Langerhans Cell Histiocytosis

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 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 (organs in which disease involvement portends a worse prognosis), which include the liver, spleen, and organs of the hematopoietic system, 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.

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.

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 years 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 Ewing sarcoma of bone Primary malignant bone tumors are much less common than metastatic bone tumors, particularly in adults. Primary malignant bone tumors include multiple myeloma, osteosarcoma, adamantinoma, chondrosarcoma... read more , osteosarcoma Osteosarcoma (osteogenic sarcoma) Primary malignant bone tumors are much less common than metastatic bone tumors, particularly in adults. Primary malignant bone tumors include multiple myeloma, osteosarcoma, adamantinoma, chondrosarcoma... read more , other benign and malignant conditions, or osteomyelitis Osteomyelitis Osteomyelitis is inflammation and destruction of bone caused by bacteria, mycobacteria, or fungi. Common symptoms are localized bone pain and tenderness with constitutional symptoms (in acute... read more .

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 MAPK pathway 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:

Imaging studies include the following:

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

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

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

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.

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 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 BRAFV600E mutations are more prone to relapses.

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 a week. 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 neurologic lesions 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 lesions (including zygomatic, orbital, sphenoid, temporal, and ethmoid bones— 1, 2 Treatment references 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... read more ). Protocols sponsored by the Histiocyte Society are used; treatment protocols vary according to the risk category. Imaging studies are repeated at 6 and 12 weeks to assess response to therapy. Patients with a good response will continue on therapy (3 Treatment references 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... read more ). Patients with a poor response or progression during therapy should have more intensive therapy. 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. These treatments 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.

Historically, radiation therapy was sometimes given to patients at risk of skeletal deformity, vision loss secondary to proptosis, pathologic fractures, vertebral collapse, or spinal cord injury or to patients with severe pain. However, with the use of chemotherapy and targeted drugs, it is rarely necessary.

Patients with Langerhans cell histiocytosis 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 Hematopoietic Stem Cell Transplantation Hematopoietic stem cell (HSC) transplantation is a rapidly evolving technique that offers a potential cure for hematologic cancers ( leukemias, lymphomas, myeloma) and other hematologic disorders... read more , experimental chemotherapy, or immunosuppressive or other immunomodulatory therapy. Patients with BRAFV600E mutations in whom multiple lines of therapy fail may be candidates for BRAF inhibitors (eg, vemurafenib, dabrafenib) alone or in combination with MEK inhibitor (eg, trametinib), and those with other mutations can be considered for RAS-RAF-MEK-ERK inhibitor therapy (eg, trametinib, cobimetinib— 4 Treatment references 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... read more ).

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