Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis

INTRODUCTION — Langerhans cell histiocytosis (LCH) is a neoplastic histiocytic disorder that most commonly affects bones and skin, but it can also involve the bone marrow, liver, spleen, lungs, pituitary gland/central nervous system, and other organs. LCH is rare, but it is considerably more common in children (especially younger children) than in adults.

LCH is so-named because the neoplastic cells resemble dendritic Langerhans cells in the skin and mucosa; however, the CD1a+, CD207+ neoplastic cells of LCH are derived from myeloid dendritic cells, rather than from epidermal Langerhans cells. The BRAF V600E mutation is present in more than half of cases, and activation of the mitogen-activated protein kinase (MAPK) pathway is a key driver of this neoplastic disorder. The historical terms for LCH: histiocytosis-X, Letterer-Siwe disease, Hand-Schüller-Christian disease, and diffuse reticuloendotheliosis should be abandoned.

This topic discusses the epidemiology, clinical manifestations, pathologic features, diagnosis, and differential diagnosis of LCH.

The management of non-pulmonary LCH and pulmonary LCH are presented separately. (See "Treatment of non-pulmonary Langerhans cell histiocytosis" and "Pulmonary Langerhans cell histiocytosis".)

HISTIOCYTIC DISORDERS — Histiocytic disorders are rare diseases that are characterized by tissue infiltration of histiocytes (dendritic cells) and other inflammatory white blood cells. The archaic term "histiocyte" refers to large white blood cells resident in tissues and includes Langerhans cells, monocytes/macrophages, and dermal/interstitial dendritic cells [1].

There are two contemporary classifications of histiocytic disorders; the Histiocytic Society classification [2] includes both malignant and non-malignant, while the World Health Organization (WHO) 2017 classification addresses only malignant disorders [3].

Histiocyte Society classification — We favor the Histiocytic Society classification, which divides histiocytic disorders into five categories, based on clinical, histologic, immunophenotypic, and molecular features [2]:

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

●Cutaneous and mucocutaneous (C) group – The C group includes juvenile xanthogranuloma, adult xanthogranuloma, cutaneous Rosai-Dorfman disease, and other entities localized to the skin and/or mucosal surfaces that do not meet diagnostic criteria for LCH. (See "Juvenile xanthogranuloma (JXG)".)

●Rosai-Dorfman disease (R) group – The R group 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'.)

●Malignant histiocytosis (M) group – The M group 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). (See "Histiocytic sarcoma".)

●Hemophagocytic lymphohistiocytosis (H) group – The H group includes primary hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndromes (MAS) that can be due to inherited conditions and/or associated with infections, malignancies, rheumatologic conditions, iatrogenic immune suppression or activation, or other conditions. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis".)

WHO classification — The WHO provided a classification of histiocytic and dendritic cell neoplasms in its 2017 classification of hematologic malignancies, but it does not classify non-malignant disorders [3]:

●Histiocytic sarcoma – Malignant proliferation of cells with morphologic and immunophenotypic features of mature tissue histiocytes, excluding acute monocytic leukemia. (See "Histiocytic sarcoma".)

●Tumors of Langerhans cells – There are two subtypes, according to cytologic atypia and clinical aggressiveness:

•Langerhans cell histiocytosis – Malignancies of Langerhans-type cells that express CD1a, langerin, and S100 and exhibit Birbeck granules with electron microscopy.

•Langerhans cell sarcoma – High-grade malignancies with the Langerhans cell immunophenotype (ie, expression of CD1a, langerin, S100) with overtly malignant features.

●Indeterminate dendritic cell tumor – Rare cases in which neoplastic proliferation of spindle-shaped to ovoid cells based in the dermis have phenotypic features similar to indeterminate cells (IDC), the alleged precursors of Langerhans cells.

●Interdigitating dendritic cell sarcoma – Very rare cases of neoplastic proliferation of spindle to ovoid cells that resemble interdigitating dendritic cells and arise with paracortical distribution in residual lymph node follicles.

●Follicular dendritic cell sarcoma – Neoplastic proliferation of spindle-shaped to ovoid cells with morphology and immunophenotype of follicular dendritic cells that are found in lymph nodes and/or extranodal sites and may arise in conjunction with Castleman disease.

●Inflammatory pseudotumor-like follicular/fibroblastic dendritic cell sarcoma – Neoplastic spindled cells within a lymphoplasmacytic infiltrate that is predominant in females and typically involves the liver or spleen.

●Fibroblastic reticular cell tumor – Very rare cytokeratin-positive spindle cells involving lymph nodes, spleen, or skin.

●Disseminated juvenile xanthogranuloma – Proliferation of small oval histiocytes, which resemble those of dermal juvenile xanthogranuloma, that involve skin or soft tissues, but can occasionally disseminate.

●Erdheim-Chester disease – Clonal systemic proliferation of foamy histiocytes in bone that can also involve the heart, central nervous system, and retroperitoneum.

PATHOPHYSIOLOGY — LCH is a clonal disorder of malignant myeloid cells that is driven by activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathway (also referred to as the Ras-Raf-MEK-ERK pathway). Mutated BRAF V600E is present in more than half of cases of LCH, but mutations of components of the MAPK-ERK pathway may be detected in LCH cases with wild-type BRAF.

●Cell of origin – Malignant Langerhans cells are derived from myeloid dendritic cells, as demonstrated by gene expression data and mutation tracing. Gene expression array data demonstrated their origin from bone marrow-derived myeloid cells, rather than being derived from epidermal Langerhans cells (which they resemble morphologically) [4]. Their myeloid origin was confirmed by demonstration of BRAF V600E in subsets of dendritic cells, mature monocytes, committed myeloid progenitors, and CD34+ cells of affected LCH patients [5-7].

●Aberrant MAPK/ERK signaling – Somatic mutations that activate the MAPK/ERK pathway are detectable in most patients with LCH [5,8-17]. BRAF V600E is present in more than half of LCH cases in children, but it is less common in adult LCH.

•BRAF mutations – BRAF V600E was identified in 173 of 315 children (55 percent) and the mutation was associated with more severe clinical presentations [18]. In another study, BRAF V600E was present in 63 percent of biopsies from 100 children with LCH [19]. The BRAF V600E mutation appears to be less common in adults and in pulmonary LCH. The frequency of BRAF V600E in adults with LCH has ranged between 32 to 44 percent [8,20,21]. In addition, BRAF-indels (insertions or deletions) were reported in approximately 28 percent of cases in two studies [20,21].

•MAPK/ERK pathway – Mutations in MAP2K1, which encodes MEK1, is present in 20 to 25 percent of cases of LCH. In one study, MAP2K1 mutations were detected in 17 of 21 LCH tumors that had wild-type BRAF [10]. Mutations of ARAF have also been reported [14].

Activation of the MAPK/ERK pathway is revealed by immunohistochemistry. In one study, expression of cyclin D1 (which lies downstream of MAPK/ERK signaling) by Langerhans cells was demonstrated in all 39 cases of LCH; phospho-ERK, an indication of pathway activation, was detected in all but one of these cases [22].

MAPK alterations have also been reported in >80 percent of single-system pulmonary LCH, with BRAF V600E frequency between 28 to 36 percent [21,23].

EPIDEMIOLOGY — LCH is more common in children than adults and is more common in males than females, but the incidence of this rare disorder is poorly defined. LCH is likely underreported because of its rarity and variable clinical manifestations.

The incidence has been estimated as high as 5 cases per million children, but it is less common in adults [3,24-27]. LCH is most common in children from one to three years old, but it has been diagnosed in all age groups. A male predominance has been described in some case series, but not by all reports [26,28-32]. The incidence appears to be higher in White populations than Black populations [27].

Except for pulmonary LCH, there are no consistent environmental associations with LCH. An epidemiologic study from the United States suggested a connection between perinatal infections and solvent exposure in parents, but no increased incidence after viral epidemics [33]. Single-system pulmonary LCH is nearly universally associated with cigarette smoking, but there are no clear environmental associations of extrapulmonary LCH with smoking or other environmental agents. (See "Pulmonary Langerhans cell histiocytosis", section on 'Role of cigarette smoking'.)

A genome-wide association study identified increased susceptibility to LCH in families with a single nucleotide polymorphism of the SMAD6 gene [34]. Rare familial clusters of LCH have been described [35-37]. LCH has been described in patients with Erdheim-Chester disease, Rosai Dorfman disease, or other concomitant histiocytic disorders [38-41].

CLINICAL MANIFESTATIONS

Overview — Symptoms, affected organ systems, and disease tempo of LCH vary between patients. Affected individuals range from neonates to adults, although it is more common in young children than adults. The diagnosis may not be made for years after the first clinical manifestations because of its variable presentation.

LCH can present as a single site or multiple sites of disease in one organ (eg, in bone or skin) or it can present in multiple organ systems simultaneously or sequentially. This distinction is important for determining prognosis and disease management (see "Treatment of non-pulmonary Langerhans cell histiocytosis", section on 'Overview of management'):

●Single-system LCH – Patients who present with single-system LCH can be of any age; they typically do not have systemic symptoms of weight loss or fever. The following organs are most often affected and can exhibit unifocal or multifocal involvement:

•Bone

•Skin

•Lungs

•Pituitary

•Central nervous system (CNS)

•Lymph nodes (excluding draining lymph node of another LCH lesion) and other rare locations (eg, thyroid, thymus)

●Multisystem LCH – Two or more organs/systems are involved. Among patients with multisystem disease, it is important to identify those with involvement of critical organs (CNS and lung) and "risk" organs (bone marrow, liver, spleen).

•Children – Among children, LCH is limited to one organ system in approximately 55 percent of cases; the remainder present with multisystem disease [42]. Acute disseminated multisystem disease is most often seen in children <3 years, while involvement of a single organ is more common in older children and adults.

A report involving 1741 children with LCH registered in prospective trials reported the following areas of involvement at the time of diagnosis [42]:

-Bone – 77 percent

-Skin – 39 percent

-Lymph nodes – 19 percent

-Liver – 16 percent

-Spleen – 13 percent

-Oral mucosa – 13 percent

-Lung – 10 percent

-CNS – 6 percent

●Adults – Adults most commonly present with skin rash, skull or jaw tumor, dyspnea or tachypnea, polydipsia/polyuria, bone pain, lymphadenopathy, weight loss, fever, gingival hypertrophy, ataxia, and memory problems [17,26,28-32,43].

Adults have single-site (unifocal) disease in 15 to 20 percent of cases, single-system multifocal disease (>1 disease site) in 5 percent cases, single-system pulmonary LCH (almost always smoking-related) in 40 to 50 percent of cases, and multisystem disease in 35 to 50 percent of cases [32,43,44]. The distribution of organ involvement varies between studies [31,32,44]:

-Pulmonary – 50 percent

-Bone – 30 to 50 percent

-Pituitary and hypothalamus – 25 percent

-Liver – 10 to 15 percent

-Spleen – 10 to 15 percent

-Skin – 10 to 15 percent

-CNS – 5 to 10 percent

-Lymph nodes – 10 to 20 percent

Sites of involvement

Lytic bone lesions — Bone is one of the most common sites involved with LCH. Although some lesions are asymptomatic, the patient may complain of localized bone pain with a raised, soft, tender spot. Imaging typically demonstrate a lytic, "punched out" appearance (image 1), sometimes with an accompanying soft tissue mass.

LCH can involve any bone; the most common sites vary with age. In children, the most frequent sites are skull (40 percent), femur, rib, vertebra, and humerus; the digits are involved only in the most widespread cases [45]. In adults, the primary sites of bone involvement were jaw (30 percent), skull (21 percent), vertebra (13 percent), pelvis (13 percent), extremity (17 percent), and rib (6 percent) [26].

Involvement of certain bones can cause problems with nearby organ systems:

●Vertebrae – Spine lesions in children are most often located in the cervical vertebrae and are frequently associated with other bone lesions [46]. Symmetrical vertebral flattening (vertebra plana) may develop in some children. In a series of adults with LCH of the spine, neurologic defects occurred in 21 of 30 [47]. 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.

●Skull – Patients with involvement of the calvaria, base of the skull, or maxillofacial bones may note scalp and/or facial swelling, seizures, hearing loss, recurrent otitis media, gingival bleeding, proptosis, arginine vasopressin deficiency (AVP-D; previously called central diabetes insipidus), and cranial nerve palsies [48]. Affected bones in the mouth may cause jaw pain and loose or lost teeth; posterior regions of the jawbones are affected more often than anterior regions [49]. There is a high recurrence rate with bone disease of the mouth.

In children, involvement of the facial bones or anterior or middle cranial fossae (eg, temporal, sphenoid, ethmoid, zygomatic bones) are considered "CNS risk" lesions because this is associated with increased risk for CNS involvement, including AVP-D. (See "Treatment of non-pulmonary Langerhans cell histiocytosis", section on 'Multiple bone lesions'.)

Skin and oral mucosa — Skin involvement is seen in approximately 40 percent of patients [42]. Cutaneous involvement can be skin-only disease or a component of multisystem LCH; it is important to exclude involvement of other organs in patients with apparent skin-only LCH.

The most common skin manifestations are an eczematous rash resembling a candidal infection and/or brown to purplish papules; other skin lesions may be pustular, purpuric, petechial, vesicular, or papulo-nodular [50].

●Papules – Infants may present with brown to purplish papules over any part of the body; this is referred to as congenital self-healing reticulohistiocytosis or Hashimoto-Pritzker disease (picture 1) [51,52]. If solitary, this manifestation is benign and the lesions disappear during the first year of life without treatment. However, neonates with apparently isolated skin involvement need a thorough evaluation and close follow-up to confirm that no other sites are involved. (See "Skin nodules in newborns and infants", section on 'Congenital self-healing reticulohistiocytosis'.)

A series of neonatal LCH cases with skin involvement reported that 12 of 19 children also had multisystem disease that affected other organs [53]. In another report of 61 neonatal cases from 1069 patients in the Histiocyte Society database, 59 percent had multisystem disease and 42 percent had "risk" organ involvement [54]. In other studies, 40 percent of neonates who had solitary skin LCH at presentation had multisystem disease when comprehensive staging was performed or later developed multisystem involvement [55,56]. Children with true 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 severe 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 caused by lesions of the bones or soft tissues [49,57]. Some infants with LCH present with early tooth eruption.

Lungs — Lung involvement is more common in adults than in children. Patients may present with a nonproductive cough, dyspnea, chest pain, constitutional symptoms (eg, fever, weight loss), or spontaneous pneumothorax; however, nearly 20 percent of patients with lung involvement are asymptomatic. The lungs may be the only involved organ or it can be a component of multisystem disease [44]. Isolated lung involvement is almost entirely associated with smoking.

The most sensitive test for lung involvement is a high-resolution computed tomography (CT) scan, which reveals cysts and nodules characteristic of LCH (image 2A-C). Pulmonary function tests may be normal or may show reduced lung volumes and reduced diffusing capacity. Evaluation and diagnosis of pulmonary LCH is discussed separately. (See "Pulmonary Langerhans cell histiocytosis", section on 'Evaluation'.)

Central nervous system — LCH involves the CNS in 5 to 10 percent of cases at diagnosis, but patients may be at risk for subsequent CNS involvement during their disease course. Symptoms related to CNS involvement vary depending on the site of disease. The most common manifestations are AVP-D and symptoms of neurodegeneration (ataxia, cognitive dysfunction); patients may also have proptosis due to soft-tissue masses in the orbital area.

CNS involvement develops in up to one-quarter of children who have LCH of facial bones or bones of the anterior or middle cranial fossae; these bones are considered "CNS risk" lesions and their involvement affects prognosis and treatment. It is uncertain if adults face the same risks for CNS involvement with facial/cranial bone disease. (See "Treatment of non-pulmonary Langerhans cell histiocytosis", section on 'Overview of management'.)

Magnetic resonance imaging (MRI) typically reveals T2 hyperintense, gadolinium-enhancing lesions of the pituitary stalk, pineal gland, and other circumventricular regions; parenchymal involvement is rare.

Clinical manifestations of CNS involvement with LCH include:

●Pituitary dysfunction – LCH can affect both the anterior and posterior pituitary gland. AVP-D and other clinical manifestations of pituitary involvement are described below. (See 'Endocrinopathies' below.)

Loss of the posterior bright spot of the pituitary gland may be seen with MRI [58,59], but this finding is not diagnostic and imaging abnormalities may not be apparent at the time of pituitary dysfunction. An enlarged pituitary may be biopsied for a definitive diagnosis of LCH, but total removal should be avoided because the resulting total pituitary dysfunction causes more difficult management.

●Neurodegenerative LCH – Neurodegenerative LCH refers to imaging abnormalities and/or neurologic dysfunction associated with CNS involvement that is mostly reported in survivors of pediatric LCH. This can be a devastating condition, with severe ataxia and behavioral and cognitive dysfunction (eg, executive function), but relative sparing of short-term memory. Some patients have minimal or no clinical neurologic dysfunction [60,61]. LCH involvement may first be manifest only by symmetric lesions on MRI in the dentate nucleus of the cerebellum, cerebellar white matter, pons or basal ganglia (image 3) [62,63].

Patients with hypothalamic-pituitary involvement are at high risk for later development of neurodegenerative changes and neuropsychological deficits [64]. LCH neurodegeneration may not be manifest clinically for more than a decade after the initial diagnosis of LCH [61,62,65-69]. Early treatment with targeted therapies to the MAPK pathway and cytarabine have reversed radiologic and clinical abnormalities. (See "Treatment of non-pulmonary Langerhans cell histiocytosis".)

●Mass lesions – Approximately 1 percent of patients develop mass lesions or granulomas in the brain parenchyma or choroid plexus, with the latter leading to blockage of cerebral spinal fluid flow [62,63]. (See "Clinical features and diagnosis of leptomeningeal disease from solid tumors" and "Evaluation and management of elevated intracranial pressure in adults" and "Elevated intracranial pressure (ICP) in children: Clinical manifestations and diagnosis".)

Endocrinopathies — AVP-D is the most frequent endocrine abnormality associated with LCH; it typically presents with polyuria, nocturia, and/or polydipsia. Patients who present with AVP-D may have deficiencies of other pituitary hormones, including hypogonadism, growth failure, impaired glucose tolerance/diabetes mellitus, and thyroid enlargement [70,71].

●Risk for AVP-D – AVP-D is seen in approximately one-quarter of patients at diagnosis. AVP-D can occur prior to (4 percent), concomitant with (18 percent), or after the diagnosis of LCH [65,72]. In a study of 1741 children, the risk for AVP-D was nearly fivefold higher for patients with multisystem disease and craniofacial involvement at diagnosis, compared with those with single-system disease [42]. Fewer than half of patients with hypopituitarism have abnormal imaging; conversely, nearly all patients with abnormal imaging have pituitary hormonal deficiencies [73].

In patients with apparent "isolated" AVP-D, LCH is often diagnosed at a later time. In two studies, 15 percent of patients with isolated AVP-D were found to have LCH [30,71]. Of LCH patients initially presenting with AVP-D, half were diagnosed with LCH within one year of AVP-D diagnosis, and over 80 percent by two years [65,72]. In some patients, LCH may be diagnosed many years after AVP-D [70]. In a series of children and adults with LCH presenting as isolated AVP-D, 42 of 44 patients with AVP-D had involvement of other organ systems: bone (68 percent), skin (57 percent), lung (39 percent), and lymph nodes (18 percent) [29].

Effective treatment of LCH can reduce the risk for later development of AVP-D. Among patients treated with vinblastine and prednisone for six months, approximately one-quarter were diagnosed with pituitary involvement within 10 years of LCH diagnosis, but this declined to 12 percent in patients who completed six months of continuation therapy [71,74]. Endocrinopathies may persist despite effective treatment of pituitary involvement [64].

●Association with other endocrinopathies – Patients who present with AVP-D may demonstrate abnormalities of other pituitary hormones. The most common is deficiency of growth hormone followed by gonadotropin deficiency, while corticotropin and thyrotropin deficiencies are less frequent; prolactin may be elevated [59,75]. In two series of patients initially presenting with AVP-D, 80 percent had a deficiency in another pituitary hormone within five years [30,72]. In another series, 28 percent of patients with AVP-D had anterior pituitary deficiencies by the time they were diagnosed with LCH and half had anterior pituitary hormone abnormalities within a year of AVP-D diagnosis [65].

Other organs

●Lymph nodes – Lymphadenopathy is present in up to 20 percent of patients, but it is less common in adults than in children [42,76]. Involved nodes are usually soft and matted; cervical nodes are most often involved [76]. Because lymphadenopathy is so uncommon in adults with LCH, other causes must be considered. 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.

●Bone marrow – The incidence of bone marrow involvement varies with the age at presentation. Bone marrow involvement may be underrecognized histologically, but immunohistochemical staining with anti-CD1a or molecular testing for BRAF V600E can detect morphologically inapparent Langerhans cells.

One study reported bone marrow involvement with LCH in one-third of children [77]. Most patients with bone marrow involvement are young children with diffuse disease in the liver, spleen, lymph nodes, and skin. However, Langerhans cells can be detected in patients with multifocal bone disease and normal blood counts, as well as in low-risk patients with single-site disease involvement [77].

A study of multisystem LCH in 83 adults detected none with bone marrow involvement [78]. However, LCH is associated with increased incidence of hematologic neoplasms (acute myeloid leukemia, lymphoblastic lymphoma) and these may cause cytopenias [27,79,80].

●Liver and spleen – Liver involvement may manifest as hepatomegaly, tumor-like or cystic lesions, and may be associated with elevated liver enzymes and hepatic dysfunction that can lead to hypoalbuminemia with ascites, hyperbilirubinemia, and/or clotting factor deficiencies [81-85]. Massive splenomegaly may cause cytopenias from hypersplenism or result in respiratory compromise. Ultrasound, CT, or MRI of the abdomen can assess for LCH involvement of the liver and/or spleen in patients with hepatosplenomegaly.

Sclerosing cholangitis is an especially serious complication of LCH that can be progressive, even when other manifestations of LCH respond to treatment. It is marked by elevated alkaline phosphatase, liver transaminases, and gamma glutamyl transpeptidase. Magnetic resonance cholangiopancreatography (MRCP) may be helpful in cases suspected to have sclerosing cholangitis based on liver enzyme abnormalities [86,87].

The liver and spleen are both considered "risk" organs; involvement denotes a worse prognosis and affects the choice of treatment. (See "Treatment of non-pulmonary Langerhans cell histiocytosis", section on 'Overview of management'.)

●Gastrointestinal system – Gastrointestinal (GI) involvement of LCH is uncommon. Approximately 2 percent of patients present with diarrhea or malabsorption [88]. The diagnosis is challenging because there may be only intermittent LCH lesions in the GI tract.

A case report and literature review of GI LCH involvement found that LCH was diagnosed by endoscopy in 91 percent of children [89]. Of these patients, 86 percent had LCH in the duodenum and 64 percent in the rectal, sigmoid, or colon. A study of 10 adult patients with GI involvement reported a mean age of 58 years, three-quarters were female, and half were asymptomatic; most had a solitary, small, intramucosal polyp in the colorectum [90].

EVALUATION

Clinical — Clinical findings vary according to the sites of disease, the severity and extent of involvement of affected organs (unifocal versus multifocal/extensive disease), and whether the patient has single-system versus multisystem disease. Young children may be unable to accurately describe their symptoms.

History and physical examination should evaluate the patient for:

●Constitutional findings – Fever, sweats, weight loss

●Bone pain – Location, severity, and duration of pain

●Skin rash – Distribution and nature of the rash and other manifestations

●Lungs – Cough, dyspnea

●Central nervous system (CNS) – Headache, diplopia, altered mental status

●Endocrine – Polydipsia, polyuria, thirst, and growth or developmental delay

●Gastrointestinal (GI) – Abdominal pain, diarrhea, weight loss

Laboratory — Laboratory studies should include:

●Complete blood count (CBC) and differential count.

●Coagulation – Prothrombin time (PT) and activated partial thromboplastin time (aPTT) for patients with hepatomegaly, jaundice, abnormal liver enzymes, or a low total protein or albumin.

●Serum chemistries – Electrolytes, kidney function tests, calcium, liver function tests, total protein, albumin.

●Endocrine – Patients with arginine vasopressin deficiency, growth delay, or symptoms of hypothyroidism or hypoadrenalism should undergo endocrine evaluation at baseline.

Testing for these patients may include thyroid stimulating hormone (TSH), free T4; prolactin and IGF-1; morning serum cortisol, ACTH, and osmolality; follicle stimulating hormone (FSH)/luteinizing hormone (LH; for males) or estradiol (for females); and/or morning urine osmolality.

●Bone marrow examination should be performed if CBC is abnormal or there are concerns for a myeloid neoplasm or hemophagocytic lymphohistiocytosis.

●Pulmonary function tests for patients with cardiorespiratory findings or abnormal chest radiograph. (See "Pulmonary Langerhans cell histiocytosis", section on 'Pulmonary function testing'.)

Imaging — Full-body positron emission tomography (PET)/computed tomography (CT), including the distal extremities, should be performed in patients ≥2 years old.

Other imaging varies according to affected organ systems. Examples include:

●Central nervous system (CNS) – Brain magnetic resonance imaging (MRI) with gadolinium contrast is the imaging modality of choice to visualize CNS involvement. MRI should be performed in children to detect involvement of the CNS or skull (eg, base of skull bones), which are often asymptomatic. For adults, we perform brain MRI only in patients with pituitary dysfunction or involvement of cranial bones.

Findings on MRI (image 4) include mass lesions or enhancement of the meninges, pons, basal ganglia, and white matter of the cerebellum [91]. In a report of 163 patients, meningeal lesions were found in 29 percent and choroid-plexus involvement in 6 percent [69]. In another study, pineal glands were enlarged and often had cystic changes [92].

●GI tract – Ultrasound, CT, or MRI of the abdomen can assess involvement of the liver and/or spleen in patients with hepatosplenomegaly. Findings of liver involvement include low echogenicity along the biliary tract by ultrasound and low T1 or high T2 signal intensity along the portal vein and portal triads [93,94].

Pathologic features — Identifying characteristic pathologic features is key to diagnosing LCH. (See 'Diagnosis' below.)

PET-CT may help to identify a safe and high-yield biopsy site. Biopsy of an osteolytic bone lesion or skin lesion is generally preferred for histopathologic evaluation, but the surgeon should not perform a wide excision. For most bone lesions, curettage provides diagnostic tissue and it may be sufficient for management. It is important to ensure that tissue handling of bone biopsies is coordinated with pathology, as most decalcification procedures damage the DNA integrity and may render mutation testing impossible; alternative methods like EDTA-based decalcification can be used. (See "Treatment of non-pulmonary Langerhans cell histiocytosis", section on 'Bone'.)

Involved tissue usually demonstrates a sparse distribution of Langerhans cells with surrounding inflammatory cells and/or fibrosis.

●Morphology – 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. The neoplastic cells often show cytologic atypia. Unlike dermal Langerhans cells, these cells do not have dendritic cell processes. Hemophagocytosis on bone marrow specimens and myelodysplastic changes may be seen, but this finding is not diagnostic for LCH [95,96].

A heterogeneous infiltrate surrounds the Langerhans cells, which includes eosinophils, neutrophils, lymphocytes, and macrophages (which may form multinucleated giant cells) [97,98]. Eosinophilic abscesses may be present, demonstrating central necrosis with or without Charcot-Leyden crystals. There may be variable degrees of fibrosis. For ambiguous cases, histopathologic re-evaluation at a center with LCH expertise should be considered.

Histopathologic findings vary with the site of biopsy:

•Bone, skin, cerebrum, hypothalamus, pituitary – These lesions have classic CD1a-reactive Langerhans cells and CD8+ T cells [97].

•Cerebellum – Lesions of the cerebellum show a diffuse perivascular infiltration with BRAF V600E+ cells of monocyte lineage with T lymphocytes in the background [99].

•Liver – Liver biopsies may show no CD1a+ cells, but many lymphocytes clustered around bile ducts. Biopsy of sclerosing cholangitis may not reveal CD1a+ cells of LCH; rather, it may show a CD1a-negative inflammatory infiltrate, reactive histiocytes, and fibrosis [86,87].

●Immunohistochemistry – Langerhans cells express the histiocyte markers CD1a and CD207 (langerin) and may express S100. BRAF V600E can be demonstrated by immunohistochemistry using the VE-1 reagent and should be applied to all biopsy specimens [23].

Diffuse cyclin D1 positivity can help to distinguish neoplastic Langerhans cells from reactive ones (eg, in skin biopsies). Staining for cyclin D1, a downstream marker of MAPK pathway activation, was found in 39 of 39 LCH cases tested [22].

●Cytogenetics – No cytogenetic abnormalities are characteristic or diagnostic for LCH.

●Genetics – Mutated BRAF V600E is present in more than half of cases of LCH. Polymerase chain reaction (PCR) testing for BRAF V600E should be applied to all tissue biopsies.

For cases that have wild-type BRAF by PCR or immunohistochemistry (see above), next-generation or targeted sequencing panels for mutations of MAP2K1, ARAF, CCD1 (cyclin D1), or other components of the MAPK-ERK signaling pathway should be performed. Rarely, kinase fusions (BRAF, ALK, NTRK) may be detected and can have therapeutic implications.

Detection of these mutations in blood samples can support the diagnosis of LCH when the pathology is equivocal or if it was not possible to obtain a tissue diagnosis. (See 'Diagnosis' below.)

DIAGNOSIS — LCH is a rare condition, but it should be suspected in a patient of any age with an unexplained lytic bony lesion, skin rash, arginine vasopressin deficiency (AVP-D), pituitary mass, or respiratory symptoms. Most patients present to their primary care providers with nonspecific clinical findings or to a subspecialist, according to their symptoms.

The diagnosis is based on pathologic evidence of LCH in the setting of suggestive clinical and imaging features. Establishment of the diagnosis may require multiple biopsies.

●Pathology – Confirmation of the morphologic appearance of Langerhans cells must be corroborated by immunohistochemical staining for CD1a, CD207, and S100. Biopsy of an osteolytic bone lesion or skin lesion is generally preferred.

●Clinical findings and imaging – The clinical and imaging findings vary between patients and according to the presentation. Suggestive findings include a lytic bone lesion, skin rash (eg, brown to purplish papules, eczema), AVP-D or other endocrinopathy, and other clinical manifestations, as described above. (See 'Sites of involvement' above.)

In rare cases, when it is not possible to obtain a biopsy (eg, certain brain lesions) or when the histopathology is equivocal, the diagnosis can be based on characteristic clinical features and imaging. In such cases, molecular analysis of blood or bone marrow for mutation of BRAF or components of the MAPK-ERK pathway or CCD1 (cyclin D1) can enhance confidence in the diagnosis. As an example, a neurosurgeon might choose to not biopsy the pituitary gland because of the size of the abnormality. In such a setting, 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 [100].

Diagnosis of pulmonary LCH is discussed separately. (See "Pulmonary Langerhans cell histiocytosis", section on 'Diagnosis'.)

DIFFERENTIAL DIAGNOSIS — LCH can be difficult to diagnose since it is a rare disease that can affect many organ systems. LCH in bone, lymph nodes, thymus, liver, or spleen can be distinguished from lymphomas, solid tumors, or primary central nervous system (CNS) tumors. Cutaneous involvement can mimic vasculitis, cutaneous lymphoma, or other histiocytic disorders. Pulmonary involvement can have the clinical appearance of various interstitial lung diseases.

LCH is distinguished from other histiocytic and dendritic cell disorders, metastatic solid tumors, hematopoietic neoplasms, hemophagocytic lymphohistiocytosis/macrophage activation syndromes, and other conditions by histologic and immunophenotypic findings. (See 'Pathologic features' above.)

Langerhans cell sarcoma (LCS) — LCS can be difficult to distinguish from LCH, as they share immunophenotypic features and they can occasionally coexist. LCS is also positive for CD1a and Langerin, but it has an overtly malignant cytology; prominent mitotic activity with atypical mitoses and cellular atypia are mandatory for diagnosis of LCS [3].

Erdheim-Chester disease (ECD) — ECD is a rare multisystem histiocytic disorder most often seen in adults, which may be difficult to distinguish from LCH. In ECD, histiocytic infiltration leads to xanthogranulomatous infiltrates of one or multiple organ systems (eg, skin, lung, bone, cerebral, facial, orbital and retro-orbital tissue, pituitary, retroperitoneum, cardiovascular system). The diagnosis of ECD is suggested by symmetric, painful osteosclerotic lesions in long bones and the diagnosis is confirmed by presence of histiocytes with non-Langerhans features (eg, negative for CD1a and positive for factor XIIIa and CD163). Cases of concomitant LCH and ECD (ie, mixed histiocytosis) have been described [40]. (See "Erdheim-Chester disease", section on 'Differential diagnosis'.)

Juvenile xanthogranuloma (JXG) — JXG is a benign proliferative disorder of histiocytic cells of the dermal dendrocyte phenotype. JXG is a non-Langerhans cell histiocytosis that typically presents in the first two years of life as a solitary reddish or yellowish skin papule or nodule (picture 4), most often on the head, neck, and upper trunk. JXG generally follows a benign course with spontaneous resolution over a period of a few years. Less often, there may be multiple skin lesions (picture 5) and, rarely, there are extracutaneous or systemic forms involving brain, lung, kidney, spleen, liver, bone marrow, and retro-orbital tumors. Histologically, JXG is distinguished by the presence of foamy or Touton giant cells, which are CD1a and CD207 negative. (See "Juvenile xanthogranuloma (JXG)".)

Multiple myeloma (MM) — The osteolytic lesions of bone in LCH can be confused with those of MM. MM is readily distinguished from LCH by histologic features (eg, plasma cells with abundant basophilic cytoplasm; round, eccentrically located nuclei with "spoke wheel" chromatin, without nucleoli; and a marked perinuclear cytoplasmic clearing), immunophenotype (ie, expression of either kappa or lambda light chains, no surface immunoglobulin, and typical plasma cell markers, such as CD79a, CD138, and CD38), and a serum and/or urine monoclonal protein. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Diagnosis'.)

Hemophagocytic lymphohistiocytosis (HLH) — HLH and the related macrophage activation syndrome (MAS) are systemic disorders that demonstrate tissue infiltration by non-neoplastic histiocytes. LCH can cause HLH/MAS (especially in children) and HLH and LCH can coexist. Unlike LCH, HLH may demonstrate prominent hemophagocytic activity in the bone marrow, and fever, splenomegaly, and a constellation of laboratory abnormalities and/or an underlying genetic defect. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis".)

Rosai-Dorfman disease (RDD) — RDD (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 in children, but it can be limited to the skin in adults [101-106]. RDD histiocytes are negative for CD1a and CD207 and are histologically distinguished from other histiocytic diseases because most cases of RDD have normal-appearing lymphocytes or plasma cells residing in the macrophage cytoplasm (emperipolesis); this also distinguishes RDD from 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

●Histiocytic disorders – Langerhans cell histiocytosis (LCH) is a malignant histiocytic disorder of myeloid origin; it is not derived from epidermal Langerhans cells, which they resemble morphologically. Although rare, LCH is the most common neoplastic histiocytic disorder. It can affect patients of all ages, although LCH is most common in children from one to three years old. Classification systems for histiocytic disorders are presented above. (See 'Histiocytic disorders' above.)

●Pathophysiology – LCH is a clonal disorder driven by activation of the MAPK-ERK signaling pathway, which offers a treatment opportunity for some patients; BRAF V600E mutation is present in more than half of cases. (See 'Pathophysiology' above.)

●Clinical manifestations – Affected individuals range from neonates to adults. Symptoms, affected organ systems, and disease tempo vary widely. LCH can present as a single site or multiple sites of disease in one organ system or it can present in multiple organ systems simultaneously or sequentially. The distinction between single-system and multisystem LCH affects prognosis and management.

•Single-system LCH – Unifocal or multifocal involvement of bone, skin, lungs, and central nervous system (CNS).

•Multisystem LCH – Two or more organs/systems are involved. It is especially important to identify involvement of critical ("risk") organs: CNS, heart, liver, and spleen, which affects prognosis and treatment choices.

●Sites of involvement – Lytic bone lesions (image 1), eczematous or papular rash (picture 2A), or pituitary involvement causing arginine vasopressin deficiency (AVP-D) are the most common manifestations; clinical findings in various organs are described above. (See 'Sites of involvement' above.)

●Evaluation – The extent of disease is evaluated with history and physical examination, laboratory studies, imaging, and biopsy.

•Imaging – Patients ≥2 years should have whole-body fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT). Other imaging is guided by involved sites; examples include magnetic resonance imaging (MRI) for brain lesions or CT, MRI, or ultrasound for abdominal symptoms. (See 'Imaging' above.)

•Pathology – Demonstration of CD1a+, CD207+ Langerhans cells (picture 6) in a heterogeneous inflammatory infiltrate. Biopsy of an osteolytic bone lesion or skin lesion is generally preferred. (See 'Pathologic features' above.)

Evaluation and diagnosis of LCH in lungs are discussed separately. (See "Pulmonary Langerhans cell histiocytosis".)

●Diagnosis – LCH should be suspected in a patient of any age with an unexplained lytic bony lesion, skin rash, AVP-D, pituitary mass, or respiratory symptoms.

The diagnosis is based on pathologic evidence of LCH in the setting of suggestive clinical and imaging features. (See 'Diagnosis' above.)

●Differential diagnosis – The differential diagnosis varies according to the clinical presentation. In general, LCH must be distinguished from other histiocytic/dendritic cell disorders, solid tumors, hematopoietic neoplasms, and/or hemophagocytic lymphohistiocytosis/macrophage activation syndromes by clinical, histologic, and immunophenotypic findings, as described above. (See 'Differential diagnosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges the late Laurence A Boxer, MD, for his previous role as a section editor for this topic.