by Jason Wasserman MD PhD FRCPC and Aleksandra Paliga MD FRCPC
January 3, 2026
Langerhans cell histiocytosis is a rare disorder of the immune system in which a specific type of immune cell proliferates and accumulates in tissues where it does not normally reside. These abnormal cells resemble Langerhans cells, which are immune cells involved in responding to infection and inflammation. In Langerhans cell histiocytosis, these cells multiply in a clonal (non-random) way and form lesions that can damage surrounding tissue.
Langerhans cell histiocytosis can involve a single organ or body system (most often bone) or multiple organs simultaneously. The extent of organ involvement is one of the most critical factors affecting symptoms, treatment, and prognosis.
Where does Langerhans cell histiocytosis occur?
The location depends on whether the disease affects a single system or multiple systems.
In single-system disease, the most commonly involved site is bone, especially the skull, femur, spine, pelvis, ribs, and jaw. Less commonly, the disease can affect the skin, lymph nodes, or lungs.
In multisystem disease, multiple organs may be involved simultaneously. The most frequently affected organs include the skin, bone, liver, spleen, and bone marrow. In advanced cases, other organs can also be involved.
What are the symptoms of Langerhans cell histiocytosis?
Symptoms vary widely depending on the number of organs involved and which organs are affected.
Single-system disease
Single-system Langerhans cell histiocytosis most often affects older children or adults. When bone is involved, patients typically present with localized pain caused by a destructive lesion in the bone. The affected area may be tender, swollen, or prone to fracture. Lesions in the skull or jaw may be noticed as a lump or facial asymmetry.
If the disease affects the skull or nearby brain structures, damage to the pituitary gland can lead to diabetes insipidus, a condition that causes excessive thirst and frequent urination.
When single-system disease involves the skin or lymph nodes, it may appear as a localized rash or mass.
Multisystem disease
Multisystem Langerhans cell histiocytosis is more common in infants and very young children and tends to be more severe. These patients may present with fever, poor appetite, weight loss, and fatigue. Skin rashes and multiple bone lesions are common.
Involvement of the liver, spleen, or bone marrow can lead to enlargement of these organs and abnormalities in blood counts (cytopenias). These features indicate higher-risk disease and usually require more intensive treatment.
How common is Langerhans cell histiocytosis?
In children, Langerhans cell histiocytosis occurs in about 5 cases per million per year. It is less common in adults, with an incidence of 1–2 cases per million per year. The disease affects males slightly more often than females and is more frequently reported in individuals of European or Hispanic ancestry.
Langerhans cell histiocytosis can occur on its own or, rarely, alongside other histiocytic disorders such as Erdheim–Chester disease.
What causes Langerhans cell histiocytosis?
The exact cause is not fully understood. The disease is not inherited.
Research has shown that Langerhans cell histiocytosis is driven by acquired genetic mutations that affect a signaling pathway in cells called the MAPK pathway. A genetic mutation is a change in DNA, the instruction manual inside cells. These mutations cause immune cells to survive longer than they should and to accumulate in tissues.
The most common mutation involves the BRAF gene (specifically the BRAF p.Val600Glu mutation). Other cases involve mutations in related genes such as MAP2K1. These mutations help explain why the disease can behave like both an inflammatory condition and a cancer-like process.
How is the diagnosis made?
The diagnosis is made by examining a biopsy sample under the microscope and confirming the identity of the abnormal cells with special tests.
Microscopic (pathologic) features
Under the microscope, the abnormal cells in Langerhans cell histiocytosis are medium-sized and have characteristic grooved or folded nuclei, often described as “coffee-bean–shaped.” The chromatin inside the nucleus is fine, and the nucleoli are small or inconspicuous. The cytoplasm is moderately abundant and lightly pink.
These cells are usually found in a mixed inflammatory background that often includes eosinophils, a type of white blood cell commonly seen in this disease. Other immune cells, such as lymphocytes and macrophages, may also be present. In bone lesions, cells that resemble osteoclasts may be seen.
In early lesions, Langerhans cells are abundant. In older lesions, there may be fewer, with more fibrosis and foamy macrophages replacing them.
Immunohistochemistry
Immunohistochemistry uses special stains to identify proteins made by cells.
Langerhans cell histiocytosis cells characteristically express CD1a and CD207 (langerin), as well as S100 protein. These markers confirm that the cells have a Langerhans cell phenotype. CD68 and HLA-DR are also commonly positive.
A specific stain can detect the BRAF p.Val600Glu mutation in many cases, helping guide treatment decisions.
Molecular testing
Molecular testing looks for genetic changes in the Langerhans cells that help explain why the disease developed and how it may behave. These tests are usually performed on biopsy tissue using methods such as next-generation sequencing, PCR-based mutation testing, or, in some cases, immunohistochemistry designed to detect specific mutations.
Results are typically reported by naming the affected gene and the specific mutation, such as BRAF p.Val600Glu (V600E) or MAP2K1 mutation. The report may also describe the mutation as present (positive) or not detected (negative). Identifying a MAPK pathway mutation can help confirm the diagnosis and may guide treatment decisions, especially in patients with recurrent or multisystem disease.
How is Langerhans cell histiocytosis staged?
Staging is based on the number of organs involved, not tumour size.
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Single-system disease involves one organ or system, either at a single site or at multiple sites.
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Multisystem disease involves two or more organs or systems.
Some organs, such as the liver, spleen, and bone marrow, are considered risk organs. Their involvement indicates higher-risk disease.
What is the prognosis for a person with Langerhans cell histiocytosis?
Prognosis depends primarily on the extent of disease at diagnosis.
Patients with single-system disease have an excellent outlook, with survival rates approaching 100%. Many cases resolve completely with limited treatment.
Patients with multisystem disease, especially when risk organs are involved, have a more complicated course but still have a relatively low overall mortality rate with modern therapy. Long-term complications can occur, particularly in patients with pituitary or brain involvement.
Specific genetic mutations, especially BRAF p.Val600Glu, are associated with a higher risk of relapse and may influence treatment choices.
Questions to ask your doctor
- Is my disease single-system or multisystem?
- Which organs are involved?
- Was molecular testing performed, and were any mutations found?
- What treatment options are recommended for my stage of disease?
- What long-term follow-up will I need?
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