269

Pulmonary Langerhans Cell Histiocytosis

Brian Shaw, MD1 Michael Borchers, PhD2,3 Dani Zander, MD4 Nishant Gupta, MD, MS2,3

1 Department of Internal Medicine, University of Cincinnati, Address for correspondence Nishant Gupta, MD, MS, Division of
Cincinnati, Ohio Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati,
2 Medical Service, Veterans Affairs Medical Center, Cincinnati, Ohio 231 Albert Sabin Way, MSB Room 6053, ML 0564, Cincinnati, OH
3 Division of Pulmonary, Critical Care, and Sleep Medicine, University 45267 (e-mail: guptans@ucmail.uc.edu).
of Cincinnati, Cincinnati, Ohio
4 Department of Pathology and Laboratory Medicine, University of
Cincinnati, Cincinnati, Ohio

Semin Respir Crit Care Med 2020;41:269–279.

Abstract Pulmonary Langerhans cell histiocytosis (PLCH) is a diffuse cystic lung disease that is
strongly associated with exposure to cigarette smoke. Recently, activating pathogenic

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mutations in the mitogen-activated protein kinase pathway have been described in the
dendritic cells in patients with PLCH and have firmly established PLCH to be an
inflammatory myeloid neoplasm. Disease course and prognosis in PLCH are highly
variable among individual patients, ranging from spontaneous resolution to develop-
ment of pulmonary hypertension and progression to terminal respiratory failure. A
subset of patients with PLCH may have extrapulmonary involvement, typically involv-
Keywords ing the skeletal system in the form of lytic lesions, skin lesions, or the central nervous
► PLCH system most commonly manifesting in the form of diabetes insipidus. Smoking
► pneumothorax cessation is the cornerstone of treatment in patients with PLCH and can lead to
► MAPK disease regression or stabilization in a substantial proportion of patients. Further
► BRAF insight into the underlying molecular pathogenesis of PLCH has paved the way for the
► cladribine future development of disease-specific biomarkers and targeted treatment options
► smoking directed against the central disease-driving mutations.

Pulmonary Langerhans cell histiocytosis (PLCH) is a rare
diffuse cystic lung disease characterized by the development
of centrilobular lesions composed of CD1aþ dendritic cells
(DCs) and other inflammatory cells, with variable degrees of
fibrosis. These DCs have recently been discovered to carry a
variety of damaging mutations that lead to constitutive
activation of the mitogen-activated protein kinase (MAPK)
pathway. As such, PLCH is now classified as an inflammatory
myeloid neoplasm. In addition to the MAPK mutations, PLCH
has a strong association with cigarette smoke exposure and is
almost exclusively seen in active/former smokers.
PLCH is part of a spectrum of histiocytic disorders that was
first described by Farber in 1941.1 The most recent classification
scheme for histiocytic disorders recognizes the following five
groups: the L group (Langerhans), the C group (cutaneous and
mucocutaneous histiocytosis), the M group (malignant histio-
cytoses), the R group (Rosai–Dorfman’s disease and miscella-
neous noncutaneous, non-Langerhans cell histiocytoses), and
the H group (hemophagocytic, lymphohistiocytic, and macro-
phage activation syndrome). The L group contains several
diseases: Langerhans cell histiocytosis (LCH), indeterminant
cell histiocytosis, Erdheim–Chester’s disease (ECD), and mixed
LCH/ECD diseases. LCH is further categorized on the basis
of organ or system involvement: single system LCH, LCH with
pulmonary involvement (PLCH), multisystem LCH with
involvement of risk organs, multisystem LCH without involve-
ment of risk organs (risk organs being liver, spleen, and
bone marrow), and LCH associated with another myeloprolif-
erative/myelodysplastic disorder.2
The majority of adults with PLCH tend to have isolated
pulmonary disease; however, extrapulmonary involvement
can be seen in 15 to 20% of cases.3–5 The most common

Issue Theme Orphan Lung Diseases; Copyright © 2020 by Thieme Medical DOI https://doi.org/
Guest Editors: Jay H. Ryu, MD, Nishant Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0039-1700996.
Gupta, MD New York, NY 10001, USA. ISSN 1069-3424.
Tel: +1(212) 760-0888.
270 Pulmonary Langerhans Cell Histiocytosis Shaw et al.

extrapulmonary features are lytic bone lesions, diabetes

insipidus from posterior pituitary involvement, and skin
lesions.3,5–12 Although involvement of risk organs (liver,
spleen, and hematopoietic system) is rare, it portends a
poor prognosis.13 The course of PLCH is variable and unpre-
dictable, ranging from asymptomatic with spontaneous res-
olution to relentless progression despite smoking cessation
and aggressive pharmacological treatment.

Epidemiology
Due to its rarity, limited epidemiological data are available
for PLCH. There is a strong association with exposure to
cigarette (and marijuana) smoke and the development of
PLCH.14 PLCH can occur at any age; however, it is most
commonly diagnosed in patients aged 20 to 40 years.1,4,15
There is no known sex predilection, and both males and
females appear to be equally affected by PLCH. There was a

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suggestion of male predominance in the past, however, that
likely relates to the differences in historical smoking rates
between males and females.16 It is estimated that PLCH
accounts for 3 to 5% of all diffuse lung diseases in
adults.17–19 A national survey of hospital discharges con-
ducted in Japan estimated the prevalence of PLCH to be 0.27
per 100,000 males and 0.07 per 100,000 females in the
Japanese population.12 Extrapolating these numbers to the
current population estimates suggests that there are 1,100
patients with PLCH in the United States and 26,000 world-
wide. Similar to other rare diseases, these numbers are
almost certainly an underestimate of the true disease
prevalence.

Pathogenesis
The pathogenesis of PLCH is now better understood and can
broadly be visualized as progression along a linear pathway:
DCs harboring activating MAPK mutations accumulate in the
pulmonary parenchyma under the influence of cigarette
smoke, where they lead to secondary immune system activa-
tion and migration, forming cellular nodules. The accumulated
leukocytes including myeloid cells, monocytes, and cytotoxic
lymphocytes20 release cytotoxic mediators and matrix-degrad-
ing enzymes which contribute to the bronchiolar destruction
characteristic of PLCH (►Fig. 1).

Accumulation of Dendritic Cells

DCs are members of the mononuclear phagocyte system and
are composed of a heterogenous population of cells whose
primary function is to serve as antigen-presenting cells to T-
cells. Langerhans cells (LCs) are a subset of DCs that are localized
to the epidermis and mucosal epithelium (including the tra-
cheobronchial epithelium) and are characterized by the pres-
ence of cell surface markers CD1a and CD207 (langerin).2
The earliest lesion in PLCH involves the accumulation and
invasion of distal bronchiolar walls by abnormal CD1aþ DCs.
The exact factors that drive the recruitment and subsequent
accumulation of the DCs in PLCH are not fully characterized.
Immature DCs express CCR6 and migrate toward the CCL20
Fig. 1 The pathogenesis of PLCH. DC, dendritic cells; MAPK, mitogen-
activated protein kinase; MMP, matrix metalloproteinase; PLCH,
pulmonary Langerhans cell histiocytosis.
ligand, expressed by airway epithelial cells.21 As DCs mature,
CCR6 expression diminishes and CCR7 expression predom-
inates.22 Mature DCs then exit the lung and migrate to the
draining lymph nodes along a CCR7 ligand-driven chemokine
gradient of CCL19 and CCL21.23 It has been demonstrated
that cigarette smoke affects DC numbers and maturity by

Seminars in Respiratory and Critical Care Medicine Vol. 41 No. 2/2020


increasing the expression of several proinflammatory medi-
ators in the lung.24–26 However, the effects of cigarette smoke
on DC function and pulmonary accumulation in PLCH are
unknown.27 Several chemokines including CCL5, CCL20, and
CXCL11 have been identified as candidates with the potential
to drive DC accumulation in nonpulmonary LCH lesions, but
these have not been confirmed in PLCH.28 The lesions in PLCH
are focal, which suggests that changes in the bronchiolar
epithelial microenvironment are essential to the accumula-
tion of the DCs.4 Evaluation of the loosely formed DC
aggregates around the small airways has revealed that there
are a portion of cells that produce CD1a, but not CD207
(langerin), indicating that the cells are undergoing matura-
tion and differentiation.14
Secondary Immune Activation
The CD1aþ DCs in PLCH express multiple costimulatory
molecules, and by producing cytokines such as interleukin
1-β, granulocyte macrophage colony-stimulating factor
(GM-CSF), and tumor necrosis factor (TNF)-α, they help
in secondary recruitment of other immune cells, forming
cellular nodules comprised DCs, T-cells, B-cells, fibroblasts,
eosinophils, neutrophils, plasma cells, and pigmented mac-
rophages.18,29,30 As the disease progresses, the nodules are
gradually replaced by fibroblastic proliferation with central
scarring and peripheral cellular tentacles.31
Lung Destruction in PLCH
A unique characteristic of PLCH nodules is their ability to
replace and remodel the surrounding tissues. The exact mech-
anisms responsible for lung destruction in PLCH are not well
understood. CD1aþ cells of PLCH nodules express membrane
maturation markers that are similar to ones that are on the
surface of DCs after being activated by cytokines or patho-
gens.32 One of the proposed mechanisms for the destruction
and remodeling is direct, local cytotoxic damage by pulmonary
macrophage, natural killer cells, and cytotoxic CD8 T-cells that
have been aberrantly activated by the abnormal DCs. This is
demonstrated by immunohistochemical analyses of PLCH
cellular lesions.20 Recent research has discovered several
different metalloproteinases in LCH nodules, and it is
theorized that this could contribute to, or be the primary
underlying cause of, the tissue destruction.14,33,34 Progressive
centrilobular destruction with fibrosis leads to the formation
of the hallmark cystic airspace dilation that is characteristic of
PLCH.
Role of Cigarette Smoke
There is a very high prevalence of smoking in patients with
PLCH, which suggests a causal relationship.1,4,5,15 The vast
majority of the patients (90–100%) diagnosed with PLCH
are current or former smokers.4,16 A significant proportion of
patients who were diagnosed with LCH in childhood and
later developed PLCH had a history of cigarette smoking as
opposed to the patients who only had LCH and did not
develop lung involvement.35 Cigarette smoke likely serves
as the inciting external antigen in patients with PLCH that
leads to an uncontrolled response by the DCs.
Pulmonary Langerhans Cell Histiocytosis Shaw et al. 271
Smoking induces accumulation of CD1aþ cells in patients
with healthy lungs and patients with COPD.36–38 Production of
the glycoprotein, osteopontin, is increased with exposure to
nicotine, and it is found in high levels in bronchoalveolar lavage
(BAL) fluid in smokers with PLCH and may act as a chemo-
attractant to monocytes, macrophages, and DCs.14 Cigarette
smoke also stimulates local production of cytokines (TNF-α,
GM-CSF, transforming growth factor-β, and CCL20) that are
important for the recruitment and differentiation of DCs, and
have been reported to be elevated in PLCH lesions.39–42
However, the fact that only a minority of individuals who
smoke cigarettes go on to develop PLCH suggests that cigarette
smoke is unlikely to be the sole causative agent for PLCH, and
rather acts as a potentiator in the pathogenic pathway in
genetically susceptible individuals.
PLCH Is an Inflammatory Neoplasm
There has been significant debate over whether PLCH is a
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neoplastic disorder or an inflammatory disease. Previously, it
was thought that PLCH is caused by cigarette smoke-induced
polyclonal expansion of the DCs.43 However, recent data
have revealed the DCs in PLCH to be of clonal origin,44–46
thus suggesting a neoplastic nature for PLCH. Finally, the
discovery of mutations involving the MAPK pathway in PLCH
has transformed our understanding of the field and firmly
established PLCH as a neoplasm. The MAPK mutations found
in the PLCH lesions are similar to mutations found in other
malignancies such as melanoma,47 hairy cell leukemia,48
papillary thyroid cancer,49 as well as other histiocytic dis-
orders such as ECD.50 The most common mutation described
in PLCH is the BRAFV600E mutation, present in 50% of the
patients.51,52 Mourah et al analyzed biopsies in adult LCH
patients (26 pulmonary lesions and 37 nonpulmonary
lesions) and found some key differences in the genetic
landscape of PLCH as compared with the nonpulmonary
lesions of LCH.51 Similar to systemic LCH, mutations involv-
ing BRAFV600E and MAP2K1 were seen in 50 and 20% of the
pulmonary lesions, respectively. In addition, the pulmonary
lesions were found to have a separate DC clone harboring the
NRASQ61K/R mutation, often concurrently along with a
BRAFV600E mutation. NRAS mutations were not identified in
the nonpulmonary lesions.
The exact molecular mechanisms by which MAPK muta-
tions drive abnormal DC accumulation in PLCH is not fully
understood and represents a high priority area of future
research. The CD1aþ cells do not appear to proliferate
abnormally53,54; instead these cells exhibit increased sur-
vival and are resistant to apoptosis.55 Other potential patho-
genic mechanisms proposed in PLCH include activated MAPK
pathway-induced senescence of the myeloid DCs,56 and
reduced migration of DCs from lungs to the lymph nodes.
In summary, the current understanding of PLCH can be
conceptualized as a state of universal ERK activation due to
upstream mutations involving one or more oncogenes in the
MAPK pathway. We propose that PLCH is a myeloid neoplasm
that follows the classic two-hit paradigm of malignancy as
described by Knudson,57 where genetically susceptible indi-
viduals harboring MAPK mutations in the DCs develop PLCH
Seminars in Respiratory and Critical Care Medicine Vol. 41 No. 2/2020
272 Pulmonary Langerhans Cell Histiocytosis
after being exposed to an external environmental stimulus
(i.e., the second hit, cigarette/marijuana smoke).
Clinical Features
Patients with PLCH can have wide-ranging presentations,
from asymptomatic disease detected incidentally to pro-
gressive debilitating disease. Initial symptoms can be insid-
ious onset of dyspnea on exertion or cough, and it is not
uncommon for patients to attribute these symptoms to
smoking.4,16 Approximately two-thirds of patients present
with dry cough and dyspnea on exertion as the initial
complaint.3,11 In a recent survey-based assessment of
patients with PLCH, dyspnea on exertion was the most
common symptom (described in 89% of the patients),
followed by fatigue (74%) and dry cough (72%).58 About
10 to 20% of patients can present with constitutional
symptoms such as malaise, fever, night sweats, and weight
loss.18 About 25% of PLCH patients are asymptomatic
and are diagnosed based on incidental imaging
findings.8,9,12,59,60 Spontaneous pneumothorax, either uni-
lateral or bilateral, can be the presenting manifestation in
10 to 20% of patients.5,60,61 Pulmonary hypertension in
patients with PLCH tends to be worse than pulmonary
hypertension observed in comparable advanced diffuse
lung diseases.62,63 This is likely due to the direct involve-
ment of the small pulmonary arteries and arterioles by the
disease process, rather than just loss of a portion of the
cross-sectional area of the pulmonary circulation that is
seen with other diffuse lung diseases. Although hemosider-
in-laden macrophages may be seen histologically, hemop-
tysis is an uncommon symptom and should not be
attributed to PLCH unless other etiologies, specifically
malignancies, have been ruled out.4,7,8,11,61,64
Fig. 2 Imaging findings in PLCH: (A) Coronal CT chest demonstrating nodules, thick-walled cavities, and thin-walled cysts in an upper-mid lung
zone predominance with relative sparing of the lung bases. (B) Repeat CT chest performed 7 months following reduction in cigarette smoke
exposure demonstrating significant radiological improvement with almost complete resolution of the nodules and thick-walled cavities and
persistent cysts. CT, computed tomography; PLCH, pulmonary Langerhans cell histiocytosis.
Seminars in Respiratory and Critical Care Medicine Vol. 41
Shaw et al.
Imaging
PLCH lesions are classically bilateral, symmetric, and charac-
terized by upper lobe predominant nodules and cysts which
spare the lung bases near the costophrenic sulci
(►Fig. 2).31,65,66 PLCH lesions are focal, located both centrally
and peripherally, and are separated by normal-appearing
parenchyma.18 In the early stages of disease, imaging may
show bilateral, upper lobe predominant irregular, small
nodules ranging between 1 and 10 mm in size.5 As disease
progresses, the nodules start to develop cystic changes and
both thick-walled cavities and thin-walled cysts can be
visualized on chest computed tomography (CT) scans. The
cysts in PLCH will initially appear to be round, small, and
have thick walls; however, as the disease progresses, the
cysts will start to have thinner walls and become larger and
irregular, bilobed, cloverleafed, or branched.31 The irregular-
ity of the cysts as the disease progresses is thought to be due
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to the coalescence of the nodules.16 Mediastinal lymphade-
nopathy is not a common finding in PLCH and should prompt
workup for an additional/alternate diagnosis.31 In later
stages, the disease can get “burnt out” and evolve into an
upper lung predominant reticular pattern with fibrosis, and
can be difficult to differentiate from other fibrosing intersti-
tial lung diseases.31 Longitudinal studies involving serial
high-resolution CT (HRCT) scans have shown that over
time the nodules and cavitated nodules can resolve, but
the cysts tend to persist or enlarge over time.67 Ground-
glass opacities, linear densities, and emphysematous bullae
can also be seen, and reflect the concomitant presence of
cigarette smoke-induced lung damage in addition to PLCH.68
In pediatric patients with lung involvement from systemic
LCH, it is not uncommon to have lesions present diffusely,
including the lung bases.69
No. 2/2020
 Pulmonary Langerhans Cell Histiocytosis Shaw et al. 273

Pulmonary Function Testing presence of a convoluted nuclear membrane, and a nuclear

In early disease, pulmonary function tests (PFTs) can be normal
in 10% of patients with PLCH.70 Patients can have restrictive,
obstructive, or combined defects on PFTs; the most common
defect is decreased diffusing capacity of lung for carbon
monoxide (DLCO), seen in 70 to 90% of patients.3,5–7,11,12
Almost all patients have an obstructive pattern on PFTs that is
out of proportion to the smoking history, likely a reflection of
small airway damage.3,5,7,11 A purely restrictive pattern is
uncommon but can occur.3
groove may also be visualized in some of the LCs. The nucleus
lacks a prominent nucleolus and is surrounded by abundant
cytoplasm, with poorly defined cellular borders.71,72 Diagnosis
is confirmed by immunohistochemical staining for CD1a,
CD207 (langerin), and S-100.15 Birbeck granules on electron
microscope are characteristic of LCs and helpful for diagnosis
of PLCH; however, this mode of confirmation is not commonly
utilized in clinical practice due to the associated expense and
the fact that immunohistochemical staining for cell surface
markers such as CD1a is readily available.16,71

Pathology
On gross examination, early lesions in PLCH are focal, tan-
white nodules, and have irregular borders.71 On microscopic
examination, lesions are centered around terminal and respi-
ratory bronchioles and can be seen infiltrating the bronchiolar
Diagnosis
Definitive diagnosis of PLCH requires histopathological confir-
mation, either from the lungs (most common) or other extrap-
ulmonary locations, typically skin or bone.4 In some cases,
however, a combination of characteristic HRCT findings in the

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walls and epithelium.72 As PLCH lesions grow, they progres-
sively envelope the terminal bronchioles.73 The increasing
obstruction of the small airways that results from this process
is thought to be responsible for the distal perilesional airspace
enlargement and cyst formation.74 As the disease progresses,
the lesions evolve into stellate fibrotic scars that are sur-
rounded by cystic areas and honeycombing (►Fig. 3).71,72
Histologically, the hallmark of PLCH is the accumulation of
CD1aþ cells organized into aggregates in the nodules and
airspaces comprising the PLCH lesions (►Fig. 3). The CD1aþ
cells are accompanied by variable numbers of eosinophils,
macrophages, plasma cells, and lymphocytes.52,73 A key his-
tological feature of LCs, which can help in identification, is the
presence of a compatible clinical history, especially in patients
with a history of exposure to cigarette smoke, may be sufficient
to establish a clinical diagnosis of PLCH.
Bronchoalveolar Lavage
The presence of more than 5% CD1aþ cells on BAL has been
proposed as a confirmatory diagnostic finding in patients
with suspected PLCH. However, this cutoff, while being quite
specific, suffers from a lack of sensitivity and is not clinically
useful in most patients. As such, BAL has limited utility in
establishing the diagnosis of PLCH but can be of value in
some patients for excluding other etiologies of upper lobe
predominant nodules and cysts, such as atypical infections.

Fig. 3 Histopathological findings in PLCH: (A) Stellate inflammatory and fibrotic nodule with peripheral accumulation of smokers’ macrophages.
(B) Older lesion consisting of fibrotically thickened interstitial “tentacles” with accompanying inflammation and cystic airspace enlargement at
the periphery on the right. (C) Inflammatory infiltrate from the center of an active nodule, including Langerhans cells, conspicuous eosinophils,
and other inflammatory cells. (D) Langerhans cells (arrowhead) with ovoid cell shapes and folded or indented nuclei, some of which have
grooves. (E) High-power image of (B) highlighting the fibrotic and inflamed interstitium, and Langerhans cells and macrophages in an alveolus.
(F) Numerous Langerhans cells demonstrate brown membranous staining for CD1a. PLCH, pulmonary Langerhans cell histiocytosis.

Seminars in Respiratory and Critical Care Medicine Vol. 41 No. 2/2020

274 Pulmonary Langerhans Cell Histiocytosis
Lung Biopsy
Transbronchial forceps-guided lung biopsy can establish the
diagnosis of PLCH in approximately one-third of the cases.
False negatives occur due to inadequate sampling of lesions or
interpretative challenges. A critical review of the biopsy speci-
mens by an expert pathologist familiar with the disease
manifestations is essential prior to determining the procedure
to be nondiagnostic. Transbronchial cryobiopsy of the lung is a
relatively new procedure where the lung parenchyma is frozen
by using cold compressed gas and taken out en bloc. This
procedure yields bigger tissue specimens than the traditional
forceps biopsies and has been shown to have a diagnostic yield
approaching 70% in patients with diffuse parenchymal lung
diseases. The diagnostic utility of transbronchial cryobiopsy in
patents with PLCH is not well established; however, it is quite
likely to be clinically useful in patients with suspected PLCH
given the bronchiolocentric nature of the disease. Expert
centers familiar with this technique should consider trans-
bronchial lung cryobiopsy in patients with suspected PLCH
prior to performing surgical lung biopsy.
The gold standard diagnostic modality in patients with
suspected PLCH remains video-assisted thoracoscopic sur-
gery–guided surgical lung biopsy and may be needed in some
instances where all other non- or less-invasive forms of
diagnostic confirmation have been exhausted. In a subset
of patients who present with a spontaneous pneumothorax,
the biopsy may be done at the same time as pleurodesis.
Management
Smoking Cessation
Given the central role of cigarette smoke exposure in disease
pathogenesis, smoking cessation is an essential component
of management in patients with PLCH. In a substantial
proportion of patients, smoking cessation alone may lead
to disease regression and/or stabilization without the need
for any other pharmacological treatment.1,61,75–77 The
patients should be closely monitored, though, as smoking
cessation may be short lived and in a subset of patients
(approximately one-third), the disease may progress despite
successful smoking cessation. It is important to note that
while discussing smoking cessation, clinicians take into
account both active and passive smoke exposure, as well as
marijuana smoking.
Pharmacological Treatment
Systemic corticosteroids are often prescribed to patients
with PLCH. Although there have been reports of symptomatic
and radiological improvement after systemic corticosteroids,
these reports suffer from a less-than-perfect characteriza-
tion of the timing of corticosteroid initiation with respect to
smoking cessation, and it is possible that these patients may
have improved by smoking cessation alone rather than a true
treatment effect of corticosteroids. Long-term administra-
tion of corticosteroids is associated with a plethora of
adverse effects. Given the overall lack of evidence, we typi-
cally do not prescribe systemic corticosteroids routinely for
patients with PLCH, except for a short, well-defined trial in
Seminars in Respiratory and Critical Care Medicine Vol. 41 No. 2/2020
Shaw et al.
patients with severe/progressive disease. Inhaled cortico-
steroids in addition to bronchodilators can be tried, espe-
cially in patients with reversible defects or obstruction on
PFTs.1,4
Vinblastine, and sometimes methotrexate, has been used
in severe multisystemic LCH with some efficacy; however,
these drugs have not been shown to have a consistently
positive effect in patients with isolated PLCH.4,78 Cladribine
(2-chlorodeoxyadenosine) has been shown to be helpful in
refractory systemic LCH and has also been used in isolated
PLCH.79–81 It is directly toxic to monocytes and lymphocytes
and can induce remission or improve pulmonary function in
PLCH.81–87 A phase II clinical trial investigating the safety and
efficacy of cladribine in PLCH is currently underway
(NCT01473797, www.ClinicalTrials.gov).
The recent discovery of multiple MAPK mutations in PLCH
has suggested the possibility of targeted therapeutic inter-
ventions similar to other histiocytic disorders and malignan-
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cies harboring activating mutations in the MAPK pathway.
Vemurafenib, a BRAF kinase inhibitor, has shown clinical
efficacy in patients with ECD and was recently approved by
the U.S. Food and Drug Administration to treat ECD.88 Given
the similarities in pathogenesis, especially considering the
central role of BRAF mutations in both PLCH and ECD,
treatment with BRAF inhibition may be a clinically useful
future strategy in PLCH. A combination of BRAF and MEK
inhibition has shown promising results in patients with
malignant melanoma, and may represent a viable treatment
approach in patients harboring concurrent BRAF and NRAS
mutations.47,51 Excellent response using an oral MEK inhibi-
tor, cobimetinib, has recently been described in a diverse
category of histiocytic disorders.89 The use of a MEK inhibitor
(trametinib) has also been described in a patient with
progressive PLCH harboring a MAP2K1 mutation, with
significant improvement in dyspnea and 6-minute walk
distance.90 All of these studies are building on a small, but
growing body of evidence that targeted therapies directed at
MAPK mutations could have a significant impact on the
treatment paradigm of PLCH in the near future.
Spontaneous Pneumothorax
Spontaneous pneumothorax is a common pulmonary compli-
cation of PLCH, with reported prevalence estimates ranging
between 16 and 32%.58,61,91 In a subset of patients, spontane-
ous pneumothorax can be the presenting manifestation of
PLCH, and it is important to maintain a high index of clinical
suspicion for underlying secondary causes when evaluating
patients with an apparent primary spontaneous pneumotho-
rax. Patients with PLCH should be educated about the signs and
symptoms of a spontaneous pneumothorax and advised to seek
immediate medical attention in the event that they experience
these symptoms. Spontaneous pneumothorax in PLCH tends to
recur frequently, if managed conservatively, with reported
recurrence rates approaching 60%.58,61 Surgical pleurodesis
can substantially reduce the risk of recurrence to 0 to 20%58,61
and should be considered following the first episode of
spontaneous pneumothorax rather than waiting for a recurrent
episode. The risk of a spontaneous pneumothorax associated
 Pulmonary Langerhans Cell Histiocytosis Shaw et al. 275

with air travel is less than 1 per 100 flights, and air travel is
considered safe for majority of the patients with PLCH.
General Recommendations
Overall, smoking cessation remains the focal point of man-
agement for most patients with PLCH. Attention should be
paid toward optimal vaccinations including annual influenza
vaccination and appropriate pneumococcal vaccination
using both PPSV23 and PCV13. Some patients with PLCH
will require supplemental oxygen therapy; recommenda-
tions for prescribing supplemental oxygen to patients with
PLCH are the same as other chronic lung diseases. Pulmonary
hypertension in PLCH portends a worse prognosis, and
patients should be monitored periodically for signs and
symptoms suggestive of pulmonary hypertension. History
taking in PLCH should include enquiries about extrapulmo-
nary organ involvement such as weight loss, polyuria, poly-
dipsia, bone pain, and skin rashes. There are some reports of
who underwent lung transplantation in the United States
over the past three decades. The median posttransplant
survival in patients with PLCH was similar to other lung
diseases (5.1 years in the PLCH group vs. 5.5 years in patients
with other lung diseases), with actuarial Kaplan–Meier 1-, 5-,
and 10-year survival of 85, 49, and 22%, respectively. For
reasons that are not entirely clear, females had a significantly
increased median survival as compared with males (9.3 vs.
3.9 years, p ¼ 87).100 Similar to other lung transplantation
recipients, bronchiolitis obliterans syndrome was the lead-
ing cause of posttransplant morbidity and mortality in
patients with PLCH.100
Monitoring Disease Extent and Progression
The natural history of PLCH can be quite variable in individual
patients. All patients with newly diagnosed PLCH should have
close follow-up with serial PFTs every 3 to 4 months at least for
the first 1 to 2 years, to confidently establish their individual

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worsening diabetes insipidus in pregnant females; however,
PLCH is not a contraindication to pregnancy unless associat-
ed with pulmonary hypertension and/or chronic respiratory
failure.92,93 Key recommendations for management of
patients with PLCH are summarized in ►Table 1.
Lung Transplantation
Lung transplantation has been used to treat patients with
end-stage PLCH and patients with severe pulmonary hyper-
tension with some success. Disease recurrence following
lung transplantation has been described in several cases,
highlighting the neoplastic nature of PLCH where the abnor-
mal DCs carrying the MAPK mutations originate from their
hematopoietic precursors and metastasize to the lungs.94–98
In 2006, Dauriat et al reviewed data from 39 PLCH patients
who had been transplanted in France, and found the 1-, 5-,
and 10-year posttransplant survival rates to be 77, 57, and
54%, respectively.99 Recurrent disease was seen in 20% of
the transplanted patients.99 Recently, Wajda et al analyzed
the posttransplantation outcomes from 87 PLCH patients
disease trajectory. Subsequently, the follow-up PFTs can be
spaced to every 6 months, and then perhaps annually after
establishing a stable trajectory.70,101,102 Rapid decline in
forced expiratory volume in 1 second (FEV1) and/or changes
in functional status should prompt consideration of obtaining
a repeat CTof the chest to evaluate disease progression. History
and physical examination aimed at ascertaining extrapulmo-
nary organ involvement from PLCH (diabetes insipidus, skin
rashes, and bone pain) or other disease-specific complications
such as pulmonary hypertension should be performed at the
initial and each subsequent encounter. Laboratory tests that
might be useful in patients with PLCH include tests aimed at
monitoring renal function and electrolyte imbalances, as well
as involvement of high-risk organs (spleen, liver, and bone
marrow) (►Table 2).
Natural History and Prognosis
Disease course in PLCH is highly variable and unpredictable.
Published reports suggest a median survival of 12 to 13 years

Table 1 Recommendations for optimal management of patients with PLCH

Obtain detailed history with regard to smoke exposure, cigarettes (both active and passive), as well as marijuana, and counsel
patients on complete cessation of active smoking and avoidance of passive smoking
Enquire about extrapulmonary symptoms at each visit: weight loss, polyuria, polydipsia, bone pain, and skin rashes
Pay attention to the signs and symptoms of pulmonary hypertension
Make attempts to ascertain the underlying genetic mutation (in patients with available tissue specimens)
Consider a trial of bronchodilators and inhaled corticosteroids in symptomatic patients with obstructive defect on PFTs
Consider pharmacological treatment with cladribine or targeted treatment with BRAF (in patients with known single BRAFV600E
mutation) or MEK inhibitors (in patients with other MAPK mutations or unknown mutation status). Candidates for pharma-
cological treatment should be chosen after a thorough and careful consideration of the risk-to-benefit ratio of treatment. For
instance, potential candidates may include patients with progressive disease despite successful smoking cessation, or patients
with multisystem LCH especially with risk-organ involvement
Educate patients about the signs and symptoms of a spontaneous pneumothorax
Educate patients about the safety of air travel and counsel to avoid scuba diving
Annual influenza vaccinations and appropriate pneumococcal vaccinations (both PCV13 and PPSV23)

Abbreviations: LCH, Langerhans cell histiocytosis; MAPK, mitogen-activated protein kinase; PCV13, pneumococcal conjugate vaccine; PFT,
pulmonary function test; PLCH, pulmonary Langerhans cell histiocytosis; PPSV23, pneumococcal polysaccharide vaccine.

Seminars in Respiratory and Critical Care Medicine Vol. 41 No. 2/2020

276 Pulmonary Langerhans Cell Histiocytosis Shaw et al.
Table 2 Disease monitoring in patients with PLCH
Initial visit Every 3–4 mo until
clinical stability
Enquire about symptoms of X X
extrapulmonary involvement
PFTs X X
CBC, renal and liver X X
function tests
CT chest X X
Echocardiogram
Brain MRI
PET scan
Bone scan
Abbreviations: CBC, complete blood count; CT, computed tomography; MRI, magnetic resonance imaging; PET, positron emission tomography; PFT,
pulmonary function test; PLCH, pulmonary Langerhans cell histiocytosis.
following disease diagnosis.3,14 However, the mortality and
morbidity in PLCH are likely overestimated in the literature,
as a significant proportion of patients with mild disease are
lost to follow-up.3,4,18,64 About 50% of patients with PLCH
will experience a favorable outcome.103 About 10 to 20% of
patients have early severe symptoms that consist of recur-
rent pneumothoraces or progressive respiratory failure with
cor pulmonale.4,18 Approximately 30 to 40% of patients have
persistent symptoms of variable severity with conversion of
radiographic findings from nodules to cysts over time.4
Predictors of poor outcomes are diagnosis at older age,
multisystem involvement (especially involvement of the
liver, spleen, and/or bone marrow), extensive cysts and
honeycombing on imaging, and abnormal PFT parameters
such as reduced DLCO, low FEV1/forced vital capacity ratio at
diagnosis, and high residual volume/total lung capacity ratio
at diagnosis.3,61 In a prospective, multicenter natural history
study of 58 patients with newly diagnosed PLCH, ongoing
cigarette smoking and reduced PaO2 were associated with a
faster rate of lung function decline.70
Future Needs
There are several gaps in our understanding of the disease
biology that have hindered meaningful progress in PLCH.
Perhaps, the most important need for the field is an improved
understanding of the disease pathogenesis. Improved under-
standing of the role of MAPK mutations and their effect on DC
function, and the exact role of cigarette smoke exposure on
the disease pathogenesis will help develop novel therapies.
The development of disease-specific diagnostic biomarkers
can obviate the need for invasive procedures such as lung
biopsies to establish the diagnosis with certainty. Prospec-
tive, natural history studies are required to determine pre-
dictors of disease progression that can help design pivotal
treatment trials evaluating novel agents and determine the
optimal population to be included in these trials. Finally,
targeted therapies aimed at MAPK pathway inhibition need
to be investigated in a controlled fashion to understand
Seminars in Respiratory and Critical Care Medicine Vol. 41 No. 2/2020
Annual visit Focused assessments based
following stability on symptoms and exam findings
X
X
X
X
X
X
Downloaded by: Universiteitsbibliotheek Amsterdam. Copyrighted material.
optimal dosing strategies as well as determine their safety
and efficacy in this patient population.
Conclusion
PLCH is a cigarette smoke-driven inflammatory myeloid neo-
plasm, where DCs harboring pathogenic MAPK mutations
drive progressive nodulocystic lung destruction. Improved
understanding of the underlying genetic landscape of PLCH
has transformed and energized the field, and provided a
promise for accelerated scientific discoveries, disease-specific
biomarkers, targeted therapies, and overall improved patient
outcomes.
Conflict of Interest
None declared.
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