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Central nervous system involvement in Langerhans cell histiocytosis: the importance of long term follow‐up

L angerhans cell histiocytosis (LCH) is a rare disease predominantly afflicting children but also occurring in adults. This enigmatic disease is a disorder of cells of the mononuclear phagocyte system with the abnormal proliferation of dendritic cells accompanied by features of a chronic inflammatory disease [1]. The disease may present as either lesions affecting a single organ or as multi-organ disease and the lesions may be self-resolving or lead to progressive severe and even fatal disease. It has long been recognized that LCH may affect the central nervous system (CNS) although the reported frequency varies widely between different cohorts [2]. The most common feature of CNS involvement is the presence of diabetes insipidus (DI) and other endocrinological problems indicating involvement of the pituitary. However, in some cases the disease may have features of a progressive neurodegenerative disease. It is clearly important to detect CNS involvement in LCH since the degree of morbidity that can result from CNS damage may be significant and include motor deficits, cognitive deficits, and diverse behavioral problems. Furthermore, in an organ with limited capacity for repair early intervention is likely critical. In this issue of Pediatric Blood & Cancer Laurencikas et al. report the incidence of CNS involvement in a cohort of children in Stockholm County, Sweden diagnosed with LCH during 1992– 2001. Of 29 children diagnosed with LCH magnetic resonance imaging (MRI) was performed at a single center on 16 of the children on the basis of clinical indicators including abnormal endocrine findings and clinical CNS symptoms. CNS abnormalities were detected in eight children with amedian time of 3.5 years from the diagnosis of LCH. Importantly, 7 of the 29 children (24%) had an MRI signature consistent with some degree of neurodegeneration. The authors conclude that their findings imply a minimal incidence of 2.1/10 children per year with LCH-associated CNS neurodegeneration. The relatively high incidence of CNS involvement in children with LCH reported in this study not only highlights the need for long-term follow up in children diagnosed with LCH, using appropriate neurological, radiological, and psychological testing, but also raises important questions as to the nature of the pathology in CNS–LCH. What we know of the CNS pathology in LCH is limited but theHistiocyte Society CNSLCH study group havemade important advances [3]. The combination of MRI and study of limited tissue samples highlights the importance of both tumorous lesions, typically in sites lacking a blood brain barrier (BBB) such as the pituitary and pituitary stalk, and non-tumorous lesions with an MRI signal more consistent with neurodegeneration [2,3]. The tumorous or granulomatous lesions have a cellular composition similar to that seen in peripheral LCH tissue lesions with accumulations of CD1aþ cells and other inflammatory cells. The brain parenchymal lesions in the cerebellum and brain stem appeared to lack CD1aþ cells but there was evidence of inflammation, including the accumulation of CD8þ T cells, with evidence of axonal damage and neuronal loss [3]. The absence of CD1aþ is puzzling but may reflect the fact these cells have invaded but failed to persist in the CNS, have altered their phenotype once within the CNS, or reflect an autoimmune disease processes perhaps triggered by the initial LCH lesion. These pathological findings also raise fundamental questions as towhy theLCH lesions should have a predilection for particular brain regions such as the pituitary, cerebellum, and brainstem. A possibility is that the lesion distribution is related to the absence of the BBB and/or rates of local mononuclear phagocyte cell turnover by replacement from the blood. The absence of the BBB may account for the incidence of pituitary involvement but there are other circumventricular organs that also lack aBBB and appear not to be commonly involved. There is evidence of cells with bothmacrophage andDC phenotypes in the anterior and posterior pituitary [4] although there is no data to informon how rapidly these cells populations are replaced by bloodborne cells. The resident macrophages populations of the brain have been extensively studied in recent years, given their involvement in essentially all injuries and diseases of the CNS [5]. The microglia and perivascularmacrophages of the brain aremyeloid-derived cells but there is no direct evidence that the brain parenchyma contains a population of dendritic cells [5]. The evidence from animal models suggests that there is limited traffic of blood-borne cells to the healthy brain [6] and the rate of local turnover of microglia is very slow when compared to other tissues [7]. The risk factors for CNS involvement in LCH beyond the pituitary include the presence of craniofacial LCH lesions, pituitary lesions, and chronic LCH disease [2]. These observations suggest that there may be pathways of cellular migration shared between tissue compartments of the craniofacial lesions, pituitary lesions, and invasion of the parenchyma per se. It is unclear that there are such shared pathways and the coincidence betweenCNS lesions and craniofacial lesions is unexplained although it has been suggested that intracranial lesions may stimulate chemokine synthesis in the brain that leads to parenchymal invasion [2]. However, recent