Recurrent pneumothorax, skin lesions and frequent urination

Discussion

LCH is a rare disorder characterised by abnormal function and proliferation of histiocytes, which are cells of the mononuclear phagocyte system. Abnormal histiocytes, along with lymphocytes, eosinophils and normal histiocytes, form infiltrates in various organs [1]. It can affect any age group but is better recognised in children. The incidence of LCH among adults is estimated to be 1–2 cases per million [12].

The clinical presentation is diverse and varied, ranging from self-limited lesions to life-threatening disease depending on the organs involved. Of all adult patients registered in the international Histiocyte Society registry, 31% have single-site disease while 69% have multisystemic disease [12]. Bone, skin, liver, ear and lymph node involvement are less common in adults than children. Isolated pulmonary involvement and involvement of genital and oral mucosa are more common in adults than children. Mortality is high if the liver, spleen, central nervous system or bone marrow is involved, and hence these patients are classified as having high-risk LCH [13]. Chest radiography may be normal or may show reticulonodular opacities and cysts. High-resolution CT of the chest reveals nodules, cavitating nodules and cysts with normal intervening lung parenchyma. Cysts predominantly involve the upper and middle lobes but when LCH develops in teenagers, cysts may be lower lobe predominant. In the early stages, only nodules are present, which later cavitate and form cysts. As the disease progresses, cysts coalesce to form irregularly shaped cysts. A skeletal survey with radiographs of the skull, spine, pelvis, and upper and lower limbs is recommended to look for bone lesions. FDG-PET-CT is needed to detect bony lesions and lesions at other sites [14]. Bronchoalveolar lavage may show ≥5% CD1a⁺ cells but has low sensitivity. Transbronchial lung biopsy is diagnostic in 17–50% of cases and may obviate the need of a surgical lung biopsy. Biopsies should be obtained from nodular areas [15, 16]. Histopathological examination shows loosely formed granulomas containing CD1a⁺/CD207⁺ cells especially around small airways [14]. CD1a and CD207 are present on Langerhans cells and they are used as specific markers to distinguish Langerhans cells from other dendritic cell subtypes [17]. BRAF V600E genotyping and MAP2K1 gene sequencing can be performed, as it has been shown that patients with these mutations may exhibit an aggressive course, may show poor response to vinblastine, have high risk of relapse and may benefit from targeted therapy [18, 19]. The patient refuses these investigations due to cost. Biopsy of an extrapulmonary lesion like skin or bone, if present, may also confirm the diagnosis. As your patient complains of polyuria and polydipsia, and as diabetes insipidus is known to occur in LCH, 24-h urinary volume and osmolarity are measured [20]. Diabetes insipidus is due to deficiency of arginine vasopressin due to involvement of the posterior pituitary, which is confirmed in our case by magnetic resonance imaging of brain showing loss of the posterior pituitary bright spot with a thickened nodular stalk.

Pneumothoraxes caused by rupture of subpleural cysts are common and may be recurrent. Definitive management may be challenging, and may involve surgical and/or medical interventions. There are no randomised controlled trials on treatment of adult LCH, so therapeutic regimens have not yet been confirmed. At present, standard chemotherapy regimen for multisystemic LCH in children is the combination of prednisolone (1 mg·kg⁻¹ up to a maximum of 60 mg for 4 weeks) and vinblastine (6 mg·m⁻² up to a maximum of 10 mg every week for 6 weeks) followed by vinblastine (every 3 weeks) along with prednisolone (first 5 days every 3 weeks) and daily 6-mercaptopurine (30 mg·m⁻² up to a maximum of 50 mg) [20].

Our patient shows a favourable response to the above regime. He does not have any recurrence of pneumothorax, FVC increases, skin lesions resolves and no new lesions appear. Diabetes insipidus, once established, is permanent and our patient requires nasal desmopressin for control of diabetes insipidus [21]. His peripheral neuropathy resolves after reducing the dose of vinblastine.

Pulmonary Langerhans cell histiocytosis (PLCH) is almost exclusively seen in smokers. Our case is a never-smoker. Lung involvement in multisystemic LCH is believed to be due to clonal proliferation of Langerhans cell histiocytes in the lungs. Cigarette smoke plays an important role in pathogenesis of PLCH. Cigarette smoke activates the Langerhans cells in the lung directly and indirectly by stimulating the airway epithelial cells and macrophages to secrete various cytokines and chemokines that cause recruitment, retention and activation of Langerhans cells. These activated Langerhans cells, in certain individuals with favourable host factors, recognise autoantigens in the lung and are responsible for lung parenchymal destruction. Thus, PLCH is due to reactive proliferation of Langerhans cell histiocytes in lung induced by smoking [22]. Unlike PLCH, lung involvement in multisystemic LCH occurs irrespective of smoking status.