-weighted or fluid-attenuated inversion recovery images.67
These brain MRI abnormalities gradually deteriorate and never
reverse. One quarter of patients with the brain MRI abnormalities
will present with neurological symptoms (neurological ND-CNS
disease), including ataxia, tremor, dysarthria, dysphagia and
hyperreflexia, within several years, followed by further deterio-
ration. Patients with neurological ND-CNS disease eventually
become bedridden. Histologically, ND-CNS disease is character-
ized by the presence of CD8-positive T-lymphocyte infiltration,
microglia activation, gliosis, and neuronal and axonal destruction
with secondary demyelination, as is observed in autoimmune
encephalitis. CD1a-positive LCH cells may be absent.68 First-line
therapies for LCH that include cytarabine (Ara-C) may reduce
the incidence of ND-LCH.69,70 Currently, there is no established
therapy for ND-CNS disease, although there is some promising
evidence that intravenous immunoglobulin71,72 or Ara-C73 treat-
ment may prevent the progression of ND-CNS disease.
Treatment and outcome
The clinical course of LCH varies quite widely depending on the
extent of organ involvement. The mortality rate of patients with
SS disease or without risk-organ involvement is less than 5%.
However, children with MS disease and risk-organ involvement
(Table 2) have a worse prognosis: these children often have fatal
outcomes despite intensive treatment and their mortality is
reported to be 10–50%.39 Treatment of LCH should be planned
according to the clinical presentation and the extent of organ
involvement. In 2010, the Infant LCH study group of Research on
Measures for Intractable Diseases by the Ministry of Health
Labour and Welfare in Japan presented the treatment guidance
for childhood LCH (Fig. 4). Etoposide (VP-16) is no longer
considered to be a reasonable therapeutic agent because it is not
more efficacious than vinblastine74 and has been shown to cause
therapy-related acute myeloid leukemia (t-AML).75 Radiation is

Fig. 4 Treatment guideline for newly
diagnosed childhood Langerhans cell
histiocytosis (LCH). Modification of the
guidelines produced by the Infant LCH
study group of Research on Measures
for Intractable Diseases by the Ministry
of Health Labour and Welfare in Japan
in 2010. 2-CdA, cladribine; Ara-C,
cytarabine; CNS-risk lesion, central
nervous system risk lesion (see Table 3);
MS, multisystem; PSL, prednisolone;
RIC-SCH, reduced-intensity condition-
ing stem cell transplantation; RO, risk
organ involvement (see Table 2);
SS, single-system; VCR, vincristine.
rarely used in children because of the reported increased risk of
secondary malignancies, particularly brain tumors, in irradiated
areas.76
Single-system LCH
In SS LCH, the main aims of treatment are to lessen symptoms
and reduce the chance of permanent sequelae. In patients with
localized, unifocal bone disease, LCH may resolve sponta-
neously. In the case of a single bone lesion without symptoms, a
wait-and-see approach or diagnostic curettage is the standard
method of care. Local injection of corticosteroid may be used for
these bone lesions.77 Patients with CNS-risk lesions or multifocal
bone disease should receive systemic chemotherapy with vinca
alkaloids and corticosteroids for 6 or 12 months to prevent the
development of late sequelae, such as CDI. Radical operation of
large bone lesions is discouraged as this often results in disfig-
urement and loss of bone. When there is skin involvement only,
the best option is a wait-and-see approach. Alternatively, patients
can be provided therapies such as topical corticosteroids. A
nationwide survey in Japan suggests that appropriate chemo-
therapy for patients with a single bone lesion results in an excel-
lent prognosis.38
Multi-system LCH
In MS LCH, the main aims of treatment are to increase survival
and to reduce the incidence of late sequelae. The most commonly
used regimen in other countries is systemic chemotherapy with
vinblastine (VBL) and corticosteroid for 6–12 months. Three
clinical trials designated as LCH-I, -II, and -III have tested this
regimen74,78,79 and showed that it yields excellent survival rates in
risk organ-negative patients, even in infants.78,79 However, despite
this treatment, the mortality rates of risk organ-positive patients
remain high at 16–38%.74,78,79 The combination chemotherapy
consisting of Ara-C, vincristine (VCR), and prednisolone that
was introduced by the Japan LCH Study Group (JLSG-96/02)
Recent advances in LCH 457
yields more favorable outcomes for risk organ-positive patients:
their mortality rate is about 10%.80,81 A major prognostic factor is
a response to the first 6 weeks of systemic multi-agent chemo-
therapy: risk organ-positive patients who exhibit progressive
disease during combination chemotherapy have an extremely
high mortality rate of between 40% and 80%.78–83 Moreover,
despite being treated with the regimens described above, the
reactivation rate of patients with MS disease remains high (up to
30%).79,81 To reduce the reactivation rate, the JLSG-02 regimen
plus intensification via dose-up of VCR in the early maintenance
phase was developed. The ongoing LCH-12 trial, which was
initiated in Japan recently, is testing the efficacy of this regimen.
Adult LCH
In adults, lung disease can be a life-threatening complication: one
study showed that 5 years after the diagnosis, patients with lung
LCH lesions have a mortality rate of approximately 25%.84 In
patients with isolated pulmonary LCH with functional impair-
ment, systemic chemotherapy may be indicated to reduce further
parenchymal destruction, although it remains unclear whether
chemotherapy reduces the mortality rate.
Systemic chemotherapy is required for multifocal SS or MS
disease also in adults.85 It should be noted that although most
generally have indolent and chronic clinical courses, some adult
LCH patients exhibit rapid progression and fatal courses.86
However, the optimal systemic therapy for adult LCH has not yet
been developed.87–90 Multifocal adult LCH is an orphan disease.
This has hampered the development of an effective systemic
therapy for several reasons, as follows. First, it often takes time to
correctly diagnose LCH in adults. Second, it is very common in
adult LCH to adopt a “wait and see” strategy after diagnosis, even
when it is multifocal LCH. Third, the wide range of symptoms of
this rare disease causes patients to visit a variety of clinics that
apply various therapeutic regimens. Moreover, adult patients are
often reluctant to take a leave of absence from their jobs for
© 2014 Japan Pediatric Society
458 A Morimoto et al.
hospitalization. For this reason, the JLSG has formulated an
ambulatory treatment regimen for adult patients with mul-
tifocal SS or MS disease that consists of combinations of
VBL/prednisolone (PSL) and methotrexate with daily
6-mercaptopurine (denoted the Special C regimen). This regimen
has shown signs of efficacy, particularly in patients with
multifocal SS disease.90 Adult LCH may also respond to Ara-C,
which is an effective agent for pediatric LCH.89 JLSG is now
planning a clinical trial for adult multifocal LCH using the
Special C regimen as the first-line treatment and Ara-C/PSL as
the salvage therapy for poor responders.
Salvage therapy and new treatment
In patients who have risk-organ involvement and do not respond
to the first-line therapy, more aggressive salvage therapy should
be considered. Myeloablative therapy using a combination of
high-dose Ara-C and cladribine (2-CdA)91,92 and the single agent
clofarabine93 have been reported to be effective for these patients.
However, profound and prolonged myelosuppression should be
anticipated in these therapies. Recently, it was reported that when
patients with severe and refractory BRAF V600E-positive LCH
were treated with vemurafenib, a BRAF inhibitor that was newly
approved for melanoma by the US Food and Drug Administra-
tion, they showed substantial and rapid clinical and biological
improvements without severe toxicities or adverse events.94
Allogeneic hematopoietic stem cell transplantation is another
promising approach as a salvage therapy for children with refrac-
tory LCH because of its immunomodulatory effect.95 A reduced-
intensity conditioning regimen may be sufficient to induce a cure,
which would decrease the treatment-related mortality.96
In patients who show reactivation in non-risk organs while
they are off therapy, treatment with pamidronate combined with
Cox2 inhibitor97 or 2-CdA monotherapy98,99 may be effective.
Careful attention is required to prevent known adverse effects of
therapy with 2-CdA, namely, the development of severe persis-
tent bone-marrow failure and myelodysplastic syndrome.100,101
In addition, liver or lung transplants have been successfully
performed in patients with end-stage organ involvement of
LCH.102,103
Reactivation and permanent sequelae
Nearly half of patients with MS disease exhibit reactivation,
which occurs in an unpredictable manner.104,105 Some patients
experience reactivation several times. Most of the first reactiva-
tions occur within 2 years after diagnosis. Reactivations occur
most frequently in bone and are rare in risk organs. Reactivated
lesions may sometimes resolve spontaneously. Most of the
patients with reactivation undergo second disease resolution and
survive. However, they have an increased risk of permanent
sequelae.
In many LCH patients, permanent sequelae are common.106
They are most often the result of the infiltrative nature of the
disease itself, which causes tissue destruction and granulomatous
fibrosis or gliosis of various tissues. Seventy percent of patients
with MS disease and 25% of SS disease patients develop one or
more life-long sequelae, including CDI, orthopedic problems,
© 2014 Japan Pediatric Society
hearing loss, neurological problems, growth-hormone deficiency,
loss of teeth, pulmonary fibrosis, and biliary cirrhosis with portal
hypertension. The most serious of these sequelae are those in the
CNS, such as CDI and ND-CNS disease; these sequelae occur
particularly frequently in MS disease.59,70 The incidence of these
sequelae increases over follow-up. Further novel therapeutic
measures are required to reduce these permanent sequelae.
Conclusions
The pathogenesis of LCH remains obscure and the optimal treat-
ment for LCH has not been established, although incremental
progress has been made. Whether LCH is a reactive or neoplas-
tic disorder remains unclear. Proinflammatory cytokines/
chemokines are known to participate in LCH, which suggests that
LCH is an immune disorder. However, more than half of LCH
patients have the oncogenic BRAF mutation, which suggests that
LCH is a neoplastic disorder. There are several major issues in
the treatment of LCH that remain to be resolved. First, it remains
unclear how to rescue patients with risk-organ involvement who
do not respond to first-line therapy. Moreover, the optimal treat-
ment for multifocal adult LCH is not known. Third, protocols that
effectively reduce and treat CNS-related consequences are
needed. To elucidate the pathogenesis of LCH and develop the
new treatment, genome-wide association studies107 and genera-
tion of NOG mice model108 should be performed in the future.
Acknowledgment
We thank Dr Shinsaku Imashuku for laying the foundation of the
JLSG studies, the members of JLSG for providing patient infor-
mation, and Ms Yasuko Hashimoto for her excellent secretarial
assistance. This work was supported by a Grant for Research on
Measures for Intractable Diseases from the Ministry of Health,
Labor and Welfare, Japan.
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