LANGERHANS CELL HISTIOCYTOSIS (LCH) IN CHILDREN

Definition and Pathophysiology

• Langerhans Cell Histiocytosis (LCH):
  • A disorder of Langerhans cells, which are bone marrow–derived dendritic cells involved in antigen processing.
  • In LCH, these cells lose the ability to present antigens, leading to immunologic dysfunction.
• Normal Langerhans Cells: Found in the epidermis, lymph nodes, thymic epithelium, and bronchial mucosa.
  • Migrate to lymphoid tissues and stimulate T-cell responses.

Incidence

• Rarity: Affects approximately 3–5 children per million each year.

Clinical Presentations

1. Localized Disease
   • Common presenting sites include bone, skin, or lymph nodes.
   • Skin involvement in infants: Brown-purplish papules, often benign and self-healing in the first year of life.
   • Later in infancy: Red papular rash on neck, axilla, abdomen, back, groin, and scalp.
   • When skin-limited LCH is suspected, additional workup (CT of chest and abdomen, bone marrow biopsy) is warranted to rule out multisystem involvement.
2. Multisystem Disease
   • May present later in childhood with more extensive involvement (e.g., liver, spleen, bone marrow).

Bone Involvement

• Most Common Site: Skull (lytic lesions causing localized pain, swelling, and sometimes erythema).
• Other bones: Ribs, cervical vertebral bodies, humerus, femur.
• Mass-Effect Presentations:
  • Skull base, maxillofacial bone, or sellar involvement → hearing loss, exophthalmos, cranial nerve palsies, diabetes insipidus (DI).
• Skull Radiographs: May show irregular “geographic skull” lesions.

Endocrine Manifestations

• Diabetes Insipidus (DI):
  • Most common endocrine manifestation.
  • Can be the initial presenting symptom.
  • Often associated with anterior pituitary insufficiency and thickening of the pituitary stalk on imaging.

Lymph Node Involvement

• Isolated Lymphadenopathy:
  • Usually in the cervical or mediastinal lymph nodes.

Diffuse Multisystem Disease

• Liver and Spleen:
  • Clotting factor deficiencies, increased bilirubin, low albumin (liver involvement).
  • Splenomegaly can cause cytopenias.
• Lung Involvement:
  • Cystic and nodular pattern on imaging.
  • Pneumothorax may be an initial sign.
  • Can lead to diffuse fibrosis, resulting in dyspnea.
• Bone Marrow: Commonly affected in diffuse disease.
• Central Nervous System: Ataxia, cognitive dysfunction if the cerebellum or basal ganglia are involved.

Historical Terminology

• Hand-Schüller-Christian disease: LCH with prominent skull defects, DI, exophthalmos.
• Letterer-Siwe disease: LCH with extensive multiorgan involvement.
• Eosinophilic Granuloma: Localized lesion(s) confined to bone.

LANGERHANS CELL HISTIOCYTOSIS (LCH) IN ADULTS

Definition and Pathophysiology

• Same overall mechanism as in children: LCH is a disorder of bone marrow–derived Langerhans cells that lose their antigen-presenting ability.

Incidence and Demographics

• Rarity: Affects about 1–2 persons per million each year.
• Mean Age at Diagnosis: ~32 years.

Clinical Presentation

• Common Symptoms (in approximate order of frequency):
  1. Dermatologic (rash)
  2. Pulmonary (cough, dyspnea, tachypnea)
  3. Bone Pain
  4. Diabetes Insipidus (DI) (~25% of adult patients)
  5. Systemic (fever, weight loss)
  6. Lymphadenopathy
  7. Ataxia
  8. Gingival Hypertrophy
• Skin Lesions: Papular, pigmented (red, brown), possibly ulcerating in intertriginous areas.
• Bone Involvement:
  • Common sites: Mandible, skull, long bones, pelvis, scapula, vertebral bodies, ribs.
  • Jaw pain and “floating teeth” on dental radiographs if the mandible is involved.
  • Lytic lesions with a beveled edge on radiographs.
• Pulmonary LCH:
  • May present with pneumothorax.
  • Exacerbated by cigarette smoking.
  • Imaging: Diffuse honeycomb lung appearance on chest radiographs; CT shows typical nodules and cysts.
• Endocrine:
  • Diabetes Insipidus is irreversible in many adult LCH cases due to infiltrative damage to the hypothalamus and pituitary stalk.

Diagnosis

• Biopsy of Lesion:
  • Mixed cellular infiltrate with immature clonal Langerhans cells (positive for S100, vimentin, CD1a, antilangerin).
  • Eosinophils, macrophages, granulocytes, lymphocytes often present.
  • Multinucleated giant cells (foam cells) may appear with accumulated cholesterol.
• Full Laboratory and Imaging Workup:
  • CBC, liver function tests, coagulation studies, fasting urine/serum osmolality.
  • Imaging: Skeletal survey, skull radiographs, chest radiograph, possibly head MRI, chest CT, pulmonary function tests, bone marrow biopsy depending on symptoms.

Prognosis

• Influenced by:
  1. Age of Onset (better if older than 2 years)
  2. Number of Organs Involved
  3. Degree of Organ Dysfunction (e.g., hyperbilirubinemia)
• An adult with a single bone lesion may have an excellent outlook, whereas an infant with extensive multiorgan disease has a worse prognosis.

Treatment

• Stratification by Prognosis:
  • Chemotherapeutic Agents: Cladribine (2-chlorodeoxyadenosine), vinblastine, etoposide, methotrexate, 6-mercaptopurine.
  • Corticosteroids: Topical or systemic.
  • Radiotherapy (localized) and Surgical Curettage for solitary bone lesions.
  • Anticytokine Therapies: Under investigation.
  • Bone Marrow Transplantation: In refractory cases.