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Langerhans Cell Histiocytosis

By Jeffrey M. Lipton, MD, PhD, Professor of Pediatrics and Molecular Medicine;Professor;Chief, Hematology/Oncology and Stem Cell Transplantation, Hofstra Northwell School of Medicine, Hempstead, NY;The Center for Autoimmune and Musculoskeletal Disease, Feinstein Institute for Medical Research;Cohen Children’s Medical Center of New York ; Carolyn Fein Levy, MD, Assistant Professor, Hofstra Northwell School of Medicine

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Langerhans cell histiocytosis (LCH) is a proliferation of dendritic mononuclear cells with infiltration into organs locally or diffusely. Most cases occur in children. Manifestations may include lung infiltrates; bone lesions; rashes; and hepatic, hematopoietic, and endocrine dysfunction. Diagnosis is based on biopsy. Factors predicting a poor prognosis include age < 2 yr and dissemination, particularly involving the hematopoietic system, liver, spleen, or a combination. Treatments include supportive measures and chemotherapy or local treatment with surgery or radiation therapy as indicated by the extent of disease.

Langerhans cell histiocytosis is a dendritic cell (antigen-presenting cell) disorder. It can cause distinct clinical syndromes that have been historically described as eosinophilic granuloma, Hand-Schüller-Christian disease, and Letterer-Siwe disease. Because these syndromes may be varied manifestations of the same underlying disorder and because most patients with LCH have manifestations of more than one of these syndromes, the designations of the separate syndromes (except for eosinophilic granuloma) are now mostly of historical significance. Estimates of the prevalence of LCH vary widely (eg, from about 1:50,000 to 1:200,000). Incidence is 5 to 8 cases/million children.

All patients with LCH have evidence of activation of the RAS-RAF-MEK-ERK signaling pathway. BRAFV600E mutations are identified in 50 to 60% of patients who have LCH. This mutation is monoallelic and acts like a dominant driving oncogene. About 10 to 15% of patients have MAP2K1 mutations. Because of these mutations, LCH is now considered an oncogene-driven cancer of myeloid lineage.

In LCH, abnormally proliferating dendritic cells infiltrate one or more organs. Bones, skin, teeth, gingival tissue, ears, endocrine organs, lungs, liver, spleen, lymph nodes, and bone marrow may be involved. Organs may be affected by infiltration, causing dysfunction, or by compression from adjacent enlarged structures. In about half of patients, more than one organ is involved.

Symptoms and Signs

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

Patients are divided into 2 groups based on organ involvement:

  • Single system

  • Multisystem

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.

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.

Involvement of the zygomatic, sphenoid, orbital, ethmoid, or temporal bones denotes a category of CNS 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 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.

Here, the syndromes are described by their historical designations, but few patients present with classic manifestations, and other than eosinophilic granuloma, these designations are no longer used.

Eosinophilic granuloma (single system disease)

Unifocal or multifocal eosinophilic granuloma (60 to 80% of LCH cases) occurs predominantly in older children and young adults, usually by age 30; incidence peaks between ages 5 and 10 yr. Lesions most frequently involve bones, often with pain, the inability to bear weight, or both and with overlying tender (sometimes warm) swelling.

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

This syndrome (15 to 40% of LCH cases) occurs in children aged 2 to 5 yr 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 LCH. Typically, a child < 2 yr 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.

Diagnosis

  • Biopsy

Langerhans cell histiocytosis is suspected in patients (particularly young patients) with unexplained pulmonary infiltrates, bone lesions, or ocular or craniofacial abnormalities; and in children < 2 yr with typical rashes or severe, unexplained multiorgan disease.

X-rays are often done because of presenting symptoms. Bone lesions are usually sharply marginated, and round or oval, with a beveled edge giving the appearance of depth. However, some lesions are radiographically indistinguishable from Ewing sarcoma, osteosarcoma, other benign and malignant conditions, or osteomyelitis.

Diagnosis is based on biopsy. Langerhans cells are usually prominent, except in older lesions. These cells are identified by a pathologist experienced in the diagnosis of LCH according to their immunohistochemical characteristics, which include cell surface CD1a, CD207 (langerin), and S-100 (although not specific). Tumor tissue should be tested for BRAFV600E mutation and other mutations. Once the diagnosis is established, the extent of disease must be determined by appropriate imaging and laboratory studies.

Laboratory studies used to define the extent of disease include the following:

  • Complete blood count with differential

  • Comprehensive metabolic panel

  • Coagulation studies

  • Early morning urinalysis

Imaging studies include the following:

  • Skeletal survey, including chest x-ray

  • Ultrasonography of the abdomen

  • MRI of the brain (to evaluate the pituitary gland)

  • MRI of the spine

  • MRI or CT of the skull (to look for temporal bone lesions)

  • MRI or CT of the orbit (to look for facial bone lesions)

  • CT of the chest (if the chest x-ray is abnormal)

  • CT or MRI of the abdomen (if examination reveals hepatosplenomegaly or if liver function test results are abnormal)

  • PET/CT if available (because it can identify bone lesions not seen on skeletal survey)

Prognosis

Prognosis is good for patients with Langerhans cell histiocytosis and both of the following:

  • Disease restricted to skin, lymph nodes, or bones

  • Age > 2 yr

Morbidity and mortality are increased in patients with multisystem involvement, particularly those with

  • Age < 2 yr

  • Involvement of risk organs (the hematopoietic system, liver, or spleen)

With treatment, the overall survival rate for patients with multisystem disease without risk organ involvement is 100%, but event-free survival is about 70%. Death is m rare among patients with organ involvement who do not respond to initial therapy. Disease recurrence is common. A chronic remitting and exacerbating course may occur, particularly among adults.

Some evidence suggests that patients who have BARFV600E mutations are more prone to relapses.

Treatment

  • Supportive care

  • Sometimes hormone replacement therapy for hypopituitarism, most commonly diabetes insipidus

  • Chemotherapy for multisystem involvement, single system multifocal involvement, and involvement in certain sites such as skull-based lesions

  • Sometimes surgery, corticosteroid injection, or rarely, radiation therapy (usually for unifocal bone involvement)

Because these syndromes are rare and complex, patients are usually referred to institutions experienced in the treatment of Langerhans cell histiocytosis. The majority of patients should be treated using protocols developed by the Histiocyte Society (see the Histiocyte Society web site).

General supportive care is essential and may include scrupulous hygiene to limit ear, cutaneous, and dental lesions. Debridement or resection of severely affected gingival tissue limits oral involvement. Seborrhea-like dermatitis of the scalp may diminish with use of a selenium-based shampoo twice/wk. If shampooing is ineffective, topical corticosteroids are used in small amounts and briefly in small areas.

Patients with systemic disease are monitored for potential chronic disabilities, such as cosmetic or functional orthopedic and cutaneous disorders and neurotoxicity as well as for psychologic problems that may require psychosocial support.

Many patients require hormone replacement for diabetes insipidus or other manifestations of hypopituitarism.

Chemotherapy is indicated for patients with multisystem involvement, single system multifocal involvement, and disease in certain sites, such as skull based lesions (including zygomatic, orbital, sphenoid, temporal, and ethmoid bones). Protocols sponsored by the Histiocyte Society are used; treatment protocols vary according to the risk category. Almost all patients with a good response to therapy can stop treatment. Protocols for poor responders with goals of early aggressive salvage are under study.

Local surgery, corticosteroid injection, curettage, or rarely, radiation therapy is used for disease involving a single bone. Surgery, corticosteroid injections, curettage, and radiation therapy should be done by specialists experienced in treating Langerhans cell histiocytosis. Easily accessible lesions in noncritical locations undergo surgical curettage. Surgery should be avoided when it may result in significant cosmetic deformities, orthopedic deformities, or loss of function.

Radiation therapy may be given to patients at risk of skeletal deformity, vision loss secondary to proptosis, pathologic fractures, vertebral collapse, and spinal cord injury or to patients with severe pain.

Patients with LCH that progresses despite standard therapy usually respond to more aggressive chemotherapy. Patients who do not respond to salvage chemotherapy may undergo reduced intensity hematopoietic stem cell transplantation, experimental chemotherapy, or immunosuppressive or other immunomodulatory therapy. Patients with BRFV600E mutations who fail multiple lines of therapy may be candidates for RAS-RAF-MEK-ERK inhibitor therapy (eg, vemurafenib).

Key Points

  • Langerhans cell histiocytosis (LCH) involves a proliferation of dendritic mononuclear cells that infiltrate one or more organs.

  • Manifestations vary significantly depending on the organ(s) affected.

  • Bone lesions cause pain; lesions at the skull base may affect vision, hearing, and pituitary function (particularly causing diabetes insipidus).

  • Liver, spleen, lymph nodes, and bone marrow may be affected, resulting in a worse prognosis.

  • Use surgery, curettage with or without corticosteroid injection, or rarely, radiation therapy for only single bone lesions.

  • Use chemotherapy for multisystem, multifocal and skull-based site involvement.

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