Langerhans cell histiocytosis (LCH) is an idiopathic condition characterized by proliferation of abnormal Langerhans cells (antigen-presenting immune cells). The disease has characteristics of both an abnormal reactive process and a neoplastic process. It may present initially as a rash. It can be disseminated and involve bone marrow, lungs, liver, spleen, lymph nodes, gastrointestinal (GI) tract, and the pituitary gland. Prognosis varies depending on presentation and organ involvement. LCH can occur at any age but is most common from birth to age 15 years. There is wide variation in presentation, treatment, and prognosis among individuals. Referral and long-term follow up with an oncologist are important in the management of LCH.
The cause of LCH is unknown and continues to be a debate; however, most agree that LCH is either a reactive or neoplastic process.
LGH has multiple cytokines involved, there is good survival in isolated lesions, and it can have spontaneous remissions. These characteristics support a reactive process.
However, LGH also can have organ infiltration. The widespread disease is associated with increased mortality, it typically responds to chemotherapy, and there has been at least one study that demonstrated an association with the BRAF gene mutation. These characteristics support a neoplastic process.
Langerhans cell histiocytosis is rare. It occurs in 1 to 2 newborns per million per year. The incidence in children < 15 years is 4 to 5 cases per million per year. In adults, the incidence is about 1 to 2 cases per million per year. It may occur at any age but is more likely to occur in those < 15 years of age.
The pathophysiology of LCH is unknown. Langerhans cells are dendritic antigen-presenting cells. The abnormal cells in LCH have abnormal proliferation and lower antigen-presenting capability. LCH lesion also contains inflammatory cells and cytokines such as T lymphocytes, eosinophils, neutrophils, and macrophages. It is thought that the combination or interaction of these cells accounts for the continued proliferation of the abnormal Langerhans cells. Regardless, abnormal proliferation into tissue causes disease, based on location at presentation. For example, bone marrow infiltration may lead to decreased blood cell production.
The histological features of LCH are variable and influenced by the age of lesions and their location.
The primary lesion is granulomatous with an influx of eosinophils, macrophages, T cells and multinucleated cells. The Birbeck granule is the microscopic hallmark of the disorder but may not be seen in lesions of the spleen, liver, and GI tract.
Symptoms and physical exam will depend on organ involvement at the time of presentation.
The rash is the most common presentation. In children, the rash may be misdiagnosed as seborrhea or atopic dermatitis but will not respond to typical treatment for these disorders. The rash of LCH ranges from a single lesion to widespread involvement. Characteristics include scaly papules, nodules, or plaques and can resemble seborrheic dermatitis. One may distinguish LCH by the presence of petechiae, bloody crusting, or firmly indurated nodules.
Bony involvement occurs in about 78% of patients. Solitary osseous lesions are usually incidentally found and may include the skull, hip/pelvis, femur, or ribs. This bony involvement may present incidentally, when obtaining imaging for another complaint, or may produce bone pain.
Pulmonary lesions occur in 20% of patients, and lymph node involvement in 30%. As such, the patient may present with pulmonary symptoms or lymphadenopathy. Hepatosplenomegaly may be present as well.
Langer cell histiocytosis also has a predilection for infiltration of the pituitary and causing diabetes insipidus. If this is the initial presentation, the patient may have polyuria, polydipsia, dilute urine, and hypernatremia.
Biopsy of the involved site (usually skin) is required to confirm the diagnosis. Lesions will stain positive for S-100 and CD-1a. Cytoplasmic Birbeck granules will be present on electron microscopy. When the diagnosis is confirmed, workup for systemic involvement should include a skeletal survey, abdominal ultrasound, complete blood count (with bone marrow biopsy if indication of bone marrow involvement), and evaluation for diabetes insipidus.
CT scanning or MRI
Both CT scan and MRI are invaluable for assessing the hypothalamic-pituitary area. Fluorodeoxyglucose (FDG) PET scanning also is being used to assess patients with LCH. The technique is far more sensitive than bone scan for early detection of disease in the spleen, lymph nodes, and lung. In fact, FDG PET scan is now also being routinely used to monitor disease during treatment.
Pulmonary function testing may help identify asymptomatic patients with lung involvement
Small bowel series is recommended in patients with failure to thrive, diarrhea, and malabsorption
Neurological and visual testing
Recent studies suggest that CSF fluid can be used to detect biomarkers like glial fibrillary acidic protein to evaluate the onset of disease and response to therapy.
Skin biopsy can establish the diagnosis
Treatment varies greatly depending on the involved organs. If the disease is isolated, observation alone may be appropriate. Surgical removal of an isolated area is also a treatment option. Isolated skin lesions may resolve on their own, especially if they present in infancy (congenital self-healing reticulohistiocytosis), or may be treated with topical steroids, oral methotrexate, or thalidomide. Chemotherapy and radiation may be used for more systemic involved cases. There are several different chemotherapy protocols that have been used; currently, protocols are using prednisone and vinblastine, though other regimen options include vincristine, cytosine arabinoside, prednisone, cladribine, or pamidronate.
Late complications are common; therefore, follow up with oncology is crucial. Complications include diabetes insipidus, growth failure, delayed puberty, tooth loss, mandibular bone loss, hearing loss, secondary cancers, neurologic/cerebellar effects, liver disease, and pulmonary fibrosis.
More than 50% of children under the age of 2 with disseminated Langerhans cell histiocytosis will die of the disease, but those with localized disease may have a prolonged life-span. For those who have been treated and do not have more lesions at 12 to 24 months, a full recovery can be expected. When there is lung involvement, the prognosis is not good. However, patients with isolated skin involvement and a solitary lymph node involvement tend to have a good prognosis.
Unfortunately, nearly 50% of patients with Langerhans cell histiocytosis are prone to a variety of complications which include the following:
Neuropsychiatric problems like depression, anxiety, and intellectual impairment
Secondary malignancies like lymphoblastic leukemia and sodi tumors
Prognosis depends on whether the initial presentation was a low-risk disease (isolated to the skin, lymph nodes, or pituitary gland) or high-risk disease (involving the spleen, liver, bone marrow, lung, or skeleton). Mortality may be low for isolated lesions (< 5%) and as high as 50% for the more widespread disease.