A case is presented of pulmonary Langerhans’ cell granulomatosis which recurred following lung transplantation and responded to cyclophosphamide. This suggests that the primary abnormality in this condition lies in the Langerhans’ cell or precursor dendritic cell.
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Pulmonary Langerhans’ cell granulomatosis, also known as eosinophilic granuloma of lung, is a disorder of unknown aetiology characterised by the focal interstitial proliferation of Langerhans’ cells1 which surround the terminal bronchioles and alveolar ducts. They may have marked destructive tendencies leading to cavities which can coalesce to form large bullous defects surrounded by scarring. As the disease progresses there may result a combination of fibrosis and focal emphysema culminating in the development of honeycomb lung.
The natural history is variable. Spontaneous resolution occurs in 25%, stabilisation with mild loss in pulmonary function occurs in 50%, and progressive disease in 25%.2 Death from respiratory failure or cor pulmonale occurs in approximately 5%.2Extrapulmonary manifestations such as diabetes insipidus and cystic bone lesions may occur.
Lung transplantation has been performed for patients with Langerhans’ cell granulomatosis.3 To our knowledge there have been no reported cases of symptomatic recurrence in the transplanted lung. We report a case of a young man transplanted for Langerhans’ cell granulomatosis in whom there was documented evidence of recurrence of disease in the transplanted lung which responded to treatment with cyclophosphamide.
A 32 year old man presented with a four year history of progressive dyspnoea and cough . He was cyanosed on room air and had clinical features of pulmonary hypertension. Chest examination revealed inspiratory crackles and the chest radiograph showed interstitial shadowing with small thick walled cysts and prominent pulmonary arteries. He had been a lifelong non-smoker. Diabetes insipidus had been diagnosed at the age of 12 and treated with nasal desmopressin. Lung physiology revealed a restrictive defect with a vital capacity of 3.08 litres (60% predicted) and a carbon monoxide transfer factor of 2.26 mmol/min/kPa (20% predicted). On air he had aPo2 of 7.8 kPa, Pco2 of 5.6 kPa, and Sao 2 of 90%. Pulmonary systolic artery pressure was estimated at 96 mm Hg by Doppler echocardiography.
A diagnosis was made of Langerhans’ cell granulomatosis with associated pulmonary hypertension. He deteriorated despite prednisolone, oxygen, diltiazem and warfarin and underwent bilateral sequential lung transplantation. Histological examination of his explanted lungs revealed extensive scarring and interstitial fibrosis with focal inflammatory infiltrates of histiocytic appearing cells which demonstrated immunohistochemical reactivity for S100 antigen. There was, in addition, focal air space dilatation and emphysema and intimal fibrosis in the pulmonary arteries confirming the diagnosis of Langerhans’ cell granulomatosis with associated pulmonary hypertension.
The immediate post-transplantation course was uncomplicated and shortly afterwards his requirement for nasal desmopressin was reduced, presumably as a result of immunosuppressive therapy. His course until two years after transplantation was uneventful with progressive improvement in lung function and arterial blood gas tensions until stable levels were achieved. Routine triple therapy immunosuppression (cyclosporin A, azathioprine, prednisolone) was maintained until 12 months after transplantation but azathioprine was then discontinued due to a persistently low white cell count.
Routine two year transbronchial biopsy specimens revealed interstitial infiltration by large histiocytic like cells mingled with lymphocytes and eosinophils. The histiocytic appearing cells showed characteristic features of Langerhans’ cells with eccentric and grooved nuclei and pink granular cytoplasm which again demonstrated immunohistochemical reactivity for S100 antigen. Over the next six months he developed progressively restrictive lung function associated with dyspnoea and increased requirement for nasal desmopressin. A high resolution computed tomographic scan demonstrated changes compatible with interstitial fibrosis. Repeat transbronchial biopsy specimens, now 30 months after transplantation, demonstrated interstitial fibrosis with large aggregates of Langerhans’ cells centred around terminal bronchioles (fig 1). There was no evidence of acute rejection, infection, or obliterative bronchiolitis. A diagnosis of recurrent Langerhans’ cell granulomatosis was therefore made.
He was commenced on cyclophosphamide 50 mg per day and maintained on cyclosporin and prednisolone. His symptoms and lung function improved and his requirement for nasal desmopressin was reduced. After 12 months he remains well on cyclophosphamide 50 mg per day.
Langerhans’ cell granulomatosis is a rare interstitial disorder of unknown origin with variable clinical presentation, natural history, and response to therapy. Lung transplantation has been successfully performed for refractory cases associated with progressive respiratory failure.3 We describe the first case of symptomatic recurrent Langerhans’ cell granulomatosis following bilateral sequential lung transplantation.
Langerhans’ cells are normally present in the human lung. They are morphologically similar to and most probably derived from dendritic cells and are distinguished from histiocytes by characteristic cytoplasmic immunostaining with S100 antigen.4 Dendritic cells are derived from bone marrow stem cells and arrive in the lung by the capillary bed where they differentiate into Langerhans’ cells. Langerhans’ cells are also seen with interstitial pneumonitis and other lung diseases but it is the formation of large aggregates which distinguishes Langerhans’ cell granulomatosis and leads to the destruction seen.
In our patient the presence of focal aggregates of Langerhans’ cells in association with clinical, physiological, and radiological deterioration confirms recurrence of disease. The associated increased requirement for nasal desmopressin is compatible with development of new granulomas in the pituitary/hypothalamus although this was not formally assessed by MRI scanning.
Langerhans’ cells are potent immune accessory cells whose normal role is to present antigen to lymphocytes.5 However, the initiating factor in Langerhans’ cell granulomatosis is unknown although the condition is more common in smokers. Recurrence of the disease after transplantation supports the view that the primary abnormality lies in the Langerhans’ cells or precursor dendritic cells.
There are no controlled trials of treatment of Langerhans’ cell granulomatosis. Many patients are asymptomatic and require no therapy other than advice to stop smoking and observation. For symptomatic patients corticosteroids are often effective.6Cytotoxic drugs such as cyclophosphamide have been used in patients not responding to corticosteroids and those with systemic disease.7 We elected to use cyclophosphamide as the patient was already on prednisolone and, in addition to recurrent pulmonary disease, there was also evidence of systemic activity with increased requirement for nasal desmopressin. There was an improvement in lung function and reduction in the requirement of nasal desmopressin, confirming its efficacy.
We have successfully performed lung transplantation on four other patients with Langerhans’ cell granulomatosis and reviewed the pathology of all biopsy specimens. In one other case one biopsy specimen showed aggregates of S100 staining cells but only to a mild degree and not associated with any symptoms or changes in chest radiographs or pulmonary physiology. Large aggregates of Langerhans’ cells have not been found in any other patients who have undergone lung transplantation at our institution including the three other patients transplanted for Langerhans’ cell granulomatosis.
In summary, recurrent focal aggregates of Langerhans’ cells were found in two patients transplanted for Langerhans’ cell granulomatosis. In one case this was associated with clinical, physiological, and radiological evidence of disease recurrence. Initiation of treatment with cyclophosphamide was associated with rapid improvement in symptoms and lung physiology. Recurrence of Langerhans’ cell granulomatosis in transplanted lungs has implications for the pathogenesis of the disease in keeping with the primary abnormality lying with the Langerhans’ or dendritic cells themselves.