What is eosinophilic granuloma

Eosinophilic granuloma now known as Langerhans cell histiocytosis, is a group of rare disorders in which too many Langerhans cells (a type of white blood cell) grow in certain tissues and organs including the bones, skin, and lungs, and damage them ¹, ², ³, ⁴, ⁵, ⁶, ⁷, ⁸, ⁹. Eosinophilic granuloma is a rare, benign tumor-like disorder characterized by clonal proliferation of antigen-presenting mononuclear cells of dendritic origin known as Langerhans cells ¹⁰. In people with eosinophilic granuloma (Langerhans cell histiocytosis), Langerhans cells or histiocytes cells multiply excessively and build up in certain areas of the body, causing tumors called granulomas to form. Langerhans cells have now been shown to likely derive from a myeloid precursor whose proliferation is uniformly associated with activation of the MAPK/ERK signaling pathway ¹¹, ¹². Eosinophilic granuloma (Langerhans cell histiocytosis) is a disorder that primarily affects children, but is also found in adults of all ages. Eosinophilic granuloma (Langerhans cell histiocytosis) is often less aggressive in adults than in children. Liver, spleen, and lymph node involvement are relatively uncommon in adults. Eosinophilic granuloma of bone is the most common manifestation of Langerhans-cell histiocytosis (60–80 % cases), accounting for less than 1 % of all bone tumors ¹³. In 80% of cases eosinophilic granuloma affects children and adolescents ¹⁴. Eosinophilic granuloma can affect any bone in the skeleton; however, bone lesions are more common in the skull, mandible, spine, ribs, and long bones; the femur, humerus and clavicle are the most frequent sites ¹⁵. The pathogenesis is unclear; viruses such as Epstein-Barr virus (EBV) and human herpes virus-6, bacteria, and genetic factors have been implicated ¹³. An immunological dysfunction including an increase of certain cytokines such as interleukin-1 (IL-1) and interleukin-10 (IL-10) in affected patients has also been reported; familial occurrence is very rare ¹⁶. In the spine, eosinophilic granuloma accounts for 6.5–25 % of all spinal bone tumors ¹⁴. The most common location is the thoracic spine followed by the lumbar and the cervical spine ¹⁷. Clinical symptoms are often severe and depend on spinal location ¹⁸. The most common include back or neck pain, tenderness to spinal palpation and restricted range of motion, or torticollis; spinal instability and neurological symptoms are uncommon ¹⁷. In the extremities, most lesions are diaphyseal ¹⁹. The physical examination of the child may be essentially normal. Laboratory findings are usually non-specific except for a moderate and inconsistent rise in erythrocyte sedimentation rate (ESR).

Eosinophilic granuloma (Langerhans cell histiocytosis) is described as single-system disease or multisystem disease, depending on how many body systems are affected:

• Single-system eosinophilic granuloma (Langerhans cell histiocytosis): Eosinophilic granuloma (Langerhans cell histiocytosis) is found in one part of an organ or body system (unifocal) or in more than one part of that organ or body system (multifocal). Bone is the most common single place for eosinophilic granuloma (Langerhans cell histiocytosis) to be found.
• Multisystem eosinophilic granuloma (Langerhans cell histiocytosis): Eosinophilic granuloma (Langerhans cell histiocytosis) is found in two or more organs or body systems or may be found throughout the body. Multisystem eosinophilic granuloma (Langerhans cell histiocytosis) is less common than single-system eosinophilic granuloma (Langerhans cell histiocytosis).

Eosinophilic granuloma (Langerhans cell histiocytosis) may affect low-risk organs or high-risk organs:

• Low-risk organs include the skin, bone, lungs, lymph nodes, gastrointestinal tract, pituitary gland, thyroid gland, thymus, and central nervous system (CNS).
• High-risk organs include the liver, spleen, and bone marrow.

The typical radiographic appearance of eosinophilic granuloma of the extremities is a punched-out lytic-bone lesion without reactive sclerosis. In most cases, a hypervascularized soft-tissue mass surrounds the affected bone ²⁰. The radiographic differential diagnosis should include plasmacytoma, multiple myeloma, osteochondritis, tuberculosis or osteomyelitis. In the spine, imaging studies may reveal variable vertebral involvement, ranging from isolated lytic lesions to a more significant vertebral collapse that involves the pedicles and posterior vertebral elements (vertebra plana), peridural spread and paraspinal soft tissue components ²¹. Although eosinophilic granuloma is the most common cause of vertebra plana, this finding can also be found in Ewing’s sarcoma, lymphoma and other sarcomas, infections such as tuberculosis, and osteogenesis imperfect ²². In favor of the eosinophilic granuloma are the isolated spinal disease, the lack of constitutional symptoms, and minimal laboratory abnormalities ²². Cervical spine eosinophilic granuloma more often manifests with osteolytic lesions, rather than vertebra plana ²¹.

Treatment for Langerhans cell histiocytosis (eosinophilic granuloma) depends upon the individual patient; it may differ depending on the type and severity of the condition as well as what part(s) of the body are affected. In some cases, the disease will go away without any treatment at all. In other cases, depending on the extent of the disease, limited surgery and small doses of radiation therapy or chemotherapy may be needed. Treatment is planned after complete evaluation of the patient, with the goal of using as little treatment as possible to keep the disease under control ²³.

No consensus exists for the best therapy for eosinophilic granuloma (Langerhans cell histiocytosis), especially when multiple organs are involved. However, the Histiocyte Society has done many clinical trials to evaluate the effect of several treatments, which have resulted in recommendations by the Histiocyte Society.

Nine types of standard treatment are used to treat eosinophilic granuloma (Langerhans cell histiocytosis):

1. Chemotherapy. Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Chemotherapy that is taken by mouth or injected into a vein or muscle enters the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). Chemotherapy may also be applied to the skin in a cream or lotion (topical chemotherapy). Chemotherapy may be given by injection, by mouth, or applied to the skin to treat eosinophilic granuloma (Langerhans cell histiocytosis).
2. Surgery. Surgery may be used to remove eosinophilic granuloma (Langerhans cell histiocytosis) lesions and a small amount of nearby healthy tissue. Curettage is a type of surgery that uses a curette (a sharp, spoon-shaped tool) to scrape eosinophilic granuloma (Langerhans cell histiocytosis) cells from bone. When there is severe liver or lung damage, the entire organ may be removed and replaced with a healthy liver or lung from a donor.
3. Radiation therapy. Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. External radiation therapy uses a machine outside the body to send radiation toward the area of the body with cancer. Ultraviolet B (UVB) radiation therapy may be given using a special lamp that directs radiation toward eosinophilic granuloma (Langerhans cell histiocytosis) skin lesions.
4. Photodynamic therapy. Photodynamic therapy is a cancer treatment that uses a drug and a certain type of laser light to kill cancer cells. A drug that is not active until it is exposed to light is injected into a vein. The drug collects more in cancer cells than in normal cells. For eosinophilic granuloma (Langerhans cell histiocytosis), laser light is aimed at the skin and the drug becomes active and kills the cancer cells. Photodynamic therapy causes little damage to healthy tissue. Patients who have photodynamic therapy should not spend too much time in the sun. In one type of photodynamic therapy, called psoralen and ultraviolet A (PUVA) therapy, the patient receives a drug called psoralen and then ultraviolet A radiation is directed to the skin.
5. Immunotherapy. Immunotherapy is a treatment that uses the patient’s immune system to fight cancer. Substances made by the body or made in a laboratory are used to boost, direct, or restore the body’s natural defenses against cancer. Thalidomide is a type of immunotherapy used to treat eosinophilic granuloma (Langerhans cell histiocytosis).
6. Targeted therapy. Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells. There are different types of targeted therapy:
   • BRAF inhibitors block proteins needed for cell growth and may kill cancer cells. The BRAF gene is found in a mutated (changed) form in some eosinophilic granuloma (Langerhans cell histiocytosis) and blocking it may help keep eosinophilic granuloma (Langerhans cell histiocytosis) cells from growing.
     • Vemurafenib and dabrafenib are BRAF inhibitors used to treat eosinophilic granuloma (Langerhans cell histiocytosis).
     • Trametinib is a BRAF inhibitor that is being studied in the treatment of certain childhood tumors for use alone or combined with dabrafenib.
   • Monoclonal antibodies are immune system proteins made in the laboratory to treat many diseases, including cancer. As a cancer treatment, these antibodies can attach to a specific target on cancer cells or other cells that may help cancer cells grow. The antibodies are able to then kill the cancer cells, block their growth, or keep them from spreading. Monoclonal antibodies are given by infusion. They may be used alone or to carry drugs, toxins, or radioactive material directly to cancer cells.
     • Rituximab is a monoclonal antibody used to treat eosinophilic granuloma (Langerhans cell histiocytosis).
7. Other drug therapy. Other drugs used to treat eosinophilic granuloma (Langerhans cell histiocytosis) include the following:
   • Steroid therapy, such as prednisone, is used to treat eosinophilic granuloma (Langerhans cell histiocytosis) lesions.
   • Bisphosphonate therapy (such as pamidronate, zoledronate, or alendronate) is used to treat eosinophilic granuloma (Langerhans cell histiocytosis) lesions of the bone and to lessen bone pain.
   • Anti-inflammatory drugs are drugs (such as pioglitazone and rofecoxib) that are commonly used to decrease fever, swelling, pain, and redness. Anti-inflammatory drugs and chemotherapy may be given together to treat adults with bone eosinophilic granuloma (Langerhans cell histiocytosis).
8. Stem cell transplant. Chemotherapy is given to kill cancer cells. Healthy cells, including blood-forming cells, are destroyed by the eosinophilic granuloma (Langerhans cell histiocytosis) treatment. Stem cell transplant is a treatment to replace the blood-forming cells. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient or a donor and are frozen and stored. After the patient completes chemotherapy, the stored stem cells are thawed and given back to the patient through an infusion. These stem cells grow into (and restore) the body’s blood cells.
9. Observation. Observation is closely monitoring a patient’s condition without giving any treatment until signs or symptoms appear or change.
10. Clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment. Whenever possible, patients should take part in a clinical trial in order to receive new types of treatment for eosinophilic granuloma (Langerhans cell histiocytosis). Some clinical trials are open only to patients who have not started treatment.

Generally, the choice of treatment is based on disease severity. The International eosinophilic granuloma (Langerhans cell histiocytosis) Study of the Histiocyte Society proposes classifying eosinophilic granuloma (Langerhans cell histiocytosis) cases by the number of systems involved and by the number of sites within that system (e.g., involving one or more bones, involving one or multiple lymph nodes). Although most of the trials are in children, the recommendations can also be used for adults.

Many patients with eosinophilic granuloma (Langerhans cell histiocytosis) get better with treatment. However, when treatment stops, new lesions may appear or old lesions may come back. This is called reactivation (recurrence) and may occur within 1 year after stopping treatment. Patients with multisystem disease are more likely to have a reactivation. Common sites of reactivation are bone, ears, or skin. Diabetes insipidus also may develop. Less common sites of reactivation include lymph nodes, bone marrow, spleen, liver, or lung. Some patients may have more than one reactivation.

Eosinophilic granuloma causes

The cause of eosinophilic granuloma (Langerhans cell histiocytosis) is unknown and continues to be a debate; however, most agree that eosinophilic granuloma (Langerhans cell histiocytosis) is either a reactive or neoplastic process ²⁴. However, somatic mutations in the BRAF gene have been identified in the Langerhans cells of about half of people with eosinophilic granuloma (Langerhans cell histiocytosis). Somatic gene mutations are acquired during a person’s lifetime, which means they are acquired after conception and are only present in certain cells. Because they are not present in the germ cells (egg and sperm), they are not passed on to the next generation (are not inherited) ²⁵.

The BRAF gene provides instructions for making a protein that is normally switched on and off in response to signals that control cell growth and development. Somatic mutations cause the BRAF protein in affected cells to be continuously on and to transmit messages to the nucleus even in the absence of these chemical signals. The overactive protein may contribute to the development of eosinophilic granuloma (Langerhans cell histiocytosis) by allowing the Langerhans cells to grow and divide uncontrollably ²⁵.

The protein produced by the BRAF gene is part of a signaling pathway known as the RAS/MAPK pathway, which controls several important cell functions. Specifically, the RAS/MAPK pathway regulates the growth and division (proliferation) of cells, the process by which cells mature to carry out specific functions (differentiation), cell movement (migration), and the self-destruction of cells (apoptosis). Chemical signaling through this pathway is essential for normal development before birth ²⁵.

The BRAF gene belongs to a class of genes known as oncogenes. When mutated, oncogenes have the potential to cause normal cells to become cancerous. Changes in other genes such as the MAP2K gene (20% of the cases), and other rarer genes (also involved in the RAS/MAPK pathway), have also been identified in the Langerhans cells of some people with eosinophilic granuloma (Langerhans cell histiocytosis). Some researchers believe that additional factors, such as viral infections and environmental toxins, may also influence the development of this complex disorder ²⁵.

Family members of eosinophilic granuloma (Langerhans cell histiocytosis) patients have a higher incidence of thyroid disease. Smoking is strongly associated with lung eosinophilic granuloma (Langerhans cell histiocytosis) ²³.

Although Langerhans cell histiocytosis is generally considered a sporadic, non-hereditary condition, it has reportedly affected more than one individual in a family in a very limited number of cases (particularly identical twins) ²⁶.

Eosinophilic granuloma has multiple cytokines involved, there is good survival in isolated lesions, and it can have spontaneous remissions. These characteristics support a reactive process.

However, eosinophilic granuloma (Langerhans cell histiocytosis) 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 ²⁷.

Eosinophilic granuloma (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, eosinophilic granuloma (Langerhans cell histiocytosis) 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 ²⁸.

Risk factors for eosinophilic granuloma

Anything that increases a person’s risk of getting a disease is called a risk factor. Not every child with one or more of these risk factors will develop eosinophilic granuloma (Langerhans cell histiocytosis), and it will develop in some children who don’t have any known risk factors. Talk with your doctor if you think you may be at risk.

Family history of cancer or having a parent who was exposed to certain chemicals may increase the risk of eosinophilic granuloma (Langerhans cell histiocytosis) ²⁹.

Risk factors for eosinophilic granuloma (Langerhans cell histiocytosis) may include the following ²⁹:

• Having a parent who was exposed to certain solvents.
• Having a parent who was exposed to metal, granite, or wood dust in the workplace.
• Having a family history of cancer or eosinophilic granuloma (Langerhans cell histiocytosis).
• Having a personal history or family history of thyroid disease.
• Having infections as a newborn.
• Smoking, especially in young adults.
• Being Hispanic.
• Not being vaccinated as a child.

Eosinophilic granuloma symptoms

Symptoms and signs of eosinophilic granuloma (Langerhans cell histiocytosis) vary considerably depending on which organs are infiltrated.

Patients are divided into 2 groups based on organ involvement:

1. Single system: Single system disease is unifocal or multifocal involvement of one of the following organs: bone, skin, lymph nodes, lungs, central nervous system, or other, rare locations (eg, thyroid, thymus). An example of single system disease is eosinophilic granuloma. Unifocal or multifocal eosinophilic granuloma (60 to 80% of Langerhans cell histiocytosis cases) occurs predominantly in older children and young adults, usually by age 30; incidence peaks between ages 5 and 10 years. Lesions most frequently involve bones, often with pain, the inability to bear weight, or both and with overlying tender (sometimes warm) swelling.
   
2. Multisystem: Multisystem disease is disease in two or more organ systems. Risk organs may or not be affected. An example of multisystem disease without risk organ involvement is Hand-Schüller-Christian disease. An example of multisystem disease with risk organ involvement is Letterer-Siwe disease. In a large series of patients from the Mayo Clinic, 31% had multisystem eosinophilic granuloma (Langerhans cell histiocytosis) compared with 69% registered on the Histiocyte Society adult registry; this likely reflects referral bias ³⁰. In the adult multisystem patients, the sites of disease included the following:
   1. Bone involvement can cause pain, often in a very specific area where the disease is eroding the bone. The most commonly affected bones are the skull, jaw (particularly the lower jaw), ribs, pelvis, and vertebrae, but any bone can be affected.
   2. Skin (50%). Skin involvement often presents as single or multiple small red lumps, but the skin rash can also be flat, itchy, and flaky much like eczema or psoriasis. The scalp, ear canals, and vulva are common sites of skin involvement. Some patients develop mouth sores similar to canker sores, but often larger and flatter.
   3. Mucocutaneous (40%).
   4. Diabetes insipidus (29.6%). In diabetes insipidus, your body is unable to make the hormone that allows the kidneys to reabsorb water. Conditions that cause the brain to make too little antidiuretic hormone (ADH) or vasopressin or disorders that block the effect of antidiuretic hormone (ADH) or vasopressin cause patients can have extreme thirst or make too much urine.
      1. Adults typically urinate an average of 1 to 3 quarts (about 1 to 3 liters) a day. People who have diabetes insipidus and who drink a lot of fluids may make as much as 20 quarts (about 19 liters) of urine a day. Symptoms of diabetes insipidus in adults include:
         • Being very thirsty, often with a preference for cold water.
         • Making large amounts of pale urine.
         • Getting up to urinate and drink water often during the night.
      2. A baby or young child who has diabetes insipidus may have these symptoms:
         • Large amounts of pale urine that result in heavy, wet diapers.
         • Bed-wetting.
         • Being very thirsty, with a preference for drinking water and cold liquids.
         • Weight loss.
         • Poor growth.
         • Vomiting.
         • Irritability.
         • Fever.
         • Constipation.
         • Headache.
         • Problems sleeping.
         • Vision problems.
3. Hepatosplenomegaly (16%). Liver involvement usually does not cause symptoms, but is detected by blood work or scans. Spleen involvement can be detected on physical exam or by a decrease in blood counts.
4. Hypothyroidism (underactive thyroid) (6.6%).
   1. Hypothyroidism symptoms in adults may include:
      1. Tiredness.
      2. More sensitivity to cold.
      3. Constipation.
      4. Dry skin.
      5. Weight gain.
      6. Puffy face.
      7. Hoarse voice.
      8. Coarse hair and skin.
      9. Muscle weakness.
      10. Muscle aches, tenderness and stiffness.
      11. Menstrual cycles that are heavier than usual or irregular.
      12. Thinning hair.
      13. Slowed heart rate, also called bradycardia.
      14. Depression.
      15. Memory problems.
   2. Hypothyroidism in children and teens. In general, children and teens with hypothyroidism have symptoms similar to those in adults. But they also may have:
      1. Poor growth that leads to short stature.
      2. Delayed development of permanent teeth.
      3. Delayed puberty.
      4. Poor mental development.
5. Lymphadenopathy or swollen lymph nodes (6%). Lymph node involvement is usually found on radiology scans or by feeling painless, rubbery lumps in the neck, under the arms, or in the groin.
6. Lung involvement is particularly common in smokers and can cause a chronic cough or shortness of breath.
7. Central nervous system (CNS) involvement most commonly affects the pituitary gland, a master gland that controls function of the thyroid, adrenal, and reproductive glands. A common manifestation of CNS is diabetes insipidus.

Involvement of the zygomatic, sphenoid, orbital, ethmoid, or temporal bones denotes a category of CNS (central nervous system) risk lesions that imparts a higher risk of neurodegenerative disease in the skull and front of the face.

Involvement of risk organs implies a worse prognosis. Risk organs include the liver, spleen, and organs of the hematopoietic system.

Patients with single system disease (unifocal, multifocal, and central nervous system (CNS) risk organs) and multisystem disease without risk organ involvement are considered low risk. Patients with multisystem disease and risk organ involvement are considered high risk.

Adult patients may have signs and symptoms of eosinophilic granuloma (Langerhans cell histiocytosis) for many months before receiving a definitive diagnosis and treatment. Eosinophilic granuloma in adults is often similar to that in children and appears to involve the same organs, although the incidence in an organ may be different. There is a predominance of lung disease in adults, usually occurring as single-system disease and closely associated with smoking and some unique biologic characteristics. Most adult isolated lung eosinophilic granuloma cases are polyclonal and possibly reactive, while fewer lung eosinophilic granuloma (Langerhans cell histiocytosis) cases are monoclonal ³¹.

A German registry with 121 registrants showed that 62% had single-organ involvement and 38% had multisystem involvement, while 34% of the total had lung involvement. The median age at diagnosis was 44 years ± 12.8 years. The most common organ involved was lung, followed by bone and skin. All organ systems found in childhood eosinophilic granuloma (Langerhans cell histiocytosis) were seen, including endocrine and central nervous system, liver, spleen, bone marrow, and gastrointestinal tract. The major difference is the much higher incidence of isolated pulmonary eosinophilic granuloma (Langerhans cell histiocytosis) in adults, particularly in young adults who smoke. Other differences appear to be the more frequent involvement of genital and oral mucosa. There may possibly be a difference in the distribution of bone lesions, but both groups suffer reactivations of bone lesions and progression to diabetes insipidus, although the exact incidence in adults is unknown ³².

Presenting symptoms from published studies are (in order of decreasing frequency):

1. dyspnea or tachypnea,
2. polydipsia and polyuria,
3. bone pain,
4. lymphadenopathy,
5. weight loss,
6. fever,
7. gingival hypertrophy,
8. ataxia, and
9. memory problems.

The signs of eosinophilic granuloma (Langerhans cell histiocytosis) are:

• skin rash,
• scalp nodules,
• soft tissue swelling near bone lesions,
• lymphadenopathy,
• gingival hypertrophy, and
• hepatosplenomegaly.

Patients who present with isolated diabetes insipidus should be carefully observed for the onset of other symptoms or signs characteristic of eosinophilic granuloma (Langerhans cell histiocytosis). At least 80% of patients with diabetes insipidus had involvement of other organ systems, including bone (68%), skin (57%), lung (39%), and lymph nodes (18%) ³³. However, isolated diabetes insipidus in adults is similar to that in pediatric patients, with progression from posterior to anterior pituitary/hypothalamus and to cerebellar involvement.

Eosinophilic granuloma of skin and oral cavity

Thirty-seven percent of adults with eosinophilic granuloma (Langerhans cell histiocytosis) have skin involvement, usually as part of multisystem disease. Skin-only eosinophilic granuloma (Langerhans cell histiocytosis) occurs but it is less common in adults than in children. The prognosis for adults with skin-only eosinophilic granuloma (Langerhans cell histiocytosis) is excellent, with 100% probability of 5-year survival. The cutaneous involvement is clinically similar to that seen in children and may take many forms ³⁰. Infra-mammary and vulvar involvement may be seen in adult women with skin eosinophilic granuloma (Langerhans cell histiocytosis).

Many patients have a papular rash with brown, red, or crusted areas ranging from the size of a pinhead to a dime. In the scalp, the rash is similar to that of seborrhea. Skin in the inguinal region, genitalia, or around the anus may have open ulcers that do not heal after antibacterial or antifungal therapy. The lesions are usually asymptomatic but may be pruritic or painful. In the mouth, swollen gums or ulcers along the cheeks, roof of the mouth, or tongue may be signs of eosinophilic granuloma.

In infants, signs or symptoms of eosinophilic granuloma (Langerhans cell histiocytosis) that affects the skin may include:

• Flaking of the scalp that may look like “cradle cap.”
• Flaking in the creases of the body, such as the inner elbow or perineum.
• Raised skin rash with brown or purple areas that occur anywhere on the body.

In children and adults, signs or symptoms of eosinophilic granuloma (Langerhans cell histiocytosis) that affects the skin and nails may include:

• Flaking of the scalp that may look like dandruff.
• Raised skin rash with red, brown, or crusted areas that may be itchy or painful. The rash can occur in the groin area or on the abdomen, back, or chest.
• Bumps or ulcers on the scalp.
• Ulcers behind the ears, under the breasts, or in the groin area.
• Fingernails that fall off or have discolored grooves that run across the nail.

Signs or symptoms of eosinophilic granuloma (Langerhans cell histiocytosis) that affects the mouth may include:

• Swollen gums.
• Sores on the roof of the mouth, inside the cheeks, or on the tongue or lips.
• Teeth that become uneven or fall out.

Diagnosis of eosinophilic granuloma (Langerhans cell histiocytosis) is usually made by skin biopsy performed for persistent skin lesions ³⁰.

Eosinophilic granuloma of bones

The relative frequency of bone involvement in adults differs from that in children; the frequency of mandible involvement is 30% in adults and 7% in children, and the frequency of skull involvement is 21% in adults and 40% in children ³². The frequency of vertebrae (13%), pelvis (13%), extremities (17%), and rib (6%) lesions in adults are similar to those found in children ³².

Signs or symptoms of eosinophilic granuloma (Langerhans cell histiocytosis) that affects the bone may include:

• Swelling or a lump over a bone, such as the skull, jawbone, ribs, pelvis, spine, thigh bone, upper arm bone, elbow, eye socket, or bones around the ear.
• Pain where there is swelling or a lump over a bone.

Children with eosinophilic granuloma (Langerhans cell histiocytosis) lesions in bones around the ears or eyes have a high risk of diabetes insipidus and other central nervous system diseases.

Signs or symptoms of eosinophilic granuloma (Langerhans cell histiocytosis) that affects the bone marrow may include:

• Easy bruising or bleeding.
• Fever.
• Frequent infections.

Eosinophilic granuloma of lung

Pulmonary eosinophilic granuloma (Langerhans cell histiocytosis) in adults is usually single-system disease, but in some patients, other organs may be involved, including bone (18%), skin (13%), and diabetes insipidus (5%) ³⁴.

Pulmonary eosinophilic granuloma (Langerhans cell histiocytosis) is more prevalent in smokers than in nonsmokers, and the male-to-female ratio is nearly 1:1, depending on the incidence of smoking in the population studied ³⁵. Patients with pulmonary eosinophilic granuloma usually present with a dry cough, dyspnea, or chest pain, although nearly 20% of adults with lung involvement have no symptoms ³⁶. Chest pain may indicate a spontaneous pneumothorax (10%–20% of adult pulmonary eosinophilic granuloma cases).

Signs or symptoms of eosinophilic granuloma (Langerhans cell histiocytosis) that affects the lung may include:

• Collapsed lung. This condition can cause chest pain or tightness, trouble breathing, feeling tired, and a bluish color to the skin.
• Trouble breathing, especially in adults who smoke.
• Dry cough.
• Chest pain.

Pulmonary eosinophilic granuloma (Langerhans cell histiocytosis) can be diagnosed by bronchoscopy in about 50% of adult patients, as defined by characteristic CD1a immunostaining cells of at least 5% of cells observed ³⁷. High-resolution lung computed tomography (CT) shows characteristic changes with cysts and nodules, more prevalent at the mid and upper zones. These changes have been characterized as pathognomonic for lung eosinophilic granuloma (Langerhans cell histiocytosis) ³⁶.

The eosinophilic granuloma (Langerhans cell histiocytosis) cells in adult lung lesions were shown to be mature dendritic cells expressing high levels of the accessory molecules CD80 and CD86, unlike Langerhans cells found in other lung disorders ³⁸. Pulmonary eosinophilic granuloma (Langerhans cell histiocytosis) in adults has been considered a primarily reactive process, rather than a clonal proliferation as seen in childhood eosinophilic granuloma (Langerhans cell histiocytosis) ³¹. However, ERK pathway mutations have been demonstrated in up to two-thirds of pulmonary eosinophilic granuloma (Langerhans cell histiocytosis) lesions in adults, suggesting a clonal process in a significant proportion of patients ³⁹.

The course of pulmonary eosinophilic granuloma in adults is variable and unpredictable ³⁴.

Favorable prognostic factors for adult eosinophilic granuloma of the lung include the following:

• Minimal symptoms. Adults with pulmonary eosinophilic granuloma (Langerhans cell histiocytosis) who have minimal symptoms have a good prognosis, although some have steady deterioration over many years ⁴⁰.
• Smoking cessation or treatment. Fifty-nine percent of patients do well with either spontaneous remission with cessation of smoking, or with some form of therapy ⁴⁰. However, one study reported that smoking cessation did not increase the longevity of adults with pulmonary eosinophilic granuloma (Langerhans cell histiocytosis), apparently because the tempo of disease is so variable ⁴¹.
• Lung transplantation. Patients receiving lung transplantation for treatment of pulmonary eosinophilic granuloma (Langerhans cell histiocytosis) have a 77% survival rate at 1 year and a 54% survival rate at 10 years, with a 20% chance of eosinophilic granuloma (Langerhans cell histiocytosis) recurrence ⁴².

Unfavorable prognostic factors for adult eosinophilic granuloma of the lung include the following:

• Altered pulmonary function. Lower forced expiratory volume/forced vital capacity (FEV1/FVC) ratio and higher residual volume/total lung capacity (RV/TLC) ratio are adverse prognostic variables ⁴¹. About 10% to 20% of patients have early severe progression to respiratory failure, severe pulmonary hypertension, and cor pulmonale. Adults who have progression with diffuse bullae formation, multiple pneumothoraces, and fibrosis have a poor prognosis ⁴³.
• Age. Age older than 26 years is an adverse prognostic variable ⁴¹.

The remaining patients have a variable course, with stable disease in some patients and relapses and progression of respiratory dysfunction in others, some after many years ⁴⁴. A natural history study of 58 eosinophilic granuloma (Langerhans cell histiocytosis) patients with pulmonary involvement found that 38% of patients had deterioration of lung function after 2 years ⁴⁵. The most significant adverse prognostic variables were positive smoking statuses and low PaO2 levels at the time of inclusion.

The following results may be noted on diagnostic tests:

• Pulmonary function testing. The most frequent pulmonary function abnormality finding in patients with pulmonary eosinophilic granuloma (Langerhans cell histiocytosis) is a reduced carbon monoxide diffusing capacity in 70% to 90% of cases ⁴¹.
• CT scan. A high-resolution CT scan, which reveals a reticulonodular pattern classically with cysts and nodules, usually in the upper lobes and sparing the costophrenic angle, is characteristic of eosinophilic granuloma (Langerhans cell histiocytosis) ⁴⁶. The presence of cystic abnormalities on high-resolution CT scans appears to be a poor predictor of which patients will have progressive disease ⁴⁷.
• Biopsy. Despite the typical CT findings, most pulmonologists agree that a lung biopsy is needed to confirm the diagnosis. A study that correlated lung CT findings and lung biopsy results in 27 patients with pulmonary eosinophilic granuloma (Langerhans cell histiocytosis) observed that thin-walled and bizarre cysts had active LCs and eosinophils ⁴⁸.

Eosinophilic granuloma of liver

Liver involvement was reported in 27% of adult patients with eosinophilic granuloma (Langerhans cell histiocytosis) and multiorgan disease ⁴⁹. Hepatomegaly (48%) and liver enzyme abnormalities (61%) were present. CT and ultrasound imaging abnormalities are often found.

Signs or symptoms of eosinophilic granuloma (Langerhans cell histiocytosis) that affects the liver or spleen may include:

• Swelling in the abdomen caused by a buildup of extra fluid.
• Trouble breathing.
• Yellowing of the skin and whites of the eyes (jaundice).
• Itching.
• Easy bruising or bleeding.
• Feeling very tired.
• Diarrhea.
• Bloody stools.

The early histopathologic stage of liver eosinophilic granuloma (Langerhans cell histiocytosis) includes infiltration of CD1a-positive cells and periductal fibrosis with inflammatory infiltrates with or without steatosis. The late stage is biliary tree sclerosis; treatment with ursodeoxycholic acid is suggested ⁴⁹.

Eosinophilic granuloma of lymph nodes and thymus

Signs or symptoms of eosinophilic granuloma (Langerhans cell histiocytosis) that affects the lymph nodes or thymus may include:

• Swollen lymph nodes.
• Cough, trouble breathing, or fast breathing.
• Superior vena cava syndrome. This can cause coughing, trouble breathing, and swelling of the face, neck, and upper arms.

Eosinophilic granuloma of endocrine system

Signs or symptoms of eosinophilic granuloma (Langerhans cell histiocytosis) that affects the pituitary gland may include:

• Diabetes insipidus. This can cause a strong thirst and frequent urination.
• Slow growth.
• Early or late puberty.
• Being very overweight.

Signs or symptoms of eosinophilic granuloma (Langerhans cell histiocytosis) that affects the thyroid may include:

• Swollen thyroid gland.
• Hypothyroidism. This can cause tiredness, lack of energy, being sensitive to cold, constipation, dry skin, thinning hair, memory problems, trouble concentrating, and depression. In infants, this can also cause a loss of appetite and choking on food. In children and adolescents, this can cause behavior problems, weight gain, slow growth, and late puberty.
• Trouble breathing.

Eosinophilic granuloma of eye

Signs or symptoms of eosinophilic granuloma (Langerhans cell histiocytosis) that affects the eye may include:

• Vision problems or blindness.

Eosinophilic granuloma of central nervous system (CNS)

Signs or symptoms of eosinophilic granuloma (Langerhans cell histiocytosis) that affects the central nervous system (brain and spinal cord) may include:

• Loss of balance, uncoordinated body movements, and trouble walking.
• Trouble speaking.
• Trouble seeing.
• Headaches.
• Changes in behavior or personality.
• Memory problems.

These signs and symptoms may be caused by lesions in the central nervous system (CNS) or by CNS neurodegenerative syndrome.

Hand-Schüller-Christian disease (multisystem disease without risk organ involvement)

This syndrome (15 to 40% of Langerhans cell histiocytosis cases) occurs in children aged 2 to 5 years and in some older children and adults. Classic findings in this systemic disorder include involvement of the flat bones of the skull, ribs, pelvis, scapula, or a combination. Long bones and lumbosacral vertebrae are less frequently involved; the wrists, hands, knees, feet, and cervical vertebrae are rarely involved. In classic cases, patients have proptosis caused by orbital tumor mass. Rarely, vision loss or strabismus is caused by optic nerve or orbital muscle involvement. Tooth loss caused by apical and gingival infiltration is common in older patients.

Chronic otitis media and otitis externa due to involvement of the mastoid and petrous portions of the temporal bone with partial obstruction of the auditory canal are fairly common. Diabetes insipidus, the last component of the classic triad that includes flat bone involvement and proptosis, affects 5 to 50% of patients, with higher percentages in children who have systemic disease and involvement of the orbit and skull. Up to 40% of children with systemic disease have short stature. Hyperprolactinemia and hypogonadism can result from hypothalamic infiltration.

Letterer-Siwe disease (multisystem disease with risk organ involvement)

This syndrome (10% of LCH cases), a systemic disorder, is the most severe form of Langerhans cell histiocytosis. Typically, a child < 2 years presents with a scaly seborrheic, eczematoid, sometimes purpuric rash involving the scalp, ear canals, abdomen, and intertriginous areas of the neck and face. Denuded skin may facilitate microbial invasion, leading to sepsis. Frequently, there is ear drainage, lymphadenopathy, hepatosplenomegaly, and, in severe cases, hepatic dysfunction with hypoproteinemia and diminished synthesis of clotting factors. Anorexia, irritability, failure to thrive, and pulmonary manifestations (eg, cough, tachypnea, pneumothorax) may also occur. Significant anemia and sometimes neutropenia occur; thrombocytopenia is of grave prognostic significance. Parents frequently report precocious eruption of teeth, when in fact the gums are receding to expose immature dentition. Patients may appear abused or neglected.

Eosinophilic granuloma diagnosis

In addition to asking about your health history and doing a physical exam, your doctor may perform the following tests and procedures to diagnose eosinophilic granuloma (Langerhans cell histiocytosis) or conditions caused by eosinophilic granuloma (Langerhans cell histiocytosis):

• Complete blood count (CBC) with differential: A procedure in which a sample of blood is drawn and checked for the following:
  • The amount of hemoglobin (the protein that carries oxygen) in the red blood cells.
  • The portion of the blood sample made up of red blood cells.
  • The number and type of white blood cells.
  • The number of red blood cells and platelets.
• Blood chemistry studies: A procedure in which a blood sample is checked to measure the amounts of certain substances released into the body by organs and tissues in the body. An unusual (higher or lower than normal) amount of a substance can be a sign of disease.
• Liver function test: A blood test to measure the blood levels of certain substances released by the liver. A high or low level of these substances can be a sign of disease in the liver.
• BRAF gene testing: A laboratory test in which a sample of blood or tissue is tested for certain mutations in the BRAF gene.
• Urinalysis: A test to check the color of urine and its contents, such as sugar, protein, red blood cells, and white blood cells.
• Water deprivation test: A test to check how much urine is made and whether it becomes concentrated when little or no water is given. This test is used to diagnose diabetes insipidus, which may be caused by eosinophilic granuloma (Langerhans cell histiocytosis).
• Bone marrow aspiration and biopsy: The removal of bone marrow and a small piece of bone by inserting a hollow needle into the hipbone. A pathologist views the bone marrow and bone under a microscope to look for signs of eosinophilic granuloma (Langerhans cell histiocytosis). The following test may be done on the tissue that was removed:
  • Immunohistochemistry: A laboratory test that uses antibodies to check for certain antigens (markers) in a sample of a patient’s tissue. The antibodies are usually linked to an enzyme or a fluorescent dye. After the antibodies bind to a specific antigen in the tissue sample, the enzyme or dye is activated, and the antigen can then be seen under a microscope. This type of test is used to help diagnose cancer and to help tell one type of cancer from another type of cancer.

Tissue biopsy for histological diagnosis is necessary to confirm the diagnosis ²⁷. CT-guided biopsy for eosinophilic granuloma has been effective for histological diagnosis, with low morbidity and a diagnostic accuracy of 70–100 % ⁵⁰. Although anecdotally excellent results with biopsy alone have been previously reported for patients with eosinophilic granulomas ⁵¹, biopsy should not be considered as a strategy for treatment of these patients but rather as a step to confirm diagnosis ⁵⁰.

Biopsy lesions will stain positive for S-100 and CD-1a ²⁷. 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 ⁵².

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.

Other Tests

• 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
• Auditory 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 ⁵³

Eosinophilic granuloma treatment

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 ⁵⁴.

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.

Eosinophilic granuloma of bone treatment

Various treatment options have been reported for eosinophilic granuloma of bone, including observation and immobilization, indomethacin administration, methylprednisolone injections, radiofrequency ablation, local excision and curettage with or without bone grafting, chemotherapy and irradiation; results have been reported as satisfactory with a recurrence rate of less than 20 % ⁵⁵. In general, the treatment of typical solitary lesions in asymptomatic patients is conservative ⁵⁶. In patients with mild neurological deficits from solitary eosinophilic granulomas of the spine, immobilization and radiation therapy has been reported ⁵⁷. Low-dose radiation therapy is advocated by some authors to be effective in the healing of lytic lesions and limiting disease progression ⁵⁸; others argue that radiation therapy may damage endochondral growth plates and limit bone healing and reconstitution ⁵⁹, or lead to secondary radiation-induced morbidity such as post-radiation sarcomas and myelitis ¹⁴. Although no clear correlation between the degree of vertebral collapse and the degree of neurological symptoms has been observed ⁶⁰, in patients with severe pain and restriction of range of motion, and/or persistent spinal subluxation and neurological symptoms, surgical treatment is required ¹⁷. Chemotherapy is not recommended for solitary eosinophilic granuloma, and should be reserved for systemic involvement ²¹, or as initial therapy in children with solitary lesions in locations that preclude safe and complete surgical resection ⁶¹.

Since eosinophilic granuloma in children is known to resolve spontaneously with time, observation alone or biopsy alone to confirm the diagnosis have also been recommended as a treatment strategy ⁵¹. A previous study reported spontaneous resolution without recurrence of the lesions in six skeletally immature patients that had biopsy followed by observation alone (open biopsy in three and percutaneous in three), suggesting the intriguing possibility that surgery may result in a higher rate of recurrence than less aggressive procedures ⁵¹. However, patients, especially children with symptomatic bone lesions should not be left alone to let the disease take its natural course without a histological diagnosis. Moreover, although solitary eosinophilic granuloma is considered a benign lesion, without treatment, the time required for resolution is unpredictable and can be associated with significant morbidity secondary to unremitting pain, restricted activity, growth disturbance, or pathological fracture ⁶². Therefore, some experts recommend that these patients should undergo biopsy for histological diagnosis, and treatment is then considered ⁵⁰.

Eosinophilic granuloma in lung treatment

It is difficult to judge the effectiveness of various treatments for pulmonary eosinophilic granuloma (Langerhans cell histiocytosis) because patients can recover spontaneously or have stable disease without treatment.

Treatment options for adult patients with pulmonary eosinophilic granuloma (Langerhans cell histiocytosis) include the following:

1. Smoking cessation. Smoking cessation is mandatory because of the apparent causal effect of smoking in pulmonary eosinophilic granuloma (Langerhans cell histiocytosis) ⁶³. Most adult patients with eosinophilic granuloma (Langerhans cell histiocytosis) have gradual disease progression with continued smoking. The disease may regress or progress with the cessation of smoking ⁶⁴. A study of 27 patients with pulmonary eosinophilic granuloma (Langerhans cell histiocytosis) observed that 52% of patients improved after a mean follow-up period of 14 months; most patients improved with smoking cessation, and some patients improved with steroid treatment. Four patients (15%) had stable disease at a mean follow-up of 26 months, and nine patients (33%) demonstrated disease progression during the mean follow-up of 22 months ⁶⁵.
2. Steroid therapy. It is not known whether steroid therapy is efficacious in the treatment of adult pulmonary eosinophilic granuloma (Langerhans cell histiocytosis) because reported case series did not control for smoking cessation ⁶³.
3. Chemotherapy. Some patients have been reported to respond to cladribine therapy ⁶⁶.
4. Lung transplantation. Lung transplantation may be necessary for adults with extensive pulmonary destruction from eosinophilic granuloma (Langerhans cell histiocytosis) ⁶⁷. This multicenter study reported 54% survival at 10 years posttransplant, with 20% of patients having recurrent eosinophilic granuloma (Langerhans cell histiocytosis) that did not impact survival; longer follow-up of these patients is needed ⁶⁷. Another study confirmed an approximate 50% survival at 10 years and improved hemodynamic changes associated with pulmonary arterial hypertension, but did not alter pulmonary function testing or incidence of pulmonary edema ⁴⁰.

The best strategy for follow-up of pulmonary eosinophilic granuloma includes physical examination, chest radiographs, lung function tests, and high-resolution computed tomography (CT) scans ³¹.

Eosinophilic granuloma of skin treatment

Treatment options for adult patients with single-system skin disease include the following:

1. Surgical excision. Localized lesions can be treated by surgical excision, but as with bone, mutilating surgery, including hemivulvectomy, should be avoided unless the disease is refractory to all available therapy.
2. Topical therapy. Topical therapies are described in greater detail in the childhood isolated skin involvement section of this summary and include the following:
   • Topical or intralesional corticosteroid.
   • Topical tacrolimus.
   • Topical imiquimod ³⁷
   • Psoralen and long-wave ultraviolet A radiation (PUVA) and UVB. Therapies such as PUVA/UVB may be more useful in adults because long-term toxicity may be reduced ⁴²
3. Systemic therapy. Systemic therapy for severe skin eosinophilic granuloma includes oral methotrexate, hydroxyurea, oral thalidomide, oral interferon-alpha, or combinations of interferon and thalidomide ⁴⁴. Interferon and thalidomide are also used to treat chronic adult skin eosinophilic granuloma ⁴⁵. Recurrences may occur after treatment is stopped but may respond to re-treatment. Oral isotretinoin has induced remission in some refractory cases of skin eosinophilic granuloma in adults ⁶⁸. Chemotherapy is generally used for skin eosinophilic granuloma associated with multisystem disease in adults.

Chemotherapy for the treatment of other single-system disease and multisystem disease

Evidence (chemotherapy for the treatment of other single-system disease [not mentioned above] and multisystem disease):

1. A single-center, retrospective review of 58 adult patients with eosinophilic granuloma (Langerhans cell histiocytosis) reported on the efficacy and toxicities of treatment with vinblastine/prednisone, cladribine, and cytarabine ⁴⁶.
   • Patients treated with vinblastine/prednisone had the worst outcome, with 84% not responding within 6 weeks or relapsing within a year.
   • The no-response/relapse rate was 59% for cladribine and 21% for cytarabine.
   • Grade 3 or 4 neurologic toxic effects occurred in 75% of patients treated with vinblastine.
   • Grade 3 or 4 neutropenia occurred in 37% of patients treated with cladribine and in 20% of patients receiving cytarabine.
2. A report on the treatment of adult patients with either vindesine and prednisone or cyclophosphamide, etoposide, vindesine, and prednisone showed that more than 70% of patients relapsed with either regimen ⁴⁷.
3. Etoposide has been used with some success in single-system and multisystem eosinophilic granuloma (Langerhans cell histiocytosis).
   • Minimal toxicity was reported with the use of prolonged oral etoposide in adults with skin eosinophilic granuloma (Langerhans cell histiocytosis), while 3-day courses of intravenous etoposide (100 mg/m²/day) induced complete remission in a small number of patients with resistant single-system and multisystem disease ⁴⁸.
   • Another study at the same center found that azathioprine was the most successful drug for localized disease in adults, with the addition of etoposide for refractory and multisystem disease ⁶⁹.
4. For patients who do not respond to front-line therapy with etoposide, cladribine is effective for adults with skin, bone, lymph node, and probably pulmonary and central nervous system (CNS) disease ⁷⁰.
   • The first study that used cladribine to treat refractory and recurrent skin eosinophilic granuloma (Langerhans cell histiocytosis) disease reported on three patients (aged 33, 51, and 57 years) who received two to four courses of cladribine at 0.7 mg/kg intravenously over 2 hours/day for 5 days ⁷¹.
   • In a series of five adults (one untreated and four with refractory eosinophilic granuloma (Langerhans cell histiocytosis) treated with cladribine at the same dose noted directly above), three patients achieved a complete remission and two patients achieved a partial remission ⁷⁰.
5. An adult lymphoma treatment regimen of methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone and bleomycin (MACOP-B) was used in three patients with multisystem eosinophilic granuloma (Langerhans cell histiocytosis) and four with single-system multifocal bone eosinophilic granuloma (Langerhans cell histiocytosis) from 1995 to 2007. Total duration of therapy was 12 weeks ⁷².
   • Response was seen in all patients, two with partial response and five with complete response.
   • Three recurrences were seen after therapy was stopped.
   • Despite the small number of patients and the retrospective nature of the study, MACOP-B may be useful as salvage therapy in adult patients with eosinophilic granuloma (Langerhans cell histiocytosis) and deserves further study ⁷³.
6. Neurodegenerative CNS (central nervous system) disease. A case report suggests some benefit to treating neurodegenerative CNS eosinophilic granuloma (Langerhans cell histiocytosis) disease with infliximab, a tumor necrosis factor (TNF)-alpha inhibitor ⁷⁴. However, the TNF inhibitors infliximab and etanercept have limited ability to cross the blood-brain barrier. Thalidomide, which also has anti-TNF activity, has been effective in adults with skin and bone eosinophilic granuloma (Langerhans cell histiocytosis) ⁷⁵. One study reported an improvement in ataxia in a patient with eosinophilic granuloma (Langerhans cell histiocytosis) who was treated with vemurafenib ⁷⁶.
7. Pituitary eosinophilic granuloma (Langerhans cell histiocytosis). A report of stereotactic radiosurgery for the treatment of pituitary eosinophilic granuloma (Langerhans cell histiocytosis) in adults showed efficacy in reducing the masses ⁷⁷. However, radiation therapy is not considered the standard of care for children with pituitary involvement. Systemic chemotherapy with cytarabine and cladribine have been the preferred treatments ⁷⁸.

Targeted therapies for the treatment of single-system and multisystem disease

Early reports on the use of targeted therapies for eosinophilic granuloma (Langerhans cell histiocytosis) patients with low-risk or high-risk eosinophilic granuloma (Langerhans cell histiocytosis) sites include the following:

1. Tyrosine kinase inhibitors. Imatinib mesylate was effective in the treatment of four adult patients with eosinophilic granuloma (Langerhans cell histiocytosis) who had skin, lung, bone, and/or CNS involvement ⁷⁹. Another adult patient with eosinophilic granuloma (Langerhans cell histiocytosis) did not respond to imatinib mesylate ⁸⁰.
2. MAP2K/ERK pathway inhibitors. The finding that most patients with eosinophilic granuloma (Langerhans cell histiocytosis) have BRAF and other RAS pathway mutations led to several reports of good responses to vemurafenib, a BRAF V600E inhibitor, in adult patients with eosinophilic granuloma (Langerhans cell histiocytosis), Erdheim-Chester (ECD) disease, or mixed ECD/eosinophilic granuloma (Langerhans cell histiocytosis), as well as in severe cutaneous eosinophilic granuloma (Langerhans cell histiocytosis) ⁸¹. Of four patients with eosinophilic granuloma (Langerhans cell histiocytosis) who were treated with vemurafenib on the VE-BASKET (NCT01524978) trial, one patient had a complete response and three patients had partial responses ⁷⁶. Early results of targeted inhibitor therapy are encouraging, but many questions remain, particularly the optimal duration of therapy and the reactivation rate after therapy is discontinued. A BRAF inhibitor in combination with a MEK inhibitor have been shown to be effective in patients with melanoma who have BRAF mutations (with reduced toxicity), and this combination may be effective in patients with eosinophilic granuloma (Langerhans cell histiocytosis) ⁸². A number of clinical trials of BRAF and other RAS pathway inhibitors in adults and children with eosinophilic granuloma (Langerhans cell histiocytosis) are ongoing.

Follow-up tests

Eosinophilic granuloma (Langerhans cell histiocytosis) patients should be monitored for many years because of the risk of reactivation (recurrence). Some of the tests that were done to diagnose eosinophilic granuloma (Langerhans cell histiocytosis) may be repeated. This is to see how well the treatment is working and if there are any new lesions. These tests may include:

• Physical exam.
• Neurological exam.
• Ultrasound exam.
• MRI.
• CT scan.
• PET scan.

Other tests that may be needed include:

• Brain stem auditory evoked response (BAER) test: A test that measures the brain’s response to clicking sounds or certain tones to detect some types of hearing loss.
• Pulmonary function test (PFT): A test to see how well the lungs are working. It measures how much air the lungs can hold and how quickly air moves into and out of the lungs. It also measures how much oxygen is used and how much carbon dioxide is given off during breathing. This is also called a lung function test.
• Chest x-ray: An x-ray of the organs and bones inside the chest. An x-ray is a type of energy beam that can go through the body and onto film, making a picture of areas inside the body.

The results of these tests can show if your condition has changed or if the cancer has recurred (come back). These tests are sometimes called follow-up tests or check-ups. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests.

Eosinophilic granuloma prognosis

The prognosis (chance of recovery) for people with eosinophilic granuloma (Langerhans cell histiocytosis) 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). In general, patients who are young and those in which the disease is present in many parts of the body and organ dysfunction tend to have a poorer prognosis. Newborns who present only with skin lesions tend to do well. Therefore, the age at presentation is only important when multiple organs are affected.

The prognosis and treatment options depend on the following:

• Which organs or body systems are affected by eosinophilic granuloma (Langerhans cell histiocytosis).
• How many organs or body systems the eosinophilic granuloma (Langerhans cell histiocytosis) affects.
• Whether eosinophilic granuloma (Langerhans cell histiocytosis) is found in the liver, spleen, bone marrow, or certain bones in the skull.
• How quickly eosinophilic granuloma (Langerhans cell histiocytosis) responds to initial treatment.
• Whether there are certain mutations in the BRAF gene.
• Whether eosinophilic granuloma (Langerhans cell histiocytosis) has just been diagnosed or has come back (recurred).

High-risk patients like multisystem involvement, skeletally mature patients, more than one bone involvement, and skull-base bone involvement (sphenoid, ethmoid, orbital, and temporal bones) have a high risk for recurrence, complications, and subsequent worse prognosis. Operative treatment offers more prompt pain relief when compared to non-operative treatment ⁸³. Over 10% of patients die of this disease, including a few cases with reactivations and long term morbidity ⁸⁴.

In infants up to 1 year of age, eosinophilic granuloma (Langerhans cell histiocytosis) may go away without treatment. Children with eosinophilic granuloma (Langerhans cell histiocytosis) in high-risk organs and the gastrointestinal tract have a greater risk of not responding to treatment than patients with high-risk eosinophilic granuloma (Langerhans cell histiocytosis) and no disease in the gastrointestinal tract. High-risk eosinophilic granuloma (Langerhans cell histiocytosis) is usually seen in children younger than 2 years. Mortality may be low for isolated lesions (< 5%) and as high as 50% for the more widespread disease ²⁷. Those with disseminated disease will die within 24-48 months ²⁷. Those with localized disease do have a better prognosis but the quality of life is reduced.

Individuals who have liver, spleen, lung, or bone marrow involvement usually have a worse prognosis. In a study looking at patients from several centers, it was shown that the best prognostic indicator was the patient’s response to chemotherapy during the first six weeks of therapy. Therefore, it has been recommended by some that individuals who do not respond positively within the first six weeks of treatment should be treated more aggressively.

The prognosis for pulmonary eosinophilic granuloma varies and is related to smoking cessation. Those who continue to smoke experience disease progression, but those who quit disease stabilizes or regresses. Extreme age, large cysts, and honeycombing radiological, multiorgan involvement, and prolonged corticosteroid therapy have a worse prognosis.

Eosinophilic granuloma (Langerhans cell histiocytosis) in the skin, bones, lymph nodes or pituitary gland usually gets better with treatment and is called “low-risk.” Some patients have involvement in the spleen, liver and bone marrow. This is called “high-risk disease” and may be more difficult to treat. Some patients may develop long-term side effects such as diabetes insipidus, stunted growth, loss of teeth, bone defects, hearing loss, or neurologic problems; while other patients remain without side effects. In a few cases, the disease can be life-threatening.

Patients with eosinophilic granuloma (Langerhans cell histiocytosis) should usually have long term follow-up care to detect late complications of the disease or treatment. These may include problems of skeletal deformity or function, liver or lung problems, hormone abnormalities, dental issues or neurological and neurocognitive dysfunction.

Eosinophilic granuloma life expectancy

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 ²⁷. 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:

• Musculoskeletal disability
• Skin scarring
• Diabetes insipidus
• Hearing impairment
• Neuropsychiatric problems like depression, anxiety, and intellectual impairment
• Pulmonary impairment
• Secondary malignancies like lymphoblastic leukemia and sodi tumors
• Growth retardation
• Liver cirrhosis

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