Approach

LCH covers a wide range of clinical presentations and may affect any organ or system of the body.[2] The aim of the initial evaluation is to define the extent of the disease: that is, to determine whether the disease is single-system or multisystem, and identify which organs are involved.

Clinical manifestations: general considerations

A careful history should be taken, bearing in mind that some manifestations (e.g., skin rash, polyuria, polydipsia) may have started months, or even years, before the initial presentation.[4]

The clinician should enquire about symptoms of:[2]

  • Pain

  • Swelling

  • Skin rash

  • Fever

  • Loss of appetite

  • Faltering growth

  • Poor weight gain

  • Diarrhea

  • Otorrhea

  • Polydipsia

  • Polyuria

  • Respiratory symptoms

  • Irritability

  • Neurologic changes

  • Behavioral changes.

History of smoking should be elicited, because it increases the risk of lung involvement in adolescents and adults.[23] A history of trauma to the skin or bone should be noted to help rule out other causes of the presenting symptoms.

Single-system disease involves one organ system only. Approximately 70% of patients ages <15 years have single-system disease, most commonly with bone involvement.[10]

Multisystem disease occurs in two or more organs.[2] Most adults have multisystem disease, commonly with skin and lung involvement.[12] Multisystem disease with bone marrow involvement is also very common in children ages <2 years.[25]

Specific organs are considered high-risk in children because the associated mortality rates in those who do not respond to treatment are high. High-risk organs include the liver, spleen, and bone marrow.[2]

On physical exam, height and weight percentiles should be measured and recorded. A full ear, nose, and throat and dental/mouth evaluation should be performed, as well as an examination of other mucocutaneous junctions including the anal and vaginal areas. The whole body should be examined for the presence of skin rashes, bone lesions, and soft-tissue masses. A complete neurologic exam should also be performed.

Clinical manifestations: bone involvement

The most common type of single-system disease in children, but may also be present in multisystem disease. Bone lesions are present in 80% of patients, most commonly on the scalp.[10] Lytic osseous lesions are seen in 30% to 50% of adults, and can occur as single-system or multisystem disease.[12] Pain and/or swelling in the affected area(s) are common. The most common site of swelling is over the skull bones and this is usually painless. The lesions may be unifocal (single bone) or multifocal (>1 bone), and approximately 50% of bone lesions are asymptomatic and are only revealed on an x-ray.[10][26]

LCH is the most common cause of vertebra plana (i.e., spondylitis with reduction of the vertebral body to a thin disk) in children. This leads to compression and collapse of the vertebral body. Neurologic complications may arise from extension of Langerhans cells into the extradural space. Pathologic fractures are rare.

Central nervous system (CNS)-risk bones are bones in which, if lesions are present, patients have a 3-fold higher risk of developing CNS disease in children (the most common manifestation being diabetes insipidus). These bones are the facial bones or bones of the anterior/middle cranial fossa (i.e., temporal, sphenoidal, ethmoidal, zygomatic, and orbital bones).[27]

Clinical manifestations: skin involvement

A common type of single-system disease in children, but may also be present in multisystem disease, especially in neonates.[28] Skin is the second most commonly involved organ in the pediatric group, and skin lesions are present in up to 50% of patients, usually on the scalp.[29]

The most common lesion in the first few months of life is a papulosquamous rash that affects the scalp, skin folds, and midline of the trunk. This is easily mistaken for seborrheic dermatitis (or cradle cap in infants) or possibly a Candida infection.[30][31] A single or multiple violaceous papulonodular, and sometimes vesicular, rash may also occur, but is rare and may disappear spontaneously. This is known as Hashimoto-Pritzker disease.[32][Figure caption and citation for the preceding image starts]: Langerhans cell histiocytosis rash on an infant's abdomenReproduced with permission from Science Photo Library [Citation ends].com.bmj.content.model.Caption@5d4d194

Among adults, isolated skin involvement is less common, and mostly seen as a part of multisystem disease (30% to 50%).[12] Perianal or genital involvement is more common in adults, and can be very disabling and resistant to treatment.[33]

Clinical manifestations: lung involvement

An uncommon type of single-system disease in children, but often present in multisystem disease, especially in infants. It occurs in 15% of children; however, it is more common in adults (40% to 50%), especially heavy smokers.[34]

Patients commonly present with cough or dyspnea.[35] A minority of patients report malaise, fatigue, fever, or weight loss. Chest pain may indicate a spontaneous pneumothorax.[35]

Clinical manifestations: CNS involvement

A common type of single-system disease, but CNS involvement may also be present in multisystem disease.

Diabetes insipidus is the most common manifestation, due to posterior pituitary gland involvement. It is more common in patients with multisystem disease and those with craniofacial bone lesions, especially of the orbit and skull base.[27] The risk is high in patients when the disease has been active for a long period of time, or when the disease is reactivated. These patients generally present with polyuria and polydipsia. Patients may also present with headache, faltering growth, or delayed puberty.[2]

Among children, those with mastoid, temporal, and orbital bone lesions and diabetes insipidus are at increased risk of developing a CNS neurodegenerative syndrome. This occurs in up to 4% of patients and manifests as ataxia, dysmetria, and dysarthria.[3][36] The patient may also present with seizures, focal neurologic deficits, cognitive impairment, changes in behavior, or progressive cerebellar symptoms such as nystagmus, dysarthria, and hypotonia.[3][37]

Clinical manifestations: lymph node involvement

This is usually part of multisystem disease, but can also occur in isolation, or is sometimes associated with a single bone lesion.[38][39] It may affect single or multiple lymph nodes. Lymphadenopathy is seen on exam. Superior vena cava syndrome can result from mediastinal lymph node or thymic enlargement.[40] Careful analysis of phenotype and histopathology is recommended to differentiate reactive Langerhans cells in LCH from primary malignant histiocytosis of the lymph node.

Clinical manifestations: liver/spleen involvement

This is more common in multisystem disease. It affects 10% to 20% of patients with LCH.[41] Chronic liver disease in these patients is typically sclerosing cholangitis, which can progress to biliary cholangitis and sometimes to fatal liver failure.[41] Hepatosplenomegaly is seen on exam, and patients may have jaundice or ascites.[42]

The liver and spleen are considered high-risk organs.[2]

Clinical manifestations: bone marrow involvement

This is more common in multisystem disease. Most patients are young children presenting with cytopenias (i.e., neutropenia, anemia, or thrombocytopenia) and diffuse disease in the skin, liver, spleen, and lymph nodes.[43]

Bone marrow is considered a high-risk organ.[2] Involvement is a major component of the most severe forms of disease and is present in 70% of pediatric patients who die from LCH.[44] In adults, presence of peripheral blood count abnormalities may suggest bone marrow infiltration by LCH or another myeloid neoplasm.

Clinical manifestations: other organ systems

Eye involvement

  • More common in multisystem disease.

  • Seen in 14% of children, and generally presents with visual disturbances, such as diplopia.[45] Intrinsic eye involvement is exceptional.

  • Patients may also present with proptosis, periorbital swelling and erythema, diplopia, or ophthalmoplegia.[46]

  • Orbital disease must be differentiated from acute infection, inflammatory pseudotumor, rhabdomyosarcoma, and metastatic neuroblastoma.

Ear involvement

  • More common in multisystem disease.

  • The presence of otitis externa can be due to extension of the skin rash into the ear canal and secondary infection with Pseudomonas aeruginosa.[47] Ear pain is a typical symptom.

  • Middle ear involvement can occur secondary to lesions in the petrous temporal or mastoid bones, causing intermittent ear discharge.[48] Perforation of tympanic membranes can also occur.

  • Inner ear involvement can present with deafness, or with behavioral disturbances in younger children.[49]

Oral involvement

  • More common in multisystem disease.

  • Oral lesions are uncommon but may precede the onset of disease in other parts of the body. Gingival hypertrophy and ulcers of the palate, tongue, or lips may be seen.[50]

Other

  • Gastrointestinal involvement is more common in multisystem disease, and bloody diarrhea is the most common presenting symptom.[51]

  • Patients may present with massive thyroid enlargement; however, this is rare.[52]

Investigations

Initial investigations: children

  • A complete blood count (CBC) should be ordered to check for the presence of cytopenias, which may indicate bone marrow involvement.[2]

  • Liver function tests (LFTs), serum albumin, serum creatinine, blood urea nitrogen (BUN), electrolytes, erythrocyte sedimentation rate, and coagulation studies should be ordered in all patients to screen for organ involvement, assess degree of systemic inflammation, and establish baseline measurements.[2]

Subsequent investigations: children

  • Early morning urine specific gravity and osmolality (following an overnight fast), blood electrolytes, and water deprivation test are indicated in children if there is a history of polydipsia or polyuria, to detect central diabetes insipidus.[2] Additional pituitary function testing (e.g., follicle-stimulating hormone [FSH], luteinizing hormone [LH], testosterone or estradiol, corticotropin and morning cortisol, thyrotropin and free thyroxine, prolactin, and insulin-like growth factor 1) may be indicated if another endocrine abnormality is suspected.[2]

  • Pulmonary function tests should be performed in patients with pulmonary involvement. Bronchoalveolar lavage and lung biopsy are reserved for cases where the diagnosis is uncertain.[2] An echocardiogram is indicated in patients with pulmonary LCH to rule out pulmonary hypertension.

  • Audiometry is indicated in patients with suspected ear involvement.

  • Liver imaging and/or biopsy may be indicated if LFTs are abnormal (transaminases or bilirubin >5 times the upper limit of normal); consult a hepatologist for advice.[2]

  • Gastrointestinal endoscopy and/or biopsy may be considered for children with unexplained chronic diarrhea, evidence of malabsorption, or faltering growth.[2]

  • Neuropsychometric assessment is indicated for children with neurologic abnormalities.[2]

Initial investigations: adults

  • A CBC with differential should be ordered initially in all patients to check for the presence of cytopenias, which may indicate bone marrow involvement with LCH or a concomitant myeloid neoplasm.[53]

  • LFTs, serum creatinine, BUN, electrolytes, calcium, and inflammatory markers should be ordered in all patients to screen for organ involvement and establish baseline measurements.[53][54]

  • BRAF V600E mutation analysis should be performed on tissue biopsy where available. For cases that are negative for BRAF V600E, next-generation sequencing studies for mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK-ERK) pathway mutations should be conducted on tissue biopsy specimens.[4][53]

  • Endocrine evaluations are recommended in all adult patients with newly diagnosed LCH to detect pituitary involvement, especially in the presence of polyuria and polydipsia. These include: morning urine and serum osmolality to detect diabetes insipidus; FSH and LH; testosterone or estradiol; corticotropin and morning cortisol; thyrotropin and free thyroxine; prolactin; and insulin-like growth factor 1.[53]

Imaging

Initial imaging: children

  • Skeletal radiograph survey is recommended to detect bone lesions.[2] The classical appearance on x-ray is a punched-out lytic lesion, most commonly in the skull, with sharply demarcated margins, and little or no periosteal reaction.[55] Commonly, there is an associated mass that can extend intracranially and may cause brain compression. By contrast, lesions involving the orbit, mastoid, or other areas of the skull base are often extensive and irregular, with a soft-tissue component that must be differentiated from a malignant tumor.[55] Lesions in long bones may present with aggressive features and poorly defined borders, with or without a large soft-tissue mass that must also be distinguished from malignancy.[55][Figure caption and citation for the preceding image starts]: Skull x-ray showing lytic bone lesion in the right posterior parietal area of the skullFrom the personal collection of Oussama Abla, MD; used with permission [Citation ends].com.bmj.content.model.Caption@18c8b69e

  • A chest x-ray should be performed to detect lung involvement.[2] On chest x-ray, cysts may be visible within the infiltrates, predominating in the middle and upper lung fields, and sparing the costophrenic angles.[56] Pneumothorax, or a lytic lesion in a rib, may also be visible.

  • Abdominal ultrasound should be performed to assess the size and structure of the liver and spleen, and evaluate the intra-abdominal lymph nodes.[2]

Subsequent imaging: children

  • A high-resolution computed tomography (CT) scan of the lung is indicated for patients with pulmonary symptoms or abnormal chest x-ray. In children with known multisystem LCH, low-dose CT is sufficient to assess lung involvement and minimizes radiation exposure.[2]

  • A magnetic resonance imaging (MRI) scan of the head should be requested for children with suspected craniofacial bone lesions (including the mandible and maxilla). MRI may characterize the bony lesions and detect involvement of the brain and pituitary gland.[57] MRI head should also be performed for patients with visual, neurologic, or suspected endocrine abnormalities.[2]

  • CT of an affected craniofacial bone and the skull base should be performed if MRI is unavailable.[2] CT is useful to delineate uncertain lesions on skull x-ray, particularly if orbital, ear, or mastoid involvement is suspected. Contrast images will demarcate the soft-tissue involvement and periosteal reaction. 

  • MRI spine should be performed in all pediatric patients with suspected vertebral lesions to exclude spinal cord compression and detect any soft-tissue masses.[2]

Initial imaging: adults

  • Full-body (vertex to toes) fluorodeoxyglucose positron emission tomography (FDG-PET) is recommended to stage disease and determine a suitable biopsy site. FDG-PET uptake is increased in regions affected by LCH.[53]

  • MRI head with gadolinium contrast is performed to detect CNS involvement among patients with neurologic symptoms or symptoms suggestive of pituitary dysfunction.[53]

  • High-resolution CT chest is indicated for suspected pulmonary LCH.[53]

Subsequent imaging: adults

  • Organ-specific imaging (CT or MRI) may be needed in addition to the FDG-PET imaging to better assess structural changes associated with the disease.[53][58]

Tissue biopsy

A definitive diagnosis is made by tissue biopsy of a lytic bone lesion, skin lesion, or lymph node. Lesional cells should demonstrate positivity for CD1a and CD207 (langerin) using immunohistochemical techniques.[1]

Lesional tissue should be tested for BRAF V600E mutation by immunohistochemistry or molecular assays. Negative or equivocal immunohistochemistry results should be confirmed using molecular assays. Next-generation sequencing for MAPK-ERK pathway mutations should be conducted in patients anticipated to initiate systemic therapy.[53] In instances where tissue specimen is inadequate, peripheral blood analysis using cell-free DNA next-generation sequencing is a reasonable alternative.

Patients with hematologic cytopenias/cytosis should have a bone marrow aspirate and biopsy, to exclude other myeloid neoplasms.[2][53] The presence of clusters of large CD1a-positive cells in the marrow is diagnostic for LCH.

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