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Clinical manifestations, pathologic features, and diagnosis


of Langerhans cell histiocytosis
Author: Kenneth L McClain, MD, PhD
Section Editor: Peter Newburger, MD
Deputy Editor: Alan G Rosmarin, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Aug 2019. | This topic last updated: Jul 30, 2019.

INTRODUCTION

Langerhans cell histiocytosis (LCH) is a rare histiocytic disorder most commonly characterized by
single or multiple osteolytic bone lesions demonstrating infiltration with histiocytes having bean-
shaped nuclei on biopsy. These histiocytes, along with lymphocytes, macrophages, and
eosinophils may infiltrate nearly every organ (most notably the skin, lymph nodes, lungs, thymus,
liver, spleen, bone marrow, or central nervous system with the exception of the heart and kidneys).

LCH is so named because the morphology and immunophenotype of the pathologic cells resemble
Langerhans cells, which are specialized dendritic cells found in the skin and mucosa. However,
LCH is derived from myeloid progenitor cells from the bone marrow, and is not derived from the
Langerhans cell of the skin.

For now, "Langerhans cell histiocytosis" remains the preferred nomenclature; the historical terms
histiocytosis-X, Letterer-Siwe disease, Hand-Schüller-Christian disease, and diffuse
reticuloendotheliosis have been abandoned. The term "eosinophilic granuloma" is sometimes used
to describe the pathology of an individual lesion, particularly isolated lytic processes in bone.

The epidemiology, clinical manifestations, pathologic features, diagnosis, and differential diagnosis
of LCH will be presented here. The management of LCH is presented separately, as are specific
discussions of solitary LCH involving lung or bone. (See "Treatment of Langerhans cell
histiocytosis" and "Pulmonary Langerhans cell histiocytosis" and "Langerhans cell histiocytosis
(eosinophilic granuloma) of bone in children and adolescents".)

TERMINOLOGY

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The archaic term "histiocyte" refers to large white blood cells resident in tissues, including
Langerhans cells, monocytes/macrophages, and dermal/interstitial dendritic cells [1].

The World Health Organization classification of hematopoietic and lymphoid tumors divides
disorders of these cells into the following three categories [2]:

● Dendritic cell disorders – This grouping includes LCH, secondary dendritic cell processes,
juvenile xanthogranuloma, solitary histiocytomas with a dendritic phenotype, and Erdheim-
Chester Disease. As noted above, pathologic cells in LCH resemble Langerhans cells in the
skin, but are not actually derived from those skin-associated cells. (See "Erdheim-Chester
disease" and "Juvenile xanthogranuloma (JXG)".)

● Macrophage-related disorders – This grouping includes primary and secondary


hemophagocytic syndromes, sinus histiocytosis with massive lymphadenopathy (Rosai-
Dorfman disease), and solitary histiocytoma with a macrophage phenotype. (See "Treatment
and prognosis of hemophagocytic lymphohistiocytosis" and "Peripheral lymphadenopathy in
children: Etiology", section on 'Rosai-Dorfman disease'.)

● Malignant histiocytic disorders – This grouping includes monocyte-related leukemias (eg,


acute monocytic leukemia, acute myelomonocytic leukemia), extramedullary monocytic tumor,
and dendritic cell or macrophage-related histiocytic sarcoma. (See "Clinical manifestations,
pathologic features, and diagnosis of acute myeloid leukemia" and "Histiocytic sarcoma".)

A subsequent and preferable classification from the Histiocyte Society divides these disorders into
the following five categories [3]:

● The "L" (Langerhans) group – This includes LCH, indeterminate cell histiocytosis, Erdheim-
Chester Disease (ECD), mixed LCH/ECD, and extracutaneous juvenile xanthogranuloma.
(See "Erdheim-Chester disease" and "Juvenile xanthogranuloma (JXG)".)

● The "C" (cutaneous and mucocutaneous) group – This includes a wide range of entities
localized to the skin and/or mucosa surfaces that do not meet diagnostic criteria for LCH.
Examples include juvenile xanthogranuloma, adult xanthogranuloma, and cutaneous Rosai-
Dorfman disease. (See "Juvenile xanthogranuloma (JXG)".)

● The "R" (Rosai-Dorfman disease) group – This includes Rosai-Dorfman disease and
miscellaneous non-cutaneous histiocytoses that do not meet diagnostic criteria for LCH. (See
"Peripheral lymphadenopathy in children: Etiology", section on 'Rosai-Dorfman disease'.)

● The "M" (malignant histiocytoses) group – This includes primary malignant histiocytoses
involving the skin, lymph nodes, digestive system, central nervous system, and other locations
and includes malignant histiocytoses secondary to other entities (eg, follicular lymphoma,
lymphocytic leukemia, hairy cell leukemia, acute lymphoblastic leukemia).

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● The "H" (hemophagocytic lymphohistiocytosis) group – This includes primary hemophagocytic


lymphohistiocytosis (HLH) and macrophage activation syndromes due to Mendelian inherited
conditions and secondary HLH associated with infections, malignancies, rheumatologic
conditions, iatrogenic immune suppression or activation, or other conditions. (See "Clinical
features and diagnosis of hemophagocytic lymphohistiocytosis".)

EPIDEMIOLOGY

LCH is a rare histiocytic disorder and the true incidence is unknown. Large published studies
usually are from referral centers and the disorder is likely under-diagnosed in the general
population. LCH has been diagnosed in all age groups, but is most common in children from one to
three years old. The incidence appears to be three to five cases per million children, which is the
same as pediatric Hodgkin lymphoma, and one to two cases per million adults [4-6].

A male predominance has been described in some case series, but not all [5,7-11]. The incidence
appears to be higher in whites of northern European descent than in blacks [2]. An epidemiologic
study from the United States suggested a connection between solvent exposure in parents, as well
as perinatal infections, but no increased incidence after viral epidemics [12]. Pulmonary LCH is a
rare disorder occurring in adults that is nearly universally associated with cigarette smoking,
whereas extrapulmonary LCH does not appear to have any association with smoking. (See
"Pulmonary Langerhans cell histiocytosis", section on 'Role of cigarette smoking'.)

The genetics of LCH have not been well elucidated. There is no evidence that relatives of patients
with LCH are at increased risk of developing LCH. Very rarely are twins or singleton siblings
concordantly affected, despite a few reported cases with early disease presentation and similar
organs affected in presumed monozygotic twins [13]. One report described three cases with skin
and bone involvement in one Iranian family [14]. Another study noted an association with a family
history of thyroid disease, but the meaning of this finding is not understood [15]. Rarely, LCH has
been described in patients with other concomitant histiocytic disorders, such as Erdheim-Chester
Disease and Rosai Dorfman Disease [16,17].

PATHOGENESIS

The discovery that the pathologic Langerhans cells (LC) were myeloid dendritic cells came from
gene expression array data showing a clear distinction of these cells from the skin Langerhans
cells [18]. Subsequently it was shown that the pathologic LC carrying the BRAF V600E mutation
could be identified in CD34+ stem cells and more mature myeloid dendritic cells of LCH patients,
thus proving that LCH is a clonal myeloid malignancy [19]. A mouse model of LCH with enforced
expression of the BRAF V600E mutation in myeloid dendritic cells confirmed the observation.
Subsequent work with LCH and the related histiocytic disorder Erdheim-Chester disease tracked

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the BRAF V600E mutation in subsets of dendritic cells, mature monocytes, committed myeloid
progenitors, and CD34+ cells of affected LCH patients [20,21].

Somatic mutations that activate the MAPK signaling pathway are detectable in most patients with
LCH [19,22-28]. Examples of such studies include:

● A mass spectrometric method was used to analyze for a large number of cancer-associated
gene mutations in DNA retrieved from paraffin-embedded biopsies [22]. The oncogenic BRAF
V600E mutation was found in 35 of 61 (57 percent) cases of LCH. Interestingly, in all cases
(BRAF mutated or not), the downstream BRAF targets MEK and ERK were phosphorylated,
suggesting a common mechanism of activation of the signal transduction pathway regardless
of BRAF mutation status. The BRAF V600E mutation was also detected in 40 percent of adult
pulmonary LCH specimens tested.

● A study of 135 biopsies from 100 children with LCH showed that the BRAF V600E mutation
was present in 63 percent of cases [29]. There was no statistical difference between those
with wild type or mutated BRAF regarding age, gender, high or low risk clinical status, or
number of lesions. Circulating BRAF V600E mutated cells were detected in all patients with
high risk LCH, and, when found in low risk patients, portended a 70 percent chance of relapse.

● In another study, BRAF V600E mutations were identified in 173 of 315 patients (55 percent)
and were associated with a more severe clinical presentation [30]. BRAF V600E mutations
were identified in the majority of patients with multisystem disease with risk organ involvement
(88 percent) and those with multisystem disease without risk organ involvement (69 percent),
and were less common among patients presenting with low risk, single system disease (42
percent). Approximately three-quarters of patients with pituitary and neurodegenerative
conditions had the mutation. Patients with BRAF V600E mutations were more likely to have
resistance to initial therapy with vinblastine and prednisone and higher reactivation rates.

● Whole-exome sequencing identified mutations in MAP2K1, which encodes MEK1, in 7 of 21


LCH tumors with wild-type BRAF [24]. This mutation ultimately resulted in the phosphorylation
and activation of the extracellular signal-regulated kinase (ERK) pathway.

Further study is needed to elucidate the pathogenesis of LCH. It is unclear if the pathogenesis
differs between pulmonary LCH in adults and LCH in children. Langerhans cells in adult lung
lesions were shown to be mature dendritic cells expressing high levels of the accessory molecules
B7-1 and B7-2, unlike LC found in other lung disorders [31].

CLINICAL MANIFESTATIONS

Overview — The clinical presentation of patients with LCH varies depending on the sites and
extent of involvement. The disease is limited to one organ system (eg, bone) in approximately 55

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percent of patients, while the remainder presents with multisystem disease [32]. As an example, a
retrospective analysis of 1741 patients with LCH registered in prospective trials reported
involvement of the following areas at the time of diagnosis, in order of decreasing frequency [32]:

● Bone – 77 percent
● Skin – 39 percent
● Lymph nodes – 19 percent
● Liver – 16 percent
● Spleen – 13 percent
● Oral mucosa – 13 percent
● Lung – 10 percent
● Central nervous system (CNS) – 6 percent

The areas of involvement and the extent of disease vary at least partially with patient age. Acute
disseminated multisystem disease is most commonly seen in children less than three years, while
a more indolent disease involving a single organ is more common in older children and adults.
Presenting symptoms in adults from published studies are (in order of decreasing frequency): skin
rash, dyspnea or tachypnea, polydipsia and polyuria, bone pain, lymphadenopathy, weight loss,
fever, gingival hypertrophy, ataxia, and memory problems [5,7-11]. In general, patients can be
divided into two groups based on the extent of involvement:

● Single system LCH – Patients may be of any age and typically do not have systemic
symptoms (eg, weight loss or fever). Unifocal or multifocal involvement can be found in one of
the following organs/systems: bone, skin, lymph node (excluding draining lymph node of
another LCH lesion), lungs, CNS, or other rare locations (eg, thyroid, thymus).

● Multisystem LCH – Two or more organs/systems are involved with or without involvement of
"risk organs." Risk organs include the hematopoietic system, liver, and/or spleen and denote a
worse prognosis. Although the lung has been considered a "risk organ," more recent studies
have suggested that it has less of an effect on prognosis [33,34]. In contrast "CNS-risk" areas
include the sphenoid, orbital, ethmoid, or temporal bones and denote an increased risk of
involvement of the central nervous system [32].

Disease tempo is variable and the length of time from the first symptom(s) to diagnosis can be
frustratingly long. Many adults wait one to four years before the correct diagnosis is made, and
some have symptoms for 5 to 20 years. In this setting, diabetes insipidus is often the initial
symptom, sometimes starting in childhood and not recognized as being caused by LCH until other
symptoms occur later in the course of the disease.

Lytic bone lesions — Bone involvement occurs in the majority of patients with LCH. Although
some lesions are asymptomatic, the patient may complain of pain in a localized area of bone;
examination usually reveals a raised, soft, tender spot. Radiologic studies typically demonstrate a

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lytic, "punched out" appearance, sometimes with an accompanying soft tissue mass (image 1).
(See "Langerhans cell histiocytosis (eosinophilic granuloma) of bone in children and adolescents",
section on 'Imaging characteristics'.)

LCH can involve any bone of the body, and the most common sites differ depending upon the
patient's age. In children, the most frequent sites of involvement are the skull (40 percent), femur,
rib, vertebra, and humerus [35]. The digits are involved only in the most diffuse cases. In contrast,
the primary sites of bone involvement in adults in one study were jaw (30 percent), skull (21
percent), vertebra (13 percent), pelvis (13 percent), extremity (17 percent), and rib (6 percent) [5].
Involvement of certain bones can cause problems with nearby organ systems. These include:

● Spine lesions in children are most often located in the cervical vertebrae and are frequently
associated with other bone lesions [36]. Although vertebra plana (symmetrical vertebral
flattening) may develop in some, others have stabilization of the vertebrae after treatment and
spinal deformity is rare. In a series of adults with LCH of the spine, neurologic defects
occurred in 21 of 30 [37]. Asymmetric collapse as opposed to vertebra plana was more
common in adults. Of 33 vertebral lesions, 21 were in the cervical spine, seven in the thoracic,
and five in the lumbar spine.

● Involvement of the calvaria, base of the skull, maxillofacial bones, and hypothalamic-pituitary
axis is common. Resulting complaints include scalp and/or facial swelling, seizures, hearing
loss, recurrent otitis media, gingival bleeding, proptosis, diabetes insipidus, and cranial nerve
palsies [38]. Pain in the jaw and loose teeth may be a presenting symptom. Although bone
lesions may be asymptomatic in some areas, those in the mouth are especially troublesome
because of tooth loss and a high recurrence rate. Posterior regions of the jawbones are
affected more often than anterior regions [39].

Some skull lesions are not only lytic but may have an accompanying mass that impinges on the
dura. Lesions of the facial bones or anterior or middle cranial fossae (eg, temporal, sphenoid,
ethmoid, zygomatic) with intracranial tumor extension are part of a "CNS-risk" group. Patients with
these lesions have a threefold increased risk for developing diabetes insipidus and an increased
risk of other CNS disease. (See 'Diabetes insipidus and other endocrinopathies' below and 'Central
nervous system' below.)

Skin and oral mucosa — Skin involvement is seen in approximately 40 percent of patients [32].
The most common skin manifestations are brown to purplish papules referred to as congenital self-
healing reticulohistiocytosis and an eczematous rash resembling a candidal infection. Other skin
lesions may be pustular, purpuric, petechial, vesicular, or papulo-nodular [40].

● Brown to purplish papules – Infants may present with brown to purplish papules over any
part of their body (congenital self-healing reticulohistiocytosis, Hashimoto-Pritzker disease)
(picture 1) [41,42]. If solitary, this manifestation is benign and the lesions disappear during the

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first year of life with no therapy. However, neonates with apparently isolated skin involvement
need thorough evaluation to confirm that no other sites are involved, as well as close follow-up
for later risk organ involvement. (See "Skin nodules in newborns and infants", section on
'Congenital self-healing reticulohistiocytosis'.)

The importance of a thorough evaluation was demonstrated in a series of 19 neonatal LCH


cases with skin involvement in which 12 of the 19 also had multisystem disease that affected
other organs [43]. In another report of 61 neonatal cases from 1069 patients in the Histiocyte
Society database, 36 of 61 (59 percent) had multisystem disease and 25 of 61 (42 percent)
had risk organ involvement [44]. In a separate study, 40 percent of neonates who had solitary
skin LCH at presentation proceeded to have multisystem involvement [45].

Importantly, a subsequent study showed that 40 percent of patients referred for "skin-only"
LCH had multisystem disease when comprehensive staging procedures were done [46].
Children with truly skin-only LCH were usually less than a year of age, whereas those with
multisystem LCH were older than 18 months. Those with skin-only disease had a progression
free-survival (PFS) of 89 percent, whereas the PFS of the multisystem patients was only 23
percent.

● Eczematous rash – LCH can manifest in children and adults as an erythematous papular
rash that occurs in the groin, abdomen, back, or chest and resembles a diffuse candida diaper
rash (picture 2A-B). Lesions range in size from 1 to 10 mm in diameter. Seborrheic
involvement of the scalp may be mistaken for prolonged "cradle cap" in infants or a severe
case of seborrheic dermatitis in older individuals. Ulcerative lesions behind the ears, in the
scalp, genitalia, or perianal region are especially troublesome, as they often are misdiagnosed
as bacterial or fungal lesions. (See "Approach to the patient with a scalp disorder", section on
'Seborrheic dermatitis' and "Diaper dermatitis".)

● Oral lesions – The most common oral manifestations of LCH are intraoral mass, gingivitis,
mucosal ulcers, and loose teeth [39,47]. Pain and mass effects can derive from lesions of the
bones or soft tissues. Some infants with LCH present with abnormally early tooth eruption.

Lymph nodes and bone marrow — Lymphadenopathy is seen in approximately 20 percent of


patients [32]. Cervical nodes are most commonly involved. On physical examination, involved
nodes are usually soft and matted. An enlarged thymus or mediastinal nodes can mimic lymphoma
or an infection and may cause asthma-like symptoms due to airway compression. Accordingly,
biopsy with culture and histological examination is mandatory for these presentations.

There are less data regarding the incidence of bone marrow involvement in patients with LCH, but
one study found it to be 34 percent [48]. Most patients with bone marrow involvement are young
children with diffuse disease in the liver, spleen, lymph nodes, and skin. A longstanding
assumption has been that LCH is found in the bone marrow only when significant

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thrombocytopenia, anemia, or neutropenia is present [49]. However, analyses of bone marrow


specimens stained with anti-CD1a have shown the presence of Langerhans cell histiocytes in
patients with multifocal bone disease and normal blood counts, as well as in low-risk patients with
single-site involvement [48]. Also, analysis for the BRAF V600E mutation in the bone marrow has
revealed the presence of mutated cells in histologically normal specimens [19].

A review of LCH patients under two years of age with two or more "risk organs" (ie, hematopoietic
system, liver, spleen, and perhaps lung) involved showed that anemia with thrombocytopenia and
hypoalbuminemia were prognostic for a poor outcome [50]. When compared with those with
anemia alone, patients with anemia and thrombocytopenia had an inferior five-year survival rate
(19 percent versus 87 percent). Similarly, when compared with those with normal albumin, patients
with low albumin had a significantly lower rate of survival at five years (16 versus 65 percent).

Liver and spleen — The liver and spleen are both "risk organs" and involvement denotes a worse
prognosis. Hepatic involvement can include tumor-like or cystic lesions, or overall hepatomegaly,
and can be accompanied by elevated liver enzymes, hepatic dysfunction, leading to
hypoalbuminemia with ascites, hyperbilirubinemia, and/or clotting factor deficiencies [50-54].
Sclerosing cholangitis is an especially serious complication of LCH, marked by elevated alkaline
phosphatase, liver transaminases and gamma glutamyl transpeptidase; it may be progressive,
even when other manifestations of LCH respond to treatment, and require eventual liver
transplantation.

Ultrasound (US), computed tomography (CT) or magnetic resonance imaging (MRI) of the
abdomen can be used to assess for involvement of the liver and/or spleen in patients who have
hepato-splenomegaly. Findings of liver involvement include low echogenicity along the biliary tract
by US and low T1 or high T2 signal intensity along the portal vein and portal triads [55,56].

Massive splenomegaly may lead to cytopenias because of hypersplenism and may also result in
respiratory compromise.

Lungs — Lung involvement is seen in approximately 10 percent of cases [32]. It is less frequent in
children than in adults, in whom smoking is a key etiologic factor (figure 1) [57]. Although the lung
has been considered a "risk organ," more recent studies have suggested that it has less of an
effect on prognosis [33,34]. Patients with lung involvement may present following a spontaneous
pneumothorax or with a nonproductive cough, dyspnea, chest pain, or constitutional symptoms,
especially fever or weight loss. Recurrent spontaneous pneumothorax occurs in 15 to 25 percent
of patients. Nearly 20 percent of adults with lung involvement have no symptoms. (See "Pulmonary
Langerhans cell histiocytosis" and "Treatment of Langerhans cell histiocytosis", section on 'Risk
stratification'.)

Pulmonary function tests may be normal or may show reduced lung volumes and a reduced
diffusing capacity. Airflow limitation and hyperinflation occur in a minority of patients, typically in

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patients with more advanced, cystic disease. (See "Pulmonary Langerhans cell histiocytosis",
section on 'Pulmonary function testing'.)

The most sensitive diagnostic test is a high-resolution CT scan, which reveals cysts and nodules
characteristic of LCH. A high resolution CT scan of the chest showing a combination of multiple
cysts and nodules, with a mid to upper zone predominance, and interstitial thickening in a young
smoker is so characteristic that it can be diagnostic of pulmonary LCH (image 2A-C). (See
"Pulmonary Langerhans cell histiocytosis", section on 'Imaging'.)

If the radiographic pattern is nondiagnostic, the combination of transbronchial lung biopsy and
bronchoalveolar lavage (BAL) showing an increase in the number of CD-1a positive cells strongly
suggests pulmonary LCH, especially when more than 5 percent of BAL cells are CD1a positive.
(See "Pulmonary Langerhans cell histiocytosis", section on 'Lung biopsy'.)

Central nervous system — LCH involves the CNS in approximately 6 percent of patients at the
time of diagnosis [32]. However, the risk of CNS involvement varies with the location of bone
involvement. Lesions of facial bones or bones of the anterior or middle cranial fossae are "CNS-
risk" lesions with an almost 25 percent incidence of CNS involvement. Symptoms related to CNS
involvement vary depending on the site of disease. The most common manifestations are diabetes
insipidus and symptoms of neurodegeneration (ataxia, cognitive dysfunction). Patients may also
have proptosis due to soft-tissue masses in the orbital area.

● Diabetes insipidus usually presents with polydipsia and polyuria. It occurs secondary to
infiltration of the posterior pituitary. (See 'Diabetes insipidus and other endocrinopathies'
below.)

● Neurodegeneration is characterized by bilateral symmetric lesions on MRI in the dentate


nucleus of the cerebellum or basal ganglia (image 3) [58,59]. Affected patients may have
devastating problems with ataxia and behavioral and cognitive dysfunction, which may not be
reversible and may not be manifest clinically for over a decade following the initial diagnosis of
LCH [58,60-64]. Patients with hypothalamic-pituitary involvement are at high risk for eventual
development of neurodegenerative changes and neuropsychological deficits [65]. (See 'Lytic
bone lesions' above.)

● Approximately 1 percent of LCH patients develop mass lesions or granulomas in the brain
parenchyma or choroid plexus, with the latter leading to blockage of cerebral spinal fluid flow
[58,59]. (See "Clinical features and diagnosis of leptomeningeal metastases from solid
tumors" and "Evaluation and management of elevated intracranial pressure in adults" and
"Elevated intracranial pressure (ICP) in children: Clinical manifestations and diagnosis".)

MRI is the imaging modality of choice to visual CNS involvement. Findings on MRI include (image
4):

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● Enhancement of the pons, basal ganglia, and white matter of the cerebellum, as well as mass
lesions or meningeal enhancement [66].

● In a report of 163 patients, meningeal lesions were found in 29 percent and choroid-plexus
involvement in 6 percent [64]. Paranasal-sinus or mastoid lesions were found in over 50
percent versus 20 percent of controls, and accentuated Virchow-Robin spaces (perivascular
space) in 70 percent of patients versus 27 percent of controls. These latter findings are
hypothesized to indicate modes of entry for pathologic cells into the brain from the "CNS Risk"
areas.

In another study, pineal glands were larger in LCH patients than in the controls and often had
cystic changes [67]. However, there were no differences in the melatonin levels of LCH
patients with or without these changes, making the significance of these findings unclear.

Diabetes insipidus and other endocrinopathies — Diabetes insipidus (DI) is the most frequent
endocrine abnormality in LCH and typically presents with polyuria, nocturia, and/or polydipsia.
Other endocrine manifestations of LCH include hypogonadism, growth failure, abnormalities of
glucose metabolism (eg, impaired glucose tolerance, diabetes mellitus), and an enlarged thyroid
gland [68,69]. (See "Evaluation of patients with polyuria" and "Clinical manifestations and causes
of central diabetes insipidus", section on 'Infiltrative disorders'.)

The identification of DI can occur prior to (4 percent), concomitant with (18 percent), or after the
diagnosis of LCH [60,70]. Among patients with LCH, approximately one-quarter of patients were
diagnosed with pituitary involvement within 10 years of LCH diagnosis if they were treated with
vinblastine and prednisone for only six months [69]. When patients were treated for a year with this
regimen, the incidence of DI was 12 percent [71]. DI follows initial LCH diagnosis by a mean of one
year, and growth hormone deficiency five years after diagnosis of DI.

LCH must be considered in the differential diagnosis of patients with apparently "isolated" DI and
such patients should be carefully observed for later onset of other LCH symptoms. In two studies,
15 percent of patients with "isolated" DI were found to have LCH [9,69]. Of LCH patients initially
presenting with DI, approximately half are diagnosed with LCH within one year of DI diagnosis, and
over 80 percent by two years [60,70] but, in some, LCH may be diagnosed many years after DI
[68]. In a Mayo Clinic series of children and adults with LCH presenting as "isolated" DI, 42 of 44
patients with DI had involvement of other organ systems: bone (68 percent), skin (57 percent), lung
(39 percent), and lymph nodes (18 percent) [8].

Patients presenting with DI may demonstrate deficiencies of other pituitary hormones. In two series
of patients initially presenting with DI, 80 percent had a deficiency in another pituitary hormone
within five years [9,70]. In another series, 28 percent of patients with DI had anterior pituitary
deficiencies by the time they were diagnosed with LCH and half had anterior pituitary hormone
abnormalities within a year of DI diagnosis [60]. (See "Clinical manifestations of hypopituitarism".)

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Risk factors for the development of DI were identified in a study of 1741 children registered in
several large LCH trials [32]. When compared with those having only single system involvement,
patients with multisystem disease and craniofacial involvement at the time of diagnosis, particularly
of the ear, eye, and oral region, carried a significantly increased risk of developing DI during their
course (relative risk 4.6). This risk was augmented when the disease remained active for a longer
period of time, or reactivated. The risk for development of DI in this population was 20 percent at
15 years after diagnosis.

CNS involvement of LCH is classically seen on MRI as a loss of the posterior bright spot of the
pituitary gland [72,73], but this finding is not diagnostic. The pituitary stalk is thickened in over 70
percent of patients with DI and remains thickened in 24 percent five years later [74,75]. An
enlarged pituitary may be biopsied for a definitive diagnosis, but total removal should be avoided
because the resulting total pituitary dysfunction results in difficult management problems.

Despite treatment of LCH, anterior pituitary hormone deficiency persists indefinitely [65].

Gastrointestinal system — Gastrointestinal involvement of LCH is uncommon. Approximately 2


percent of patients present with diarrhea or malabsorption [76]. Diagnosing gastrointestinal
involvement is difficult because of intermittent involvement of LCH lesions in the gastrointestinal
tract. Careful endoscopic examination with biopsies is needed. A case report and literature review
of gastrointestinal LCH involvement found that LCH was diagnosed by endoscopy in 91 percent of
patients [77]. Of these patients, 86 percent had LCH in the duodenum and 64 percent in the rectal,
sigmoid, or colon. (See "Eosinophilic gastroenteritis", section on 'Diagnosis' and "Peptic ulcer
disease: Clinical manifestations and diagnosis", section on 'Diagnosis'.)

Ten adult patients with gastrointestinal involvement with LCH have been reported [78]. Half of
these were asymptomatic with a mean age of 58 years and 75 percent being female. Most of the
adults had a solitary, small, intramucosal polyp in the colorectum.

PATHOLOGIC FEATURES

Biopsies of involved tissue usually demonstrate heterogeneous collections of Langerhans cells


with eosinophils, neutrophils, small lymphocytes, and histiocytes (which may form multinucleated
giant cells) [2,79]. Eosinophilic abscesses may be present demonstrating central necrosis with or
without Charcot-Leyden crystals.

Morphologically, Langerhans cells are large oval mononuclear cells with few cytoplasmic vacuoles,
little or no phagocytosed material, and moderately abundant, slightly eosinophilic cytoplasm
(picture 3). The nucleus is prominent with fine chromatin and thin nuclear membranes with
grooved, folded, or indented nuclear contours, imparting a "twisted towel" or "coffee bean"
appearance. Nucleoli are not prominent. Unlike dermal Langerhans cells, these cells do not have
dendritic cell processes.
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Similar to dermal Langerhans cells, those in LCH express the histiocyte markers CD1a, S100, and
CD207 (langerin) and contain Birbeck granules (picture 4). Birbeck granules are intracytoplasmic
rod-shaped organelles with central striation that can be demonstrated on electron microscopy
(picture 5). Occasionally, there is terminal vesicular dilation giving the Birbeck granule the
appearance of a "tennis racket."

In one study, the immune checkpoint protein PD-L1 was found in seven of eight LCH cases [80].

Pathologic findings may vary depending on the site of biopsy. Bone and skin lesions as well as
mass lesions in the cerebrum, hypothalamus, and pituitary have classic CD1a-reactive Langerhans
cells and CD8-positive T cells [2,81]. Lesions in the cerebellum primarily contain CD8-positive T
cells rather than CD1a-expressing Langerhans cells. Neuronal and axonal destruction with
demyelination is prominent. Liver biopsies may show no CD1a-positive cells, but many
lymphocytes clustered around bile ducts.

Other pathologic features that are not diagnostic of LCH but are sometimes seen include
hemophagocytosis on bone marrow specimens and myelodysplastic changes [82,83]. Macrophage
activation seen in LCH patients may be a result of excessive cytokine expression in these lesions
[83]. (See "Treatment and prognosis of hemophagocytic lymphohistiocytosis".)

No cytogenetic findings are characteristic or diagnostic. Although clonality can be established in


the majority of cases, these studies are not used routinely for diagnosis.

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

LCH is diagnosed based on biopsy with the pathologic evaluation of involved tissue interpreted
within the clinical context. A biopsy of an osteolytic bone lesion or skin lesion is generally
preferred. The surgeon should not perform a wide excision as LCH bone lesions will have
complete or near complete healing with curettage alone or chemotherapy. Biopsy of the pituitary
may be required for the definitive diagnosis of a solitary pituitary lesion, but is more invasive and
dependent upon the size of the lesion and comfort of the neurosurgeon. For patients with
suspected disease isolated to the pituitary, identification of BRAF V600E in the peripheral blood or
cerebrospinal fluid can support the diagnosis, although it does not distinguish LCH from Erdheim-
Chester disease [84]. It is reasonable to initiate therapy empirically in such patients with a plan to
follow disease response with magnetic resonance imaging (MRI).

While Langerhans cells can be recognized on the basis of morphologic criteria, their identity must
be confirmed either by positive immunohistochemical staining for CD1a and CD207 or by the
identification of Birbeck granules by electron microscopy. Electron microscopy to identify Birbeck
granules is performed less frequently because of time and expense.

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LCH can be difficult to diagnose since it is an uncommon disease that can affect many organ
systems. LCH in bone, lymph nodes, thymus, liver or spleen can be confused with lymphomas,
solid tumors, or primary central nervous system (CNS) tumors including germinoma and
meningioma. Cutaneous involvement can mimic vasculitis, cutaneous lymphoma, or cutaneous
involvement with Erdheim-Chester disease (see below). Pulmonary involvement can have the
clinical appearance of any number of interstitial lung diseases. LCH must be distinguished
histologically and immuno-phenotypically from other histiocytic and dendritic cell disorders,
metastatic solid or hematopoietic neoplasms, and hemophagocytic lymphohistiocytic and
macrophage activation syndromes.

● Erdheim-Chester disease (ECD) – ECD is a rare multisystem histiocytic disorder, most often
seen in adults, that may be confused with LCH. Histiocytic infiltration leads to
xanthogranulomatous infiltrates of multiple organ systems (eg, skin, lung, bone, cerebral,
facial, orbital and retro-orbital tissue, pituitary, retroperitoneum, cardiovascular system). These
cells may be very similar to those of juvenile xanthogranuloma, as both diseases most likely
derive from the same lineage of dermal/interstitial dendrocyte [1]. Long bone pain and
symmetric osteosclerotic lesions suggest this diagnosis, which is confirmed by tissue biopsies
showing histiocytes with non-Langerhans features (eg, negative for CD1a and S-100 protein).
Cases of concomitant LCH and ECD (ie, mixed histiocytosis) have been described [85]. (See
"Erdheim-Chester disease", section on 'Diagnosis and differential diagnosis'.)

● Juvenile xanthogranuloma (JXG) – JXG is a benign proliferative disorder of histiocytic cells of


the dermal dendrocyte phenotype. JXG belongs to the broad group of non-Langerhans cell
histiocytoses and is typically a disorder of early childhood. JXG presents in the first two years
of life as a solitary reddish or yellowish skin papule or nodule (picture 6), most often on the
head, neck, and upper trunk. Histologically, JXG is characterized by the presence of foamy or
Touton giant cells. JXG generally follows a benign course with spontaneous resolution over a
period of a few years. Less commonly, skin lesions can be multiple (picture 7). Extracutaneous
or systemic forms (brain, lung, kidney, spleen, liver, bone marrow, and retro-orbital tumors) are
exceedingly rare and can be associated with considerable morbidity. (See "Juvenile
xanthogranuloma (JXG)".)

● Multiple myeloma – The osteolytic lesions of bone in LCH can be confused with those seen in
multiple myeloma. LCH can readily be distinguished from multiple myeloma by histologic and
immunophenotypic findings on biopsy and the presence of a monoclonal protein in the serum
of patient with multiple myeloma. (See "Multiple myeloma: Clinical features, laboratory
manifestations, and diagnosis", section on 'Diagnosis'.)

● Hemophagocytic lymphohistiocytosis (HLH) – HLH and the related macrophage activation


syndrome are systemic disorders that demonstrate tissue infiltration by non-neoplastic
histiocytes. Unlike LCH, these disorders may demonstrate prominent hemophagocytic activity
in the bone marrow, and are characterized by fever, splenomegaly, and a constellation of
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laboratory findings and/or an underlying genetic defect. (See "Clinical features and diagnosis
of hemophagocytic lymphohistiocytosis".)

● Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy) is a rare


macrophage-related disorder that most often presents as a systemic disorder involving lymph
nodes and other organs, but can rarely be limited to the skin [86-91]. Although the pathologic
cells in RDD and HLH are the macrophages (S100+, CD68+, CD1a–), RDD is histologically
distinct from the other histiocytic diseases because the macrophages have normal-appearing
lymphocytes residing in the macrophage cytoplasm (emperipolesis) unlike the
hemophagocytosis of HLH [1]. (See "Peripheral lymphadenopathy in children: Etiology",
section on 'Rosai-Dorfman disease'.)

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions around
the world are provided separately. (See "Society guideline links: Histiocytic and dendritic cell
neoplasms".)

SUMMARY

● Langerhans cell histiocytosis (LCH) is a rare histiocytic disorder that may be seen in all age
groups, but is most common in children from one to three years old. (See 'Epidemiology'
above.)

● The clinical presentation of patients with LCH varies depending on the sites and extent of
involvement. The disease is limited to one organ system (eg, bone) in approximately half of
patients. Acute disseminated multisystem disease is most commonly seen in children less
than three years old, while a more indolent disease involving a single organ is more common
in older children and adults. (See 'Overview' above.)

● Bone involvement occurs in the majority of patients and can involve any bone of the body.
Although some lesions are asymptomatic, the patient may complain of pain in a localized area
of bone; examination usually reveals a raised, soft, tender mass. Radiologic studies typically
demonstrate a lytic, "punched out" appearance, sometimes with an accompanying soft tissue
mass (image 1). (See 'Lytic bone lesions' above and "Langerhans cell histiocytosis
(eosinophilic granuloma) of bone in children and adolescents", section on 'Imaging
characteristics'.)

● Skin involvement is seen in approximately 40 percent of patients. The most common skin
manifestations are an eczematous rash resembling a candidal infection (picture 2A) or
ulcerative lesions in the axillae, inguinal folds, genitalia, or peri-anal regions. A much less
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common manifestation is the Hashimoto-Pritzker variant rash, which consists of brown to


purplish papules in infants (picture 1). (See 'Skin and oral mucosa' above.)

● Lung involvement occurs in approximately 10 percent of cases. It is less frequent in children


than in adults, in whom smoking is a key etiologic factor. Patients with lung involvement may
be asymptomatic or present following a spontaneous pneumothorax or with nonproductive
cough, dyspnea, chest pain, or constitutional symptoms. The most sensitive diagnostic test is
a high-resolution computed tomography (CT) scan, which reveals cysts and nodules
characteristic of LCH (image 2B). (See 'Lungs' above and "Pulmonary Langerhans cell
histiocytosis".)

● The risk of central nervous system (CNS) involvement varies with the location of bone
involvement. Lesions of facial bones or bones of the anterior or middle cranial fossae are
"CNS-risk" lesions with an almost 25 percent incidence of CNS involvement. The most
common symptoms of CNS involvement are diabetes insipidus and symptoms of
neurodegeneration (ataxia, cognitive dysfunction). Findings on magnetic resonance imaging
include thickening of the pituitary stalk; enhancement of the pons, basal ganglia, and white
matter of the cerebellum; mass lesions; and meningeal enhancement. (See 'Central nervous
system' above.)

● LCH is diagnosed based on the pathologic evaluation of involved tissue interpreted within the
clinical context. A biopsy of an osteolytic bone lesion or skin lesion is generally preferred,
when possible. While Langerhans cell histiocytes can be suspected based on morphologic
criteria, their identity must be confirmed either by positive immunohistochemical staining for
CD1a (picture 4) and CD207 or by the identification of Birbeck granules (picture 5) by electron
microscopy. (See 'Pathologic features' above and 'Diagnosis and differential diagnosis'
above.)

● LCH can be difficult to diagnose since it is an uncommon disease that can affect many organ
systems. LCH must be distinguished histologically and immuno-phenotypically from other
histiocytic and dendritic cell disorders, metastatic solid or hematopoietic neoplasms, and
hemophagocytic lymphohistiocytic and macrophage activation syndromes. (See 'Diagnosis
and differential diagnosis' above.)

ACKNOWLEDGMENT

The editorial staff at UpToDate would like to acknowledge the late Laurence A Boxer, MD, for his
previous role as a section editor for this topic.

Use of UpToDate is subject to the Subscription and License Agreement.

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GRAPHICS

Langerhans cell histiocytosis of bone

This section from a thoracic CT scan shows a solitary osteolytic lesion of the
sternum (arrow) with sclerotic margins (arrowhead) in a 38-year-old woman
presenting with chest pain. A bone scan was positive in this area, as well. The
resected surgical specimen showed Langerhans cell histiocytosis.

CT: computed tomography.

Reproduced with permission from: Fazio N, Spaggiari L, Pelosi G, et al. Langerhans'


cell histiocytosis. Lancet 2005; 365:598. Copyright © 2005 Elsevier.

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Congenital self-healing reticulohistiocytosis

Red-brown papules are present on the trunk of this infant with congenital self-
healing reticulohistiocytosis.

Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights


reserved.

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Langerhans cell histiocytosis

Yellow-brown and erythematous papules, erosions, and crusts are present on


this infant with Langerhans cell histiocytosis.

Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights


reserved.

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Langerhans cell histiocytosis

Yellow-pink papules with scale are present in the diaper area of this infant with
Langerhans cell histiocytosis.

Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights


reserved.

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Age at onset of pulmonary Langerhans cell histiocytosis

The data shown were obtained from published papers in which the age at onset
of symptoms or diagnosis could be determined (total number of subjects =
168). The peak age at onset is between 20 and 40.

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Cystic changes in Langerhans cell histiocytosis

Langerhans cell histiocytosis (eosinophilic granuloma) in an adolescent boy


characterized by multiple cysts in the upper and lower lobes. The cysts are
interspersed throughout the parenchyma and have a slightly thick wall. A
posterior right upper lobe nodule is part of the disease process.

Courtesy of Paul Stark, MD.

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Cystic changes in Langerhans cell histiocytosis

Langerhans cell pulmonary histiocytosis (eosinophilic granuloma) in an


adolescent boy characterized by multiple cysts in the upper and lower lobes. The
cysts are interspersed throughout the parenchyma and have a slightly thick
wall. A posterior right upper lobe nodule and confluent bibasal patchy lower lobe
opacities are also part of the disease process.

Courtesy of Paul Stark, MD.

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Pulmonary Langerhans cell histiocytosis

High resolution CT with thin section shows the cysts in pulmonary Langerhans
cell histiocytosis (PLCH), which vary markedly in size and may be larger than 10
mm. The cysts are bizarre in shape, often closely related to pulmonary arteries,
and mimic bronchiectasis. Few nodules are present in this case.

CT: computed tomography.

Courtesy of Talmadge E King Jr, MD.

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Neurodegenerative central nervous system in


Langerhans cell histiocytosis

T-2 FLAIR image brain in an LCH patient with neurodegenerative LCH.


Hyperintense signal in the pons and cerebellum.

LCH: Langerhans cell histiocytosis; FLAIR: fluid-attenuated inversion recovery.

Courtesy of Kenneth L McClain, MD, PhD.

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Neuroimaging of Langerhans cell histiocytosis lesions

These examples demonstrate typical manifestations of LCH CNS and spinal cord lesions.
(A) Brain MRI demonstrates T2-hyperintensity in cerebellum classic for LCH neurodegenerative syndrome. In
this case, the patient had radiologic and clinical response to treatment with cytarabine.
(B) Spinal MRI demonstrates significant spinal cord lesions. This is a somewhat atypical case of a 13-year-old
girl who had marginal response to cytarabine, then clofarabine. BRAF-V600E was detected in cells from the
CSF, and the patient ultimately had radiologic and clinical response to vemurafenib.
(C) Brain MRI demonstrates a pituitary mass classic for LCH, though differential diagnosis also includes

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germinoma, lymphoma, and pituitary hypophysitis. In this case, the lesion was biopsy proven to be LCH, and
the patient responded to cytarabine therapy.

LCH: Langerhans cell histiocytosis; CNS: central nervous system; MRI: magnetic resonance imaging; CSF:
cerebrospinal fluid.

This research was originally published in Blood. Allen CE, Ladisch S, McClain KL. How I treat Langerhans cell
histiocytosis. Blood 2015; 126:26. Copyright © 2015 American Society of Hematology.

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Lymph node biopsy in Langerhans cell histiocytosis

Langerhans cell histiocytosis extensively involving lymph node in a patient with widespread disease and
symptoms. The Langerhans cells have inconspicuous nucleoli, thin nuclear membranes, and prominent
folding of their nuclear contours, imparting a "twisted towel" appearance.
(A) Low-power view showing subtotal replacement of lymph node.
(B) High-power magnification showing cytologic features of Langerhans cells and a mitotic figure.
Hematoxylin-eosin stains.

Reproduced with permission from: Ioachim HL, Medeiros LJ. Dendritic cell neoplasms. In: Ioachim's Lymph
Node Pathology, 4th ed, Lippincott Williams & Wilkins, Philadelphia 2009. Copyright © 2009 Lippincott
Williams & Wilkins. www.lww.com.

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Lymph node biopsy in Langerhans cell histiocytosis CD1a stain

(A) The lesion fills and expands lymph node sinuses, and the Langerhans cells are associated with
eosinophils and giant cells. Hematoxylin-eosin stain.
(B) Immunostain for CD1a highlights numerous Langerhans cells. Immunochemistry with hematoxylin
counterstain.

Reproduced with permission from: Ioachim HL, Medeiros LJ. Dendritic cell neoplasms. In: Ioachim's Lymph
Node Pathology, 4th ed, Lippincott Williams & Wilkins, Philadelphia 2009. Copyright © 2009 Lippincott
Williams & Wilkins. www.lww.com.

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Birbeck granules

This electron micrograph of a Langerhans' cell shows a number of typical


Birbeck granules (arrow). (39,000 X).

Electron micrograph courtesy of Dr. Dominic V. Spagnolo, Perth, Western Australia.


From Warnke, RA, Weiss, LM, Chan, JK, Cleary, ML, Dorfman, RF. Tumors of the
lymph nodes and spleen. Atlas of tumor pathology (electronic fascicle), Third series,
fascicle 14, 1995, Washington, DC. Armed Forces Institute of Pathology.

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Juvenile xanthogranuloma

Typical solitary lesion on the abdomen of an infant.

Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights


reserved.

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Juvenile xanthogranuloma

Multiple scalp lesions in a young child.

Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights


reserved.

Graphic 81058 Version 4.0

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