Langerhans cell histiocytosis : A clinical and immunological study

Abstract: Langerhans cell histiocytosis (LCH), previously known as histiocytosis X, eosinophilic granuloma, Hand-Schüller-Christian or Letterer-Siwe disease, is a rare disease with a reported incidence in childhood of 5.4 cases per million children per year. The disease can present at any age but young children are most often affected. It is characterized by an accumulation of abnormal and clonal Langerhans cells in various organs such as the skin, bone, lymph nodes, lungs, liver, spleen and bone marrow. The course of the disease is unpredictable, varying from a spontaneously healing isolated bone or skin lesion, to a chronic relapsing course resulting in permanent consequences, or to a multiorgan disease that can be fatal. The overall aim with this thesis has been to clarify the long-term course and outcome of patients with LCH, to investigate methods to detect and monitor disease activity and, finally, to elucidate if the HLA system may play a role in the pathogenesis of LCH. Initially a follow-up study of 49 patients, with reviewed and verified pathology findings, seen at Department of Pediatrics at the Karolinska Hospital 1962-1989 was performed, 40 of whom underwent physical examination and laboratory tests, as well as imagining (n=38). The 5-yr survival of 77% (17/22) in multi-system disease was significantly lower as compared to the 100% (27/27) survival of children who had singlesystem disease at diagnosis (p=0.014). Late sequelae of the disease or its treatment had developed in 42% of the follow-up patients, leaving only 51% (23/45) of all patients alive and healthy, at a median follow- up of 16 years, with the corresponding figure being 67% (16/24) for single-system and 33% (7/21) for multi-system disease (p=0.026). The late sequlae included diabetes insipidus (15%), severe CNS- complications (10%, affecting 25% of multi-system LCH patients), and late-stage pulmonary disease (11 %). The serious permanent consequences in the lungs and the CNS were further studied. High resolution computed tomography (HRCT) revealed late-stage radiographic abnormalities of the lungs (cysts and/or emphysema) in 24% of the patients at follow-up. These patients more often had multi-system rather than single-system LCH (p=0.01), were significantly older at diagnosis (p<0.001), and had been more heavily treated with chemotherapy and/or radiotherapy. They were also more frequently smokers (p<0.0001) and most (70%) had had lung involvement at diagnosis. In two adults, diagnosed with LCH in childhood, smoking preceded pulmonary involvement by three years. We conclude that LCH patients should avoid smoking tobacco and that patients with LCH should be informed about smoking-related pulmonary morbidity. In pulmonary LCH the physical examination is often unremarkable. Chest-X-ray is a valuable screening method for detection and monitoring. HRCT is more informative in monitoring the extent of the disease. Pulmonary function tests (PFT) give a better picture of the current lung function, and it is particularly valuable for monitoring alterations in pulmonary function. Prolonged monitoring of the lungs is suggested for smokers and patients with known pulmonary involvement. One of the most feared permanent consequences of LCH is severe neurological impairment. Patients with LCH-CNS were examined with positron emission tomography (PET) scan. The ability to detect metabolic changes in the CNS with PET provides additional information about the activity of the disease, and PET may also be a valuable method to assess the efficacy of therapeutic measures in LCH-CNS. Although recent studies have revealed clonality in LCH lesions and that Langerhans cells are immature with regard to phenotype as well as function, the underlying cause of this enigmatic disease remains unknown. The histopathological features of single-system and multi-system LCH are highly similar, but it is not yet known whether these manifestations have a common cause or whether each has a separate and distinct cause. In an attempt to elucidate if the HLA system may play a role in the pathogenesis of LCH, the largest reported pediatric cohort of ethnically homogeneous LCH patients (n=84) was analyzed for HLA associations. We found that patients with single-system LCH more often had the phenotype HLA -DRB1'03 as compared to patients with multi-system disease, suggesting an immunogenetic heterogeneity in the two clinical entities of LCH and indicating that the HLA-DRB1'03 phenotype may play a protective role against developing multi-system LCH.