Langerhans' cell histiocytosis

Langerhans cell histiocytosis (LCH) is a rare condition which can occur in children and adults. About 1 in 200,000 children have this condition and there are about 50 new cases in the UK each year. LCH is more common in boys.

Histiocytes are types of white blood cells which help fight infection. In LCH, histiocytes grow excessively and can gather in bones, skin, lymph nodes, lungs, bone marrow or the pituitary gland. This can cause a variety of problems like pain in the bone, skin rash, swollen tummy, or breathing difficulties.

There has been a longstanding debate as to whether LCH is cancer. The discovery of the BRAF V600E gene mutation in LCH cells in 2010 serves as evidence that histiocytes in LCH lesions have genetic abnormalities like those seen in some cancers. Although these findings support the notion that LCH is a cancer, the way that LCH affects people is rather different to other cancers as LCH can present in a range of ways, from a very mild form that resolves spontaneously without any treatment to an aggressive form which requires treatment.

It is very important to keep in mind that genetic abnormalities are present only in LCH cells, and not in the other normal, healthy cells of the patient.

The signs and symptoms will depend on many factors including which part of the body is affected. LCH can be divided into two groups:

1. Single system LCH – if only one part of the body is affected (such as only in the bone, skin or lymph node).
2. Multisystem LCH – if two or more parts of the body are affected (such as in both skin and bones at the same time; or in skin, bones and bone marrow at the same time, etc).

• LCH often presents as a pain in the bone or lump on the skull. This might cause pain or discomfort.
• LCH of the skin can cause persistent nappy rash or cradle cap.
• LCH in the abdomen can cause a swollen tummy, jaundice or diarrhoea.
• LCH in the ears can cause discharge from the ears.
• Multisystem LCH might have a combination of these symptoms.

Symptoms of LCH are quite general and, as the disease is very rare, children often visit several doctors before the diagnosis is suspected. The diagnosis of LCH is usually made by performing a biopsy of an affected part of the body. A biopsy is the removal of a small piece of tissue under general anaesthesia in a specialist children’s hospital. This tissue is then examined under a microscope, and several additional tests may be performed on the tissue to detect any genetic abnormalities that might be present in the LCH cells.

Further tests will be done to examine whether other parts of the body are affected. These include x-rays, ultrasound scans, blood tests, urine tests, or CT or MRI scans if necessary.

Treatment of LCH depends on the position and extent of the LCH lesions.

Single system LCH often requires minimal treatment. A single bone lesion might heal itself following a biopsy and often no further treatment is needed. Skin lesions might need topical creams or ointments only. However, in multisystem LCH, chemotherapy if often needed. Chemotherapy in LCH is usually mild and is delivered in the Day Care Unit, and it is rare that children become very sick or need intensive treatment. Only in cases of widespread multisystem disease in very young children is the treatment more demanding and likely to require inpatient stay.

Chemotherapy can cause side effects such as nausea, vomiting, tiredness, and hair loss. Some of the side effects can be reduced with supportive care. Your doctor will discuss this with you before treatment begins. It is important to remember the side effects generally last only as long as the duration of the treatment.

In very rare cases when treatment with chemotherapy does not work or when there are complications from chemotherapy, specific targeted therapy can be administered. This treatment is not approved by the NHS at present and has several additional implications especially in terms of the duration of therapy. If this treatment is required, your doctor will discuss this with you in detail.

Most children are cured from LCH and there is a greater than 90% survival rate. However, in about a quarter of children with multisystem disease, the disease might reactivate after they stop treatment, and they might need to be treated again. The good news is that the treatment is usually effective when restarted.

Once the treatment is completed, patients will have regular and ongoing follow-up for five years to ensure there are no signs of the disease reactivating. Following this period, they will be transferred to the Late Effects Clinic where their wellbeing, development and general health will be monitored until the age of 18 years. Following this, they may be transitioned to an adult hospital if needed and cared for by doctors who specialise in managing adults who had LCH in childhood.

Children with LCH might still develop late complications, many years after they finished treatment. This could be in the form of condition called “diabetes insipidus” (water diabetes), where children drink large amounts of water and produce excessive amounts of urine. Diabetes insipidus is usually a lifelong condition but can be successfully managed with replacement hormone taken orally as a tablet or a spray. In rare occasions, growth can be affected, which also requires careful diagnosis and treatment.

Neurodegenerative LCH is a very rare but potential complication of LCH. If it does occur, it is usually in children with particular risk factors about 6 to 7 years after treatment for LCH is completed. We currently do not know why it occurs in certain patients, but the symptoms include balance problems, sudden development of clumsiness, tremors (slight shaking movements), and changes in behaviour or memory. Your doctor will look out for this complication as part of follow-up, and if it develops, they will discuss the treatment with you in detail.

Children with LCH are more likely to get lung disease triggered by smoking so all family members of children diagnosed with LCH must not smoke. This includes not smoking even outside of the house. A child or teenager diagnosed with LCH should never smoke either as the lung disease in LCH can be a very severe complication.

Some other histiocytoses are occasionally encountered in children. These are known as non-Langerhans cell histiocytoses and the most common are:

Juvenile xanthogranuloma (JXG) is the most common type of non-LCH histiocytosis in children. It usually presents at birth or before one year of age, and rarely in adulthood. It is more common in boys.

The cause of JXG is unknown but there is the possibility it could be a non-specific response to injury or viral infection, or similarly to LCH due to a gene mutation in the JXG cells.

JXG most often presents as yellow to red round lesions on the skin, with the commonest site being the head and neck. However, JXG can also arise on the limbs, trunk, hands, feet, mouth, or around the eyes. The skin lesions are usually smooth and firm but can break and form an ulcer. Lesions progress from red to yellow to brown before fading and disappearing spontaneously.

Very rarely the lesions can involve the back of the eye, as well as internal organs, such as liver, spleen, pancreas, kidneys and more rarely the brain.

The diagnosis is made on a biopsy of the skin lesion. This is examined under microscope and further tests might be performed. Clinical examination of the skin and body, x-rays, ultrasound of the abdomen and, if required, CT scan or MRI are the investigations that will be performed once the diagnosis is established. Blood tests and examination by a specialist eye doctor are also required.

In the majority of cases, JXG resolves spontaneously over a period of time, usually 3-6 years, so patients often need observation only. The skin lesions change colour from red to yellow and eventually turn brown, flatten out, and completely disappear usually without any scarring.

If JXG involves internal organs such as the liver, spleen, kidneys, or brain, it might also resolve spontaneously with no treatment, but there is a possibility that chemotherapy might be needed to control the disease in some cases. Like LCH, the chemotherapy given is often a mild regimen and children do not need to be hospitalised. In exceptional circumstances children might require more aggressive therapy needing inpatient stay and, in some cases, targeted therapy. Your doctor will discuss all the treatment options prior to commencing any therapy.

Rosai-Dorfman disease (RDD) is a rare histiocytic disorder which results from the overproduction of a type of white blood cell called non-Langerhans-cell sinus histiocytes. These cells grow and accumulate in the lymph nodes making them swollen and very large but can sometimes accumulate in the other areas of the body including skin, bones, internal organs and brain. RDD can also occur in association with autoimmune or immune disease and these sometimes need to be excluded. The cause of RDD is not known but it can occur as a reaction to viral or bacterial infections. As in other histiocytoses, there can be genetic changes in the abnormal cells. RDD is most commonly seen in the first 10 years of life.

Work-up for RDD includes an ultrasound scan of the lymph nodes, x-rays and other imaging studies. Patients require a biopsy under general anaesthesia and examination of the tissue under the microscope is performed to make the diagnosis.

Simple observation is often all that is required as RDD will resolve spontaneously in 20-50% of patients with lymph node or skin disease. If treatment is required, this might include surgery, steroids, chemotherapy, or targeted therapy. Your doctor will discuss all the treatment options prior to commencing any therapy.

Please be advised that all the information you read here is not a replacement for the advice you will get from your consultant and their team.

Dr Olga Slater – is a consultant paediatric oncologist with large experience in histiocytoses. Dr Slater is a member of the National Histiocytosis Advisory Panel, the European Consortium for Histiocytosis (ECHO) and a member of the LCH Steering Committee within the Histiocyte Society.

Dr Trung Nguyen – is a consultant paediatric oncologist who co-chairs the National Histiocytosis Advisory Panel. Dr Nguyen is also an executive board member of the European Consortium for Histiocytosis (ECHO) and a member of the Histiocyte Society.

Dr Vasanta Nanduri – is a consultant paediatric oncologist with large experience in managing children with LCH, particularly the longer-term complications of LCH. Dr Nanduri is an Investigator on the international LCH-IV clinical trial, and a member of the National Histiocytosis Advisory Panel and the European Consortium for Histiocytosis (ECHO). She is also President-Elect of the Histiocyte Society.

Dr Slater and Dr Nguyen provide acute and late effect care for all the children with histiocytoses. Dr Nanduri provides late effect care for children with LCH.

1. Histiocytosis Research Trust.
2. Patient and Parent Support Group for Histiocytosis
3. Children Caner and Leukaemia Group
4. Histiocyte Society