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Langerhans cell histiocytosis – 2015

UPDATED MAY 2015

1. GENERAL INFORMATION

1.1 What is the disease and how is it treated?

What is Langerhans cell histiocytosis? Langerhans cell histiocytosis is a disease in which a type of immune cells called Langerhans cells proliferate excessively for unknown reasons. It can affect one or more of several organs and present with a variety of symptoms, from mild and self-healing to life-threatening forms. It is not considered a cancer.
What are the causes of this disease? The causes of Langerhans cell histiocytosis are not known to date, but understanding of the aberrant pathways involved is improving.
Is it a frequent disease? The disease is very rare. Most patients diagnosed are children, but adults can get it too.
How is it treated? As the disease can appear in a variety of different forms, treatment varies from waiting for a spontaneous healing, to scraping out of a single lesion or local injection of drugs, to systemic drugs taken for many months.

 

2. WHAT IS IT, HOW DOES IT OCCUR, HOW IS IT DIAGNOSED?

2.1 What is Langerhans cell histiocytosis?

Histiocytoses are a group of disorders involving an abnormal increase in the number of histiocytes. Histiocytes are immune cells localized in many tissues to remove debris and toxic materials and to help fight infections. In Langerhans cell histiocytosis (formerly also known as histiocytosis X), a type of histiocytes called Langerhans cells proliferate excessively for unknown reasons, causing inflammation and forming a kind of nodules called granulomas. The disease can be acute or chronic. It can affect a single organ (single-system disease) at a single site (unifocal) or at multiple sites (multifocal), or may involve multiple organs (multisystem). According to its extension, its duration, and the affected locations, the disease can be mild and heal spontaneously leaving no consequences, or it can be more severe, sometimes requiring heavy therapies and leaving permanent damage. Sometimes the disease can relapse, even 20 years after its first appearance.

2.1.1 Disease stats

It is a rare disease. Most patients diagnosed are children, mostly between 1 and 3 years of age. In a Swedish study its incidence in children under the age of 15 years was estimated to be 9 cases per 1 million children per year, though it is probably more frequent because several cases go undetected. It is slightly more frequent in males, with around 1.2-2 affected boys for each girl. Incidence in the adult population is difficult to determine, as the disease can affect several organs with varied symptoms and is diagnosed by a variety of different specialists. It is estimated that 1 to 2 adult cases occur per 1 million adults per year. Though it is usually sporadic, sometimes it runs in families, as around 1% of patients have relatives with Langerhans cell histiocytosis.

2.2 Risk factors

The causes of Langerhans cell histiocytosis are unknown. Though cells proliferate excessively, the disease is not usually considered a cancer and it often regresses spontaneously. Many specialists see it as an inflammatory disease, perhaps in response to a virus infection, but there are no environmental risk factors associated for sure with the disease. In one study carried out in Minneapolis to investigate the issue, a number of neonatal infections and thyroid disease seemed to increase the risk, while childhood vaccinations and chickenpox infection seemed to reduce the risk, but further studies will be necessary to confirm this. In adults, smoking increases the number of Langerhans cells in the lungs and cigarette smoke increases the risk of developing severe pulmonary disease. As the disease sometimes occurs in twins, this suggests that in some cases there is probably a genetic predisposition.

2.3 What are the symptoms?

Langerhans cell histiocytosis may affect a number of different organs, so its symptoms may be extremely variable.

2.3.1 Bone

The system most commonly involved is the skeleton and around 85% of children have bone involvement at diagnosis. Doctors may come across a spectrum of findings ranging from a single painless bone lesion to multiple lesions in one or more bones, which may cause problems including dysfunction, pain, fractures, dental problems, back problems because of vertebral compression, and deformities. The skull, ribs, pelvis, vertebrae, mandible, feet and hands are most commonly affected. Some bone lesions may invade into adjacent soft tissues and cause swelling and compression of vital structures (e.g., optic nerve, spinal cord).

2.3.2 Skin

Cutaneous (skin) lesions are the second most common finding. Some 30-40% of children have skin involvement at diagnosis. Skin involvement usually begins with a scaly red rash (similar to seborrhoea) on the scalp, behind the ears and in the axillary, inguinal, or perineal (between the anus and genitals) areas, less often on the palms and soles, and sometimes with secondary infection. There may also be more discrete lesions with pinkish brown papulas scattered over the trunk, especially in the lower central (suprapubic and dorsal) areas. There may be purpura, petechiae, and also bleeding in the lesions, especially when the patient also has a low number of platelets (thrombocytopenia) because of the disease.

2.3.3 Lymph nodes

Lymph nodes may be enlarged, especially in the neck. Rarely, the enlargement can be massive and cause airway obstruction.

2.3.4 Ear

If the ear is involved there is usually pus, because of otitis or polyps of histiocytic tissue. A nearby bone of the skull, the mastoid, is often affected. In case of damage to the ossicles, which conduct sound in the middle ear, or to the vestibular system in the ear, which contributes to the sense of balance, hearing loss may follow.

2.3.5 Bone marrow

If the bone marrow is involved, various kinds of blood cells can be in low number (cytopenia), with problems such as anaemia (low red cell number) and low platelet number. This may cause an enlargement of liver and spleen, and may require transfusions.

2.3.6 Liver and spleen

Liver involvement may be severe and associated with reduced levels of albumin (hypoalbuminaemia), a major blood protein made by the liver, which may cause ascites and oedema. Liver involvement may also lead to slow blood coagulation (prolonged prothrombin time); or to inflammation and scarring of the bile ducts (sclerosing cholangitis), which may lead to high blood pressure in the portal vein (portal hypertension), which brings blood from the gastrointestinal tract and spleen to the liver. This can cause several liver problems and hypersplenism (see below). Spleen involvement may also lead to an enlarged, overactive spleen (hypersplenism) that removes the blood cells too quickly, causing low blood cell numbers.

2.3.7 Respiratory system

Pulmonary involvement in children is usually part of a multisystem disease that also involves other organs; while in adults the lung may be the only organ involved. It may cause various kinds of respiratory difficulties (tachypnoea, dyspnoea, recurring pneumothorax, fibrosis, sometimes with respiratory failure).

2.3.8 Gastrointestinal tract

The gastrointestinal tract can be involved with a range of symptoms from mouth ulcers to weight loss, diarrhoea with blood and/or mucus. Occasionally, the pancreas is involved.

2.3.9 Genital tract

The female genital tract may be involved at any age, but most commonly in young adulthood.

2.3.10 Hypothalamus and pituitary gland

The hypothalamus and the pituitary gland, or hypophysis, are two hormone-producing glands located beneath the brain that control several hormones in the body. Their dysfunction occurs in between 10%-50% of cases with multisystem involvement. The most frequent manifestation is diabetes insipidus. Often there is growth hormone deficiency, as well. Less common are growth retardation and other hormonal disorders.

2.3.11 Brain

The central nervous system may be involved many years after onset of the disease, causing difficulties in movement, speech, or swallowing (ataxia, dysarthria, dysphagia), exaggerated reflex responses to stimulations (hyperreflexia) and tremor. Recently, cognitive dysfunction has been recognized in long-term survivors.

2.4 Diagnosis

As Langerhans cell histiocytosis is rare and can be recognized only with specific exams, it may be missed because the physician fails to think of this possible diagnosis. If the disease is suspected, a biopsy of the affected organs (such as bone, skin, or colon) should be obtained. If only the lung is involved in adults, bronchial washings may be enough for confirmation and should usually be performed before biopsy, as it is less invasive. Diagnosis is based entirely on examinations of the biopsies by a pathologist. By examining the tissues microscopically with special treatments (such as a staining that reveals specific proteins), the pathologist can recognize specific signs of the disease (which may bear names like CD1a, Langerin, or Birbeck granules). However, these features may be difficult to recognize in some tissues (especially in the brain), or if the lesion is already healing, or they may be confused with signs of other diseases. So the first biopsy may not give a correct diagnosis and a further biopsy may be necessary. The biopsy can determine whether a lesion is caused by Langerhans cell histiocytosis, but it cannot distinguish if the disease is localized to just the examined lesion or if it is disseminated to several organs.

3. HOW IS LANGERHANS CELL HISTIOCYTOSIS TREATED?

3.1 General information

As the disease can present in several forms and affect different organs, treatment options vary considerably. Patients should be treated by a multidisciplinary team of health professionals who have a specific experience with this disease, as it is a rare disease, which is not widely known even within the medical community. The US Histiocytosis Association (https://www.histio.org) or the European His­tio-Net (http://www.eurohistio.net/e1610/index_eng.html) can help you find an expert and get more information.

3.2 Single-system Langerhans cell histiocytosis in children

When the disease involves only one organ system (single-system Langerhans cell histiocytosis), it most often involves the bone, skin, lymph nodes, or lungs. The two major aims of therapy are to provide relief of symptoms and reduce permanent damage.

3.2.1 Single bone lesions

Treatment options for single bone lesions include wait-and-see, oral indomethacin, curettage, intralesional steroid injections, bisphosphonates, or radiation. In case of a single bone lesion with mild or no symptoms and no risk of permanent damage, wait-and-see or diagnostic curettage (which often is followed by healing) are standard options. In some specific cases, oral indomethacin, an analgesic drug, which might also have anti-inflammatory effects, reducing the activity of the disease, may also be considered. If there are symptoms or there is a risk of permanent damage (growth impairment, fracture, loss of hearing, loss of permanent teeth, other unacceptable dysfunction or deformities), more active therapy may be necessary, but there are no firmly established standard protocols for a generic patient, and the decision has to be taken on a case-by-case basis. If treatment is needed, the preferred choice is usually injection of steroids (such as methylprednisolone) into the lesion, which commonly allows symptomatic relief. Low-dose radiation can be considered if it is not possible to inject drugs into the lesion but treatment is important to preserve function, however, it is used only in rare cases because radiation increases the risk of subsequent cancer.

3.2.2 Multifocal bone disease

If there are multiple bone lesions (multifocal bone disease), the clinical picture varies considerably, ranging from a few non-symptomatic lesions to a large number of lesions, and the treatment approach varies accordingly. Treatment options have to be selected on a case-by-case basis, and include wait-and-see (as spontaneous remissions may occur) or local treatment of more symptomatic lesions, including curettage and injection of local steroids (see above «Single-bone lesions»). Radiation, in low doses, can be considered where treatment is important to preserve function and no other therapy is available, but it is rarely used nowadays because of its risks. In some patients, especially if there are several symptomatic lesions, systemic chemotherapy is a suitable option, as recent data suggest that a more active approach may lead to less permanent damage in these patients. An international treatment protocol (called LHC-IV) is currently being tested, in which a two-drug regimen (vinblastine and prednisolone) for 6 or 12 months is suggested to all patients with multiple bone lesions or with a single cranial lesion that poses a risk to the brain.

3.2.3 Skin lesions

If only the skin is involved, the standard choices are wait-and-see or local therapy (e.g., topical steroid creams). In some cases, application on the skin lesion of a solution with nitrogen mustard at low doses may be advised (nitrogen mustard may have serious side effects when injected at high doses, but it is safe if applied on the skin at low doses).

3.2.4 Lymph nodes

If only lymph nodes are involved (lymphadenopathy), no treatment is usually necessary, since most patients recover spontaneously. However, it is important to assess whether the disease really involves only the lymph nodes or if it spread to the lymph nodes from other organs. In some cases, if the lesions do not heal, surgical removal or chemotherapy may be needed.

3.2.5 Lung

If the disease is damaging the lungs and affecting their function, systemic chemotherapy may be needed to reduce further tissue destruction. In addition, it is important that smokers quit smoking.

3.3 Multisystem Langerhans cell histiocytosis in children

When two or more organ systems are involved in children (multisystem Langerhans cell histiocytosis), the major aim of treatment is to increase survival and to accelerate regression of active disease so that late effects are reduced. Recent data indicate that systemic chemotherapy can be advisable in some patients, since it may increase survival, as well as reduce the number of permanent consequences. Corticosteroids and vinblastine for a period between 6 and 12 months are the most commonly used chemotherapeutic agents. Other drugs (such as 6-mercaptopurine or methotrexate) may be added, as there are some indications that intensified treatment increases rapid response and reduces mortality in at-risk multisystem patients. Several other drugs are being investigated and may be proposed; for example, one drug (vemurafenib) may help patients who harbour a specific gene mutation (BRAF V600E); other drugs may be considered when the disease does not improve with standard therapy. However the choice has to be made on a case-by-case basis. If the disease is aggressive, does not improve with drugs, and a suitable donor is available, bone marrow transplantation can be a suitable option. If the liver or lungs suffered severe damage, a liver transplant or heart-lung transplant can be considered, even if other organs are affected and the disease may recur in the transplanted organ.

3.4 Langerhans cell histiocytosis in adults

There are no exhaustive studies regarding how treatment for adult patients should differ from therapies for children. However, consensus recommendations for the diagnosis, therapy, and follow up of adult patients, are available to the physician.

3.5 Juvenile xanthogranuloma

Juvenile xanthogranuloma is a benign histiocytic lesion of the skin that usually occurs in neonates and young children. Usually, it persists for 1 to 2 years and then spontaneously resolves. Therefore, an initial wait-and-see approach is standard. In patients with more active disease, surgical excision of lesions may be curative. Only in some cases, systemic chemotherapy or radiation therapy may be needed. Juvenile xanthogranuloma and Langerhans cell histiocytosis can occur in the same patient.

3.6 Treatment of late consequences

Permanent consequences associated with Langerhans cell histiocytosis are common, and, rather than being the consequence of therapy – as in survivors of child cancer – they are most often the result of tissue destruction caused by the disease activity itself. Reactivation of the disease after remission occurs frequently and early in multisystem disease. Reactivations increase the risk for permanent consequences by about 2-fold, but they seldom involve risk organs (see below) and mortality is minimal. Regarding the frequency of late consequences, in one study in which patients were followed for an average of 16 years, late consequences had developed in 42% of the patients, more frequently in those with multisystem disease. The most common disabilities were diabetes insipidus (15%), neurological complications (10%) and pulmonary fibrosis (11%). Brain symptoms usually manifest many years after the diagnosis of Langerhans cell histiocytosis, and often when the disease is considered quiescent. This neurodegeneration may be progressive, causing severe symptoms, such as tremor and motor and speech difficulties (ataxia and dysarthria). Changes in personal behaviour, judgement, and cognitive function (such as memory or attention) may also occur. A brain imaging exam (gadolinium-enhanced MRI) is the best way to detect brain abnormalities. There is as yet no established therapy, though treatment reducing inflammation within the brain could also reduce secondary brain damages. A treatment (high dose immunoglobulin) has been suggested to reduce the incidence of neurodegeneration, but further studies are needed to confirm it.

3.7 Related and secondary tumours

Patients with Langerhans cell histiocytosis seem to have an increased risk of subsequent cancer, as a 5% incidence of cancer, especially leukaemia, has been reported in long-term survivors, a frequency which is higher than expected from chance alone. In addition, if radiotherapy was performed, solid tumours may arise in irradiated areas (particularly sarcoma and brain tumours), so radiation therapy, even at low doses, is discouraged unless there is no reasonable alternative.

4. STAGES

4.1 Staging classifications

Staging of a disease is the determination of distinct phases in its course, to help decide what exams and treatment the patient should undergo. The most common staging system for Langerhans cell histiocytosis is to distinguish between single-system disease (affecting only one organ/system, such as bones or skin or lymph nodes) and multisystem disease (when two or more organ systems are involved). Single-system disease of the bone can be separated into single-site or multiple-site involvement (one or more bones involved). A study in 170 patients in Vienna examined how frequent the different forms of single-system disease are. Single bone lesions were the most common (68%), followed by multiple bone lesions (19%), isolated skin disease (11%), and isolated lymph node disease (2%). In multisystem disease, the main distinction is between patients with and without involvement and damage to the functions of crucial organs such as the hematopoietic system, liver, or spleen. Patients without involvement of hematopoietic system, liver, or spleen have very high (>95%) probability of survival with a standard treatment, while the involvement of these organs increases the risk of a poor prognosis.

4.2 Staging procedures

When Langerhans cell histiocytosis is suspected, recommended investigations, in addition to a thorough clinical examination, are blood and urine tests (haemoglobin and/or haematocrit, white blood cell count and differential (the percentage of each type), platelet count; liver function tests such as serum transaminases, alkaline phosphatase, bilirubin, albumin and total protein; coagulation studies such as PT, PTT, fibrinogen; urine osmolarity and arginine vasopressin measurement) and chest and skeletal radiographs. In certain patients, to determine the involvement of abdominal organs such as liver or spleen, an ultrasound or CT of the abdomen may be indicated. In other cases, a CT scan of the chest may be useful for quantifying pulmonary involvement more accurately than with an ordinary chest radiograph. In adults and children able to cooperate, respiratory tests are performed to check lung function. Based on the organ involvements suspected, further diagnostic tests can be performed, such as a colonoscopy in patients with suspected gastrointestinal involvement. An MRI of the brain can be performed in patients with visual or neurologic problems, hormone deficiencies, or other symptoms suggestive of brain involvement, or with lesions in bones near the central nervous system. Another radiology test called PET-CT scan can also be performed to evaluate disease activity and response to therapy. Depending on symptoms, a biopsy and pathological examination of tissue samples from more than one organ may be necessary to define the number of organs involved.

5. PROGNOSIS

5.1 Natural history

The course of Langerhans cell histiocytosis may be quite variable. It may resolve spontaneously or, in a minority of cases, have a fatal outcome despite intensive treatment. It may reactivate unpredictably in one or more episodes that resolve with or without treatment, even many years (twenty or more) from onset. Permanent consequences are common. If the disease is localized solely to the bone, usually it tends to resolve spontaneously over a period of months to years, although there may be permanent consequences such as vertebral compression, bone deformities, growth impairment, loose teeth, and hearing impairment. Diabetes insipidus may already be present before the diagnosis of Langerhans cell histiocytosis and has been found in 10-50% of patients in different studies. It occurs more often among patients with multisystem disease and those with cranial bone involvement. Moreover, after 10 years with diabetes insipidus, most patients may also develop growth hormone deficiency. In patients with multisystem disease without organ dysfunction, around 50% suffer one or more long-term consequences, including small stature, growth hormone deficiency, diabetes insipidus, partial deafness, cerebellar ataxia, loss of permanent dentition, orthopaedic problems, pulmonary fibrosis and/or biliary cirrhosis with portal hypertension and also cognitive dysfunction. In adults with Langerhans cell histiocytosis, lung disease may be life-threatening and a mortality of around 25% has been reported.

5.2 Prognostic factors

Mortality is higher when more organs or systems are involved and especially if liver, lungs, hematopoietic system, or spleen are involved. Serious brain complications and diabetes insipidus are more frequent with multisystem disease and when cranial bones are involved. Risk organ involvement is more frequent in children who are less than 1 year old at diagnosis. Older patients tend to have a worse outcome, too. Patients who respond early to therapy have a better chance of a good outcome. Those who do not respond after the first 6 weeks of systemic treatment are at a high risk of poor outcome.

6. WHAT TO DO AFTER TREATMENT

Since the course of Langerhans cell histiocytosis is so variable, the main objective in follow-up is to monitor disease activity. Other tests such as regular blood counts may be needed to monitor the effects of therapies, e.g., if the patient requires chemotherapy. Even simple single-lesion disease may evolve into multisystem disease. Unfortunately, there is at present no reliable single exam that can monitor disease activity. Patients should be treated and followed up according to protocols and guidelines developed by the Histiocyte Society (the scientific society of specialists in histiocytosis; www.histiocytesociety.org). These protocols detail a series of exams to monitor patients in remission (such as blood tests and imaging or functional evaluation of the organs that were involved), in addition to clinical examination.

7. WHAT TO ASK DOCTORS

Here is a list of questions that you might wish to ask your doctor. As the disease is rare, it is not widely known even within the medical community, so your family doctor or paediatrician might be unsure about the answers to some of these questions and you might want to ask them when you consult a specialist.

General questions

  • Is Langerhans cell histiocytosis a cancer?
  • If it is caused by a virus, could a patient infect other people?
  • Is there any contraindication in living with a pet?
  • What should I do if the pain increases, or if it appears in other parts of the body?
  • May I phone you? What is the best time? If you are not available, may I ask for other specialists? Whom specifically?
  • What leaflets, books, or websites could I read to learn more about Langerhans cell histiocytosis?
  • Is there a patient association I could contact?
  • How will the disease affect the growth of my child?
  • Will my child be able to go to school regularly?
  • Should I pay special attention to my child’s activities, such as playing or sports?
  • Do you have special advice regarding my child’s nutrition?
  • Is there any contraindication regarding vaccinations?

Diagnosis and exams

  • Is biopsy painful? Is it performed under general or local anaesthesia?
  • What should I do in preparation for a CT scan or MRI?
  • How long will the exam take?
  • Is it painful?
  • Will the child be asleep?
  • Are CT or MRI dangerous because of radiation exposure?
  • How is bronchial washing performed? How will I breathe during the exam? Will I be asleep or awake?
  • How long will it take to confirm diagnosis?
  • Is the result of biopsy and bronchial washing reliable?

Treatment

  • If the doctor suggests a wait-and-see approach, could the disease get worse while waiting?
  • What signs should I recognize so that I can tell the doctor and ask if the approach needs to be changed?
  • Is surgical removal of lesions performed under general or local anaesthesia? Will it be painful? What should I do before and after the surgery?
  • What are the possible side effects of chemotherapy? Will I lose my hair? Will I have nausea and vomiting?
  • Will I have fertility problems because of the disease or treatment?
  • Will treatment reduce my pain?
  • During treatment should I take special precautions or change my habits?