Pulmonary Langerhans Cell Histiocytosis

A rare smoking related clonal myeloid neoplasm of dendritic cells (Langerhans cells), forming bronchiolocentric nodules that cavitate and become cysts.

• Mainly in smokers aged 20 to 40 years (more than 90% smoke); incidence is about 1 per million per year; BRAF V600E mutation is found in about 30 to 50% and MAP2K1 mutations in others.
• Mechanism: tobacco-driven recruitment of dendritic cells with abnormal activation of the mitogen activated protein kinase pathway, causing granulomatous inflammation, fibrosis and cystic change.
• Isolated lung disease is the most common form in adults; multisystem disease (bone, pituitary, skin, liver, lymph node) is found in about 10 to 15%.

Dry cough, exertional breathlessness, fatigue, weight loss, fever; about 25% are asymptomatic; pneumothorax occurs in 10 to 20% and is often the first sign.

• Chest pain from bone lesions, diabetes insipidus (polyuria and polydipsia) in 5 to 15% with multisystem disease, rash.
• Examination is often normal; late disease shows hyperinflation and signs of pulmonary hypertension.
• Differential diagnosis: lymphangioleiomyomatosis, emphysema, respiratory bronchiolitis interstitial lung disease, Sjogren syndrome cysts, lymphoid interstitial pneumonia, Birt-Hogg-Dube syndrome, sarcoidosis, tuberculosis, cavitating metastases, hypersensitivity pneumonitis.
• Complications: pneumothorax and recurrence, pulmonary hypertension (in up to 50% of advanced disease), respiratory failure, cor pulmonale, diabetes insipidus, bone fracture, and secondary malignancy (lung cancer and haematological cancers) in smokers.

High-resolution CT: early stage with centrilobular nodules (2 to 10 mm) and cavitating nodules, later thin and thick walled bizarre-shaped cysts in the upper and middle zones sparing the costophrenic angles; late disease with cysts only.

• Pulmonary function: reduced diffusing capacity (often markedly), normal or mildly obstructive or restrictive spirometry, reduced exercise capacity.
• Bronchoalveolar lavage: CD1a positive cells more than 5% is highly suggestive but uncommon.
• Biopsy (video assisted thoracoscopic or transbronchial cryobiopsy) when imaging is not typical: CD1a, langerin (CD207) and S100 positive cells; test for BRAF V600E.
• Staging for multisystem disease: full blood count, liver tests, osmolality and water deprivation test, MRI pituitary, skeletal survey or PET-CT, abdominal ultrasound; echocardiogram for pulmonary hypertension.

Stopping smoking is the cornerstone: varenicline 0.5 mg once daily for 3 days, 0.5 mg twice daily for 4 days, then 1 mg twice daily for 12 weeks; nicotine patch 21 mg/24 hours for 6 weeks then 14 mg for 2 weeks and 7 mg for 2 weeks; avoid passive smoke and cannabis. About one third improve or resolve, one third stabilise and one third progress.

• Corticosteroids for symptomatic or progressive disease despite quitting: prednisolone 0.5 mg/kg daily (usual 30 to 40 mg) for 4 to 6 weeks, then taper over 6 to 12 months (evidence is limited and the response is variable).
• Systemic therapy for progressive or multisystem disease:
  • Cladribine 0.1 mg/kg daily (or 5 mg/m2) by IV or SC infusion for 5 days every 4 weeks for 2 to 6 cycles (evidence limited); monitor blood counts and give Pneumocystis prophylaxis.
  • Cytarabine 100 mg/m2 daily for 5 days every 4 weeks, or vinblastine 6 mg/m2 weekly with prednisolone, as alternatives.
  • BRAF inhibitors for BRAF V600E disease: vemurafenib 960 mg twice daily or dabrafenib 150 mg twice daily (evidence limited, relapse after stopping).
• Pneumothorax: chest drain with early surgical or medical pleurodesis after the first episode because of the high recurrence rate (about 50% without pleurodesis).
• Pulmonary hypertension: oxygen to keep SpO2 90% or more; sildenafil 20 mg three times daily or tadalafil 40 mg daily (evidence limited); diuretics (furosemide 20 to 80 mg daily) for right heart failure.
• Diabetes insipidus: desmopressin 0.1 to 0.2 mg orally two to three times daily, or 10 to 20 micrograms intranasally once to twice daily, with sodium monitoring.
• Pulmonary rehabilitation, annual influenza and pneumococcal conjugate vaccine, bone care, and lung transplantation for end stage disease (recurrence in the graft is possible; 5 year survival is about 50 to 60%).
• Special groups: children (usually multisystem disease managed by paediatric oncology with vinblastine and prednisolone); pregnancy (risk of pneumothorax and worsening of pulmonary hypertension; plan with respiratory and obstetric teams, avoid cladribine and BRAF inhibitors); elderly (smoking cessation and surveillance for lung cancer); renal impairment (reduce cladribine dose); immunosuppression (prophylaxis with co-trimoxazole 960 mg three times weekly).
• Red flags: pneumothorax, haemoptysis, severe breathlessness, right heart failure, polyuria, bone pain, new mass or rapid cyst growth.
• Follow-up: spirometry and diffusing capacity every 3 to 6 months at first, CT at 6 to 12 months then yearly if stable, echocardiogram yearly, lifelong smoking abstinence reviews; overall 10 year survival is about 75% (approximate).