Langerhans’ Cell Histiocytosis
Langerhans’ cell histiocytosis is a rare disorder where a specific type of immune cell builds up in the body, potentially causing tissue damage and tumors in various organs. While it primarily affects children, the disease can occur at any age and ranges from mild conditions that resolve on their own to severe forms requiring intensive treatment.
Table of contents
- What is Langerhans’ Cell Histiocytosis?
- What Causes This Condition?
- Who Gets Langerhans’ Cell Histiocytosis?
- Signs and Symptoms
- How is LCH Diagnosed?
- Types and Classifications
- Treatment Approaches
- Outlook and Prognosis
What is Langerhans’ Cell Histiocytosis?
Langerhans’ cell histiocytosis (LCH) is a rare disorder that occurs when immune system cells called Langerhans cells build up in the body. Langerhans cells are a type of white blood cell that normally helps the immune system fight infection[1]. These cells are naturally found throughout the body, especially in the skin, lungs, lymph nodes, bone marrow, spleen, and liver[1].
In LCH, there is an overproduction and buildup of these cells, which can lead to organ damage. When excess Langerhans cells accumulate, they can damage tissue and cause lesions (areas of abnormal tissue) or tumors to form in one or more places in the body[1][4]. These cells often form structures called granulomas, which are collections of immune cells that cluster together[4].
There has been ongoing debate about whether LCH should be classified as a form of cancer or an inflammatory disease. Many researchers now consider it a type of neoplasm (abnormal growth of cells), while others view it as an inflammatory condition[1]. In 2008, the World Health Organization recognized LCH as a blood cancer, partly due to the discovery of cancer-causing genetic changes in cells from most patients[8]. Healthcare providers who treat cancer and blood disorders typically manage LCH, and sometimes use cancer therapies like chemotherapy to treat the condition[1].
What Causes This Condition?
The exact causes of Langerhans’ cell histiocytosis remain unclear, though significant progress has been made in understanding the disease[2]. It is not an inherited condition and does not spread from person to person[2][8].
Research has identified that genetic changes, called mutations, play an important role in the disease. Many patients have mutations in genes that control how immune cells function. The most common mutation affects the BRAF gene, but changes can also occur in MAP2K1, RAS, and ARAF genes[4][5]. These mutations affect a cellular signaling pathway called the RAS/MAP kinase pathway, which controls cell growth and division[3].
One working theory suggests that a clonal expansion of specific cells in the bone marrow leads to the development of LCH. This means that one abnormal cell multiplies, creating many copies of itself that then circulate in the body as Langerhans cells[3].
Several risk factors may increase the likelihood of developing LCH. These include having a parent who was exposed to certain solvents or to metal, granite, or wood dust in the workplace. A family history of cancer or LCH, thyroid disease, infections as a newborn, being Hispanic, and not being vaccinated as a child have also been identified as potential risk factors[5]. For adults, smoking is strongly associated with lung involvement[8].
Who Gets Langerhans’ Cell Histiocytosis?
Langerhans’ cell histiocytosis is a rare disease that can affect people of any age, though it most commonly occurs in children. The condition primarily affects newborns and children between the ages of 1 and 15 years[1]. It is most often diagnosed between the ages of 1 and 3 years[2], with peak onset occurring between ages 2 and 10[7].
The disease occurs in approximately 1 to 2 out of every 1 million newborns each year. Among children ages 15 and younger, it affects about 5 out of every 1 million children annually[1]. Another estimate suggests it affects about 1 out of every 200,000 children, with approximately 50 new cases in the United Kingdom each year[6]. LCH is more common in boys than girls[6].
While less common, Langerhans’ cell histiocytosis can occur in adults. Among adults aged 18 and over, the average age at diagnosis is around 40 years. The exact incidence in adults is unknown but is estimated at 1 to 2 new cases per million population per year in the United States[8]. Most adults with LCH who have lung involvement are current or past smokers[4].
Signs and Symptoms
The symptoms of Langerhans’ cell histiocytosis vary greatly from person to person, depending on which parts of the body are affected and how many areas are involved. The disease can affect almost any organ, though it most commonly involves the bones, skin, lungs, liver, spleen, and pituitary gland[2][8].
Bone symptoms: In approximately 80 percent of children with LCH, one or more lesions develop in the bones[4]. This can cause swelling or a lump over a bone, such as the skull, eye socket, ear bone, jaw bone, arms, legs, spine, hips, or ribs. The swelling may or may not be painful[1]. Additional bone-related symptoms may include headaches, neck pain, back pain, fractures, difficulty walking, and limping[1]. Bones may break from minor injury or for no obvious reason[2].
Skin symptoms: Skin involvement is common and can appear differently depending on age. In infants, it may look like cradle cap—a scaly rash on the scalp. The condition can also cause flaking in body creases such as the inner elbow or the area between the legs[5]. In children and adults, a flaky rash may resemble dandruff on the scalp[1]. Rashes can appear on the groin, arms, armpits, abdomen, back, or chest, and may be tender, painful, or itchy. Some people develop oozing blisters or bumps with red, brown, or purple areas[1][5]. The condition can also cause discoloration or hardening of the nails, or the nails may fall off[1].
Mouth symptoms: When LCH affects the mouth, it can cause loose teeth that may fall out, uneven teeth, swollen gums, or sores on the lips, tongue, inside the cheeks, or on the roof of the mouth[1].
Ear symptoms: LCH in the ears can cause recurring ear infections, cysts in the ear, or fluid draining from the ear[2].
Liver and spleen symptoms: When these organs are affected, symptoms may include swelling of the belly due to fluid accumulation, jaundice (yellowing of the skin and whites of the eyes), diarrhea, or vomiting[1][2].
Lung symptoms: Involvement of the lungs can cause coughing and trouble breathing. Lung tissue may stiffen, leading to breathing problems and increased risk of infection[1][4].
Pituitary gland symptoms: The pituitary gland, located at the base of the brain, controls many important body functions. When LCH affects this gland, it can cause excessive urination and extreme thirst—a condition called diabetes insipidus[1][2]. It may also lead to delayed or absent puberty, inability to have children, and thyroid problems that affect metabolism, body temperature, and behavior[4].
Eye symptoms: LCH can cause bulging eyes or other vision problems[2].
Other symptoms: Some people experience swollen lymph nodes, weight loss without obvious reason, failure to gain weight or grow normally, loss of appetite or feeding problems, fever, fatigue, and weakness[2][5]. In rare cases, the disease can affect the nervous system, causing neurological problems[4].
How is LCH Diagnosed?
Diagnosing Langerhans’ cell histiocytosis requires careful evaluation because the symptoms can be general and the disease is very rare. Children often visit several doctors before the diagnosis is suspected[6]. Doctors who specialize in cancer typically diagnose and treat LCH[2].
The diagnostic process typically begins with a comprehensive review by the doctor, who will check for signs of illness and ask about the patient’s health and family health history[2]. Since LCH can affect many different parts of the body, tests examine the organs and body systems where the disease may occur[5].
The definitive diagnosis of LCH requires a biopsy—the removal of a small piece of tissue from an affected area. This procedure is usually performed under general anesthesia in a specialized hospital[6]. The tissue sample may be taken from bone, skin, lung, or lymph node[2]. A specialized doctor called a pathologist then examines the biopsy under a microscope and performs tests looking for specific markers. LCH cells are positive for CD1a and CD207 (also called Langerin), which are proteins found on the surface of these cells[2][3].
Once LCH is confirmed, additional testing is important. This includes DNA sequencing to look for genetic mutations, which can help guide treatment decisions[2]. Imaging studies are used to determine if the disease is affecting other parts of the body. A PET scan (positron emission tomography) is commonly used to see the full extent of disease[2].
Blood tests provide information about blood counts, bone marrow, and organ function, particularly of the liver[2]. In some cases, a bone marrow biopsy may be performed, although LCH cells are not always visible in the bone marrow even when the disease is present there[1].
Types and Classifications
Langerhans’ cell histiocytosis can present in various forms, ranging from mild disease affecting a single area to severe disease involving multiple organ systems. The classification helps doctors determine the best treatment approach.
Single-system disease: This type affects only one part of the body, such as a single organ or tissue. For example, it might involve only the bones, skin, or lymph nodes[6][8]. Within single-system disease, there can be a single spot of involvement (unifocal) or multiple spots within the same organ system (multifocal)[7][8].
Unifocal LCH: Also historically called eosinophilic granuloma, this is characterized by a single lesion in one organ, most commonly bone. It typically has no involvement outside of the skeletal system, though rarely a lesion can be found in skin, lungs, or stomach[7].
Multisystem disease: This type involves two or more parts of the body at the same time, such as both skin and bones, or skin, bones, and bone marrow together[6][8]. Multisystem disease is more serious and requires more intensive treatment.
Risk categories: Doctors also classify LCH based on whether it affects certain high-risk organs. Low-risk disease affects areas such as skin, bones, lymph nodes, or the pituitary gland. High-risk disease is harder to treat and affects organs such as the liver, spleen, or bone marrow[2]. The presence or absence of dysfunction in these risk organs is an important factor in determining outlook and treatment strategy[3].
Pulmonary Langerhans cell histiocytosis (PLCH): This is a special category involving isolated lung disease. It is most commonly seen in adult smokers and is considered separately from other forms of LCH[7][8].
Older classification systems used names such as Hand-Schüller-Christian disease (which featured the combination of diabetes insipidus, bulging eyes, and bone lesions) and Letterer-Siwe disease (a severe form affecting infants)[7][9]. These historical names are less commonly used today, as the medical community now understands these as part of the broader spectrum of LCH.
Treatment Approaches
Treatment for Langerhans’ cell histiocytosis varies greatly depending on the extent and severity of the disease. The choice of treatment is based on how many organ systems are involved, which specific organs are affected, and whether there is dysfunction of high-risk organs[8].
For some patients, especially those with mild skin-only disease, LCH may go away on its own without any treatment. In fact, the disease may disappear spontaneously, particularly if it only occurs in the skin[1][4]. Close monitoring may be all that is needed in these cases[1].
Treatment for single-system disease: For solitary bone lesions, local treatment may be sufficient. This can include surgical removal or scraping out of the lesion (curettage), or injection of corticosteroids directly into the lesion. Painful bone lesions may require medication to manage discomfort. In rare cases, low-dose radiation therapy may be used for lesions that are unusually large, occur in difficult-to-reach locations, or involve vital structures[11].
For skin disease, treatment often starts with topical corticosteroids applied to the affected areas. In severe cases, other treatments such as topical nitrogen mustard, special medications like acitretin, or light therapy (PUVA) may be used[11].
Treatment for multisystem disease: When LCH affects multiple organs, systemic treatment is usually necessary. The most common approach involves chemotherapy, typically using a combination of vinblastine and prednisone. Treatment duration is important—longer courses of therapy have been shown to reduce the chance of disease returning[8].
High-risk patients with liver, spleen, or bone marrow involvement require more intensive therapy. If initial treatment doesn’t work, other chemotherapy drugs may be tried. These can include cytarabine or clofarabine[1].
Targeted therapy: The discovery of genetic mutations in LCH has led to new treatment approaches. For patients with BRAF mutations, targeted drugs that specifically block the abnormal protein may be used. These represent a newer, more precise way to treat the disease[8].
Other treatments: Depending on the complications that develop, patients may need additional treatments. For example, those who develop diabetes insipidus will need hormone replacement therapy. Some patients may require drugs called bisphosphonates to help with bone healing[11].
For lung disease in adults, especially those who smoke, quitting smoking is crucial and may be the only treatment needed in some cases[8].
Long-term follow-up with an experienced specialist is essential for the successful management of LCH, as the disease can recur and cause late complications even after initial successful treatment[3][8].
Outlook and Prognosis
The outlook for people with Langerhans’ cell histiocytosis varies widely depending on several factors, including which organs are affected, how many systems are involved, and the patient’s age at diagnosis. In general, the prognosis for LCH is good, and outcomes have improved markedly over the past decades[1].
For many children with LCH, the disease goes away with appropriate treatment[1]. The disease can even disappear on its own, especially if it affects only the skin[4]. Patients with single-system disease generally have an excellent prognosis.
The outlook is more guarded when LCH affects high-risk organs such as the bone marrow, spleen, or liver. These cases may require intensive therapy and have higher mortality rates[1][3]. Despite advances in treatment, mortality in high-risk patients remains a significant challenge.
Disease recurrence is a concern for some patients. Even after successful initial treatment, LCH can come back, requiring additional therapy[8]. This is why long-term follow-up is so important.
Some complications of LCH, such as diabetes insipidus or damage to organs, may be permanent even after the disease is treated successfully[4][8]. About 1 in 50 affected individuals may experience deterioration of neurological function[4].
However, with current treatment approaches and better understanding of the disease, many people with LCH can lead fulfilling lives. The key factors that affect prognosis include the number of organs involved, whether high-risk organs are affected, the patient’s age, and how well the disease responds to initial treatment[5][8].
Histiocytosis X, Hand-Schüller-Christian disease, Letterer-Siwe disease, Abt-Letterer-Siwe disease, Hashimoto-Pritzker disease, eosinophilic granuloma, Langerhans Cell granulomatosis
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- Bones (especially skull, spine, ribs, arms, legs)
- Skin
- Lungs
- Lymph nodes
- Bone marrow
- Spleen
- Liver
- Pituitary gland
- Thymus
- Central nervous system
