Langerhans Cell Histiocytosis

Langerhans cell histiocytosis is a clonal neoplasm of myeloid dendritic cells with CD1a and langerin (CD207) expression, causing granulomatous infiltration of one or more organs. Disease ranges from a self-limiting single bone lesion to life threatening multisystem disease.

The incidence is about 4 to 5 in 1 million children under 15 years. It occurs at any age, with a peak at 1 to 3 years, and is slightly more common in boys. Bone is the most commonly involved site, followed by skin, lymph nodes, pituitary, liver, spleen and lungs.

Disease is classified as single system (unifocal or multifocal bone, skin, lymph node, or central nervous system) or multisystem, with or without involvement of risk organs (liver, spleen, haematopoietic system).

Pathophysiology.

Activating mutations in the MAPK signalling cascade, most often BRAF V600E in 50 to 60% and MAP2K1 in others, drive clonal proliferation of myeloid precursor cells.

Lesions contain Langerhans type cells with eosinophils, macrophages and lymphocytes, and cytokine release causes tissue injury. Pituitary infiltration causes diabetes insipidus, and later neurodegeneration can occur.

• Bone: painful swelling, most often of the skull, with lytic punched out lesions, as well as vertebrae (vertebra plana), femur and orbit.
• Skin: seborrhoeic like scalp rash, nappy area rash and papules, resistant to treatment.
• Ear: chronic otitis externa or media with discharge, mastoid disease.
• Pituitary: polyuria and polydipsia from diabetes insipidus, short stature and other endocrine deficiencies.
• Risk organ disease: hepatosplenomegaly, jaundice, hypoalbuminaemia, cytopenias and coagulopathy. Lung: cysts, cough, dyspnoea and pneumothorax.
• Systemic: fever, weight loss, failure to thrive and irritability in infants.

Red flags.

• Cytopenias, hepatosplenomegaly, jaundice or coagulopathy (risk organ involvement).
• Craniofacial bone lesions, particularly of the orbit, mastoid or temporal bone, with a risk of central nervous system disease.
• Polyuria and polydipsia, neurological signs or spinal lesions with cord compression.

• Biopsy of the most accessible lesion with CD1a and CD207 (langerin) staining, supported by S100. This confirms the diagnosis.
• BRAF V600E testing of tissue, which guides targeted therapy.
• Staging: full blood count, liver function, albumin, coagulation screen, urine osmolality, skeletal survey or whole body MRI or PET-CT, chest imaging, abdominal ultrasound, and MRI brain with pituitary views.
• Bone marrow examination when there are unexplained cytopenias.

Differential diagnosis. Osteomyelitis, Ewing sarcoma, neuroblastoma, leukaemia, lymphoma, eosinophilic granuloma mimics, seborrhoeic dermatitis, chronic otitis, haemophagocytic lymphohistiocytosis and other histiocytic disorders.

Single system disease.

• Unifocal bone lesion: observation, curettage or intralesional corticosteroid injection. Many lesions resolve spontaneously.
• Isolated skin disease: observation or topical treatment. Localised radiotherapy is reserved for threatened vital structures such as the optic nerve or the spinal cord.
• Multifocal bone disease or central nervous system risk lesions: systemic chemotherapy.

Multisystem disease.

• Induction with vinblastine 6 mg/m2 IV weekly for 6 weeks and prednisolone 40 mg/m2 orally daily for 4 weeks followed by a taper over 2 weeks. A second induction course is given if the response is incomplete at 6 weeks.
• Continuation for 12 months in total with vinblastine 6 mg/m2 IV every 3 weeks and prednisolone 40 mg/m2 daily for 5 days at each cycle. For risk organ disease, add mercaptopurine 50 mg/m2 daily.
• Refractory disease or relapse: cytarabine, cladribine, or BRAF inhibitors (dabrafenib, vemurafenib) for BRAF V600E disease. Haematopoietic stem cell transplantation is rarely used for refractory risk organ disease.
• Diabetes insipidus: desmopressin, with monitoring of sodium.

Monitoring. Clinical and imaging response at 6 weeks and at the end of treatment, and follow up for at least 5 years for reactivation (about a third), diabetes insipidus, neurodegeneration, hearing loss and orthopaedic sequelae.

Referral and escalation. All children should be managed with a paediatric oncology or haematology centre, and referred to endocrinology, neurology and ENT services for sequelae.