Langerhans Cell Histiocytosis Patients Research Articles

High Dose Immunoglobulin (IVIG) May Reduce the Incidence of Langerhans Cell Histiocytosis (LCH)-Associated Central Nervous System Involvement

Diabetes insipidus and neurodegenerative disease are the two major CNS complications of Langerhans cell histiocytosis (LCH). Once it has developed, diabetes insipidus is permanent, while the outcome of neurodegenerative disease is dismal. The development of these CNS-LCH complications is closely correlated with "CNS-risk" organ involvement, namely, the presence at diagnosis of LCH lesions in cranio-facial areas. Based on recent data showing the beneficial effects of intravenous immunoglobulin (IVIG) treatment on inflammatory diseases of the CNS, we are currently testing whether monthly IVIG treatment (0.4 g/kg/dose) can alleviate the progression of neurodegenerative disease in LCH patients. We also hypothesize that the incidence of CNS complications could be reduced by the prophylactic administration of high dose IVIG therapy (2 g/kg/dose), combined with conventional induction chemotherapy, that is provided before CNS lesions are detected in "CNS-risk"-LCH patients.

Langerhans cell histiocytosis with multifocal bone lesions: comparative clinical features between single and multi-systems

Langerhans cell histiocytosis (LCH) can be a single system or multi-system disease. Both disease types can be associated with multi-focal bone lesions, but their bone involvement patterns have not been compared systematically. Of the new pediatric LCH cases enrolled into the JLSG-02 study during 2002-2007, 67 cases of single system multifocal bone (SMFB) LCH and 97 cases of multi-system bone (MSB) LCH were analyzed to determine if the bone involvement patterns differ in these two types, and whether these differences correlate with outcome. Statistical analysis was performed with Mann-Whitney U test, Fisher's exact test, and other measures. Onset ages were higher for SMFB (P < 0.001), but the two types did not differ in the number of bone lesions per patient. The skull was most frequently affected in both types, followed by the spine. Lesions in the temporal bone (P = 0.002), ear-petrous bone (P < 0.001), orbita (P = 0.003), and zygomatic bone (P = 0.016) were significantly more common in MSB. The two types did not differ in response to treatment, but MSB was associated with a significantly higher incidence of diabetes insipidus (DI) (P < 0.001). Novel measures are required in preventing the development of DI in MSB-type LCH patients with "risk" bone lesions.

Spontaneous Regression of Isolated Neurohypophyseal Langerhans Cell Histiocytosis with Diabetes Insipidus

In pediatric and adolescent patients, the most common causes for a thickened pituitary stalk with central diabetes insipidus are germ cell tumors, lymphocytic infundibuloneurohypophysitis (LIN), and Langerhans cell histiocytosis (LCH). We describe here a 13-year-old girl who had an abrupt onset of polyuria and polydipsia. Magnetic resonance imaging of the brain revealed thickening of the pituitary stalk, and loss of the physiological hyperintense signal of the posterior pituitary gland. Based on a histopathology, she was diagnosed as having LCH. Another LCH lesion was not detected. The prognoses for LCH patients with single-system and single-site are generally good so we decided on only simple observation. The lesion spontaneously regressed 3 months later, resembling a typical self-limiting course of LIN. In conclusion, the present case suggests that 1) radiological differential diagnosis between LIN and LCH is so difficult that histological confirmation is crucial for correct diagnosis, 2) some past cases of histologically-unconfirmed LIN can include LCH, 3) solitary neurohypophyseal LCH can shrink spontaneously up to near remission level.

Analysis of Trace Elements in Bronchoalveolar Lavage of Patients with Diffuse Lung Diseases

Airborne trace elements are implicated in the etio-pathogenesis of a large number of pulmonary diseases. The aim of this study was to evaluate the reliability and effectiveness of direct determination of Cd, Cr, Cu, Fe, Mn, Ni, Pb, V, and Zn concentrations in bronchoalveolar lavage (BAL) samples from patients with sarcoidosis, idiopathic pulmonary fibrosis, and Langerhans cell histiocytosis and healthy (smoking and non-smoking) controls. A total of 44 individuals were recruited among sarcoidosis, idiopathic pulmonary fibrosis, and Langerhans cell histiocytosis patients and healthy (smoking and non-smoking) controls. Average Mn concentrations in BAL from patients were 45% lower than in controls (p < 0.01) and remarkable decreases in average concentrations of Cr, Ni and Zn were also found in BAL from patients with idiopathic pulmonary fibrosis and Langerhans cell histiocytosis. As these diseases are characterized by the enhanced activation of certain immunomodulatory cells and by generation of free radicals, the depressed Mn, Zn, Cr and Ni concentrations in BAL from patients may be due to oxidative stress. These preliminary results indicate that assessment of the elemental composition of BAL is a promising approach to study the pathogenesis of diffuse lung diseases and Langerhans cell histiocytosis.

Neuropsychological sequelae in patients with neurodegenerative Langerhans cell histiocytosis

Patients with Langerhans cell histiocytosis (LCH) may develop neurodegeneration and significant CNS sequelae, affecting a significant proportion of the patients. We here aimed to investigate the neuropsychological consequences in more detail. Using an extensive neuropsychological test battery, we evaluated nine LCH patients, 6-20 years old, with radiological signs indicative of neurodegeneration. Altogether 3/9 patients performed below 1 SD of normal for age on full IQ. Detailed analysis revealed that 4/9 had deficient performance IQ, whereas 1/9 had subnormal verbal IQ (defined as below 1 SD). Furthermore, 3/8 patients showed slow speed of performance for age. Notably, 8/9 (89%) had deficient verbal working memory and 7/8 (88%) performed below normal on visual-spatial working memory. The results indicate a specific, uneven neuropsychological profile in patients affected by CNS-LCH, with a decline particularly on perceptual tasks whereas the verbal performance was not as negatively influenced. Furthermore, verbal and visual-spatial working memory functions were below normal for age in all but one patient studied. LCH may easily be misdiagnosed, but it is important that individuals affected by CNS-LCH are diagnosed to provide advice and support. It remains a challenge to find a treatment reducing this unfortunate neurodegeneration.

A case of adult Langerhans cell histiocytosis showing successfully regenerated osseous tissue of the skull after chemotherapy

Langerhans cell histiocytosis (LCH) is a proliferative disorder of Langerhans cells and extremely rare in adults. Adult LCH is often associated with osteolytic bone lesions, but large bone-defective lesions have been rarely reported. We report an adult case of LCH accompanied by large osteolytic lesions in the skull that successfully responded to chemotherapy. A 47-year-old woman with LCH who had multiple, large osteolytic areas of more than 3 cm in diameter in the skull was admitted to our hospital. She was treated with systemic chemotherapy consisting of prednisolone, vinblastine, and 6-mercaptopurine. Twelve months later, when she completed the treatment, osteolytic areas were covered with hard osseous tissue, and X-ray examination confirmed regeneration of the bone. This case indicates that chemotherapy can be effective even for the treatment of large osteolytic lesions in adult LCH patients.

Häufigkeit von Hörstörungen bei Langerhans-Zell-Histiozytose im Kindes- und Jugendalter

The aims of the study were to find out the frequency of hearing disorders in children with Langerhans' cell histiocytosis (LCH) and to find out possible risk factors for hearing disorders due to the disease itself and the therapy. 30 patients with LCH were examined audiologically by using standard audiometric procedures. In cases of central nervous system (CNS) lesions, brainstem evoked response audiometry (BERA) was done additionally. A significant hearing disorder was defined as a hearing impairment affecting speech, thus being characterized by the following features: Both ears should present either conductive and/or sensorineural hearing loss of at least moderate degree. The frequencies important for speech development (1 - 4 kHz) had to be affected. Also, prolongation of BERA interpeak latencies was regarded as a significant hearing impairment, because those children had an increased risk for a central auditory and speech processing disorder. In our study 3 patients had a significant hearing disorder according to our definition. The prevalence of a significant hearing disorder is increased in patients with LCH compared to the prevalence of permanent hearing disorders in German children. We found the following risk factors for the development of a significant hearing disorder: LCH of the temporal bone, CNS lesions. We recommend periodical audiological follow up examinations for LCH patients with lesions of the temporal bone and/or the brain. BERA is indicated in cases with CNS lesions, because central auditory and speech processing disorders are possible in those patients.

Skeletal Langerhans cell histiocytosis in children: Permanent consequences and health‐related quality of life in long‐term survivors

The skeleton is the most frequently involved organ in Langerhans cell histiocytosis (LCH) in children, and bone LCH generally has an excellent long-term survival. Although permanent consequences (PC) are described in half of the survivors thus raising concerns for quality of life (QOL), the impact on quality of life has not been formally studied. A retrospective review was performed on 124 LCH patients with skeletal involvement, followed by prospective evaluation of PC and health-related QOL using age-appropriate validated study tools (PedsQL or SF-36). Of the 116 survivors, PC were found in 34 (29%) patients, of whom 8 had more than 1 PC. PC were significantly more frequent in multi-system (M-S) than in single system (S-S) LCH (73% vs. 17%; P < 0.0001). While diabetes insipidus (65%) was the most common PC in M-S LCH, cosmetic and orthopedic problems made up the majority of PC in S-S LCH. The median follow-up time was 8.5 years. 27 patients completed the PedsQL survey and 22 the SF-36 survey. The QOL scores for LCH patients were not significantly different from healthy children in the PedsQL survey and from young adults in the SF-36 survey. In addition, the QOL scores were very similar between patients with and without PC and between patients with M-S and S-S LCH. Children with M-S LCH had a significantly higher risk of developing PC. Skeletal LCH did not adversely affect the quality of life of survivors, including those with PC who appeared to adapt to their disabilities and medical problems.

Lessons to be learned — Langerhans' cell histiocytosis

Langerhans' cell histiocytosis (LCH) is a neoplastic disease due to uncontrolled proliferation of Langerhans' cells (LCs); damage to organs involved appears to be due to the various cytokines secreted. The true cause of LCH remains a mystery. LCH can present at any age; there is female predominance and the skin is often the first site to be involved. Scaly papules, vesicles, purpuric nodules, plaques and ulcers are the main diverse presentations typically found on the scalp, flexures (including the perineum), crease below the breast, palms, soles and nails. The patient described here is a 35-year-old Saudi Arabian woman with a vulval ulcer that had been misdiagnosed as an infective lesion 11 months before the correct diagnosis of LCH was made by means of biopsy examination. Diffuse infiltration of LCs with large pale reniform/convoluted nuclei and abundant amphophilic cytoplasm in the company of neutrophils, eosinophils, lymphocytes and plasma cells were observed on light microscopy. Immunohistochemical staining, indicating S100 protein positivity in LCs and the demonstration of Birbeck granules by means of electron microscopy, confirmed the diagnosis. The 'skin-only' LCH may later progress to involve other organs; alternatively skin lesions may be part of the multisystem, disseminated disease. There is need for careful follow-up of all LCH patients, as the course of the disease cannot be reliably predicted from either the clinical presentation or histology of the lesion. In many cases the prognosis is good, there being limited involvement that does not progress. Surgery or local steroids might suffice as therapy. However, for severely symptomatic disease, in which there are complications associated with dysfunction (or failure) of vital organs such as the liver, lungs, and central nervous system, the use of a variety of immunosuppressive treatments--and the recently described 2-chloro-2-deoxyadenosine (2CdA) (cladribine)--have been suggested; however, the type and extent of disease that will respond to this therapy has not yet been clarified. Solid laboratory research and rigorous clinical trials are required for more effective and less toxic therapies for patients with progressive LCH.

Analysis of outcome for patients with mass lesions of the central nervous system due to Langerhans cell histiocytosis treated with 2‐chlorodeoxyadenosine

To assess the activity and tolerability of 2-chlorodeoxyadenosine (2-CDA) in treating mass lesions of the central nervous system (CNS) due to Langerhans cell histiocytosis (LCH). The records of eight children and four adults with CNS LCH who were treated with 2-CDA were reviewed. The pattern of CNS disease included involvement of the hypothalamic-pituitary axis, gadolinium enhancing parenchymal as well as dural and choroid plexus based mass lesions, and atrophy. 2-CDA (5-13 mg/m(2)/day) was given on 3-5 consecutive days and repeated every 2-8 weeks for a period ranging from 3 to 12 months. Eight patients demonstrated a complete radiographic response to 2-CDA with resolution of all enhancing mass lesions and four patients showed a sustained, partial radiographic response. One patient died from a non-treatment related cause without evidence of LCH on autopsy. With a follow-up ranging from 2 to 10 years after completion of therapy, the 11 surviving patients remain in continuous remission or are progression free. Prolonged bone marrow suppression was the most common toxicity (four patients). Permanent sequelae of CNS LCH, such as panhypopituitarism, diabetes insipidus (DI) and neurocognitive dysfunction, were not found to be reversible with 2-CDA therapy. 2-CDA is an active agent in patients with CNS LCH, with the possible exception of neurodegenerative disease, and should be further evaluated in a prospective multi-center clinical trial for LCH patients with enhancing mass lesions of the CNS.

Cardiovascular risk factors in adult patients with multisystem Langerhans-cell histiocytosis: evidence of glucose metabolism abnormalities

Langerhans-cell histiocytosis (LCH) is a rare disease with features of chronic inflammation and it may also induce hypopituitarism, conditions associated with an increased risk of cardiovascular diseases. Cardiovascular and metabolic risk profile investigation in multisystem LCH patients with and without anterior pituitary deficiency. Prospective, observational study. Fourteen adult patients with LCH, 7 with and 7 without anterior pituitary deficiency, and 42 controls matched for age, body mass index (BMI) and smoking. Cardiovascular risk factors were estimated in all subjects: glucose and lipid profile, mathematical indices of insulin resistance (IR), blood pressure, structural arterial and functional endothelial properties (intima-media thickness, brachial artery flow-mediated dilatation). Cardiovascular risk factors were estimated in the three groups studied; the effect of disease activity and/or treatment was also determined in patients with LCH. Ten patients had diabetes insipidus, and 7 anterior pituitary hormone deficiencies: 8 patients had active disease and 11 had received systemic treatment. No difference was observed between the study groups in vascular parameters, in lipid profile or in blood pressure. However, the insulin resistance index GIR was decreased in patients with LCH without anterior pituitary deficiency compared to controls (P = 0.033). Three patients had impaired glucose tolerance and one diabetes mellitus type 2. These patients were older and had active disease; there was no association with hypopituitarism and/or previous treatment. Adults patients with LCH have abnormalities of glucose metabolism that tend to occur in patients with active disease, and may be a consequence of the pro-inflammatory state.

Impact of reactivation on the sequelae of multi‐system Langerhans cell histiocytosis patients—response

Impact of reactivation on the sequelae of multi‐system Langerhans cell histiocytosis patients—response

Impact of reactivation on the sequelae of multi‐system Langerhans cell histiocytosis patients

Impact of reactivation on the sequelae of multi‐system Langerhans cell histiocytosis patients

Expansion of Regulatory T Cells in Patients with Langerhans Cell Histiocytosis

BackgroundLangerhans cell histiocytosis (LCH) is a rare clonal granulomatous disease that affects mainly children. LCH can involve various tissues such as bone, skin, lung, bone marrow, lymph nodes, and the central nervous system, and is frequently responsible for functional sequelae. The pathophysiology of LCH is unclear, but the uncontrolled proliferation of Langerhans cells (LCs) is believed to be the primary event in the formation of granulomas. The present study was designed to further investigate the nature of proliferating cells and the immune mechanisms involved in the LCH granulomas.Methods and FindingsBiopsies (n = 24) and/or blood samples (n = 25) from 40 patients aged 0.25 to 13 y (mean 7.8 y), were studied to identify cells that proliferate in blood and granulomas. We found that the proliferating index of LCs was low (∼1.9%), and we did not observe expansion of a monocyte or dendritic cell compartment in patients. We found that LCH lesions were a site of active inflammation, tissue remodeling, and neo-angiogenesis, and the majority of proliferating cells were endothelial cells, fibroblasts, and polyclonal T lymphocytes. Within granulomas, interleukin 10 was abundant, LCs expressed the TNF receptor family member RANK, and CD4+ CD25high FoxP3high regulatory T cells (T-regs) represented 20% of T cells, and were found in close contact with LCs. FoxP3+ T-regs were also expanded compared to controls, in the blood of LCH patients with active disease, among whom seven out of seven tested exhibited an impaired skin delayed-type hypersensitivity response. In contrast, the number of blood T-regs were normal after remission of LCH.ConclusionsThese findings indicate that LC accumulation in LCH results from survival rather than uncontrolled proliferation, and is associated with the expansion of T-regs. These data suggest that LCs may be involved in the expansion of T-regs in vivo, resulting in the failure of the host immune system to eliminate LCH cells. Thus T-regs could be a therapeutic target in LCH.

Bone marrow assessment in Langerhans cell histiocytosis

Bone marrow changes and their relation to blood cytopenia in patients with Langerhans cell histiocytosis (LCH) have not been extensively studied to date. The aim of the present study was to characterize the bone marrow changes in LCH patients and to ascertain their relation to disease severity. Fifty-seven marrow samples of LCH patients were studied by conventional cytology, immunocytochemistry (ICC) and flow cytometry (FCM). On conventional cytology there was no significant difference between LCH cases and controls with respect to cellularity, number of monocytes and progenitor cells, and presence of histiocytes and hemophagocytosis. The numbers of nucleated cells, CD34(pos) cells, and CD14(pos) cells on FCM did not differ, either. The CD1a staining by ICC was positive in 14/41 LCH samples, and was consistently negative in controls. FCM staining for CD1a was positive in 12/54 samples, but also in 5/35 controls. The number of the CD1a(pos) cells in LCH marrows was usually very low (<10-20 cells/slide by ICC, or <0.5% of the leukocytes by FCM). The CD1a staining was more frequently positive and more pronounced in patients with severe disease. The combination of conventional aspirate cytology with ICC (CD1a staining) appears to be the most reliable tool for bone marrow assessment in LCH.

Clinico-biologic profile of Langerhans cell histiocytosis: A single institutional study

Langerhans cell histiocytosis (LCH) is a rare atypical cellular disorder characterized by clonal proliferation of Langerhans cells leading to myriad clinical presentations and highly variable outcomes. There is a paucity of Indian studies on this subject. To present the experience of management of LCH at a single institution. This is a retrospective observational study of patients with LCH who presented at the Tata Memorial Hospital between January 1987 and December 2002. Fifty-two patients with LCH were treated in the study period. Due to the long observation period and variability in diagnostic and therapeutic protocols, the patients were risk-stratified based on present criteria. The disease pattern, management approaches and treatment outcomes of patients were recorded. Statistical analyses were done using Student's 't' test, test for proportion and survival estimates based on the Kaplan-Meier method. The median age at presentation was 3 years and more than 48% of the patients had Group I disease. Skeleton, skin and lymphoreticular system were the commonly involved organs. Majority (80%) required some form of therapy. The projected overall survival is 63% at 10 years and mean survival is 118 months. Seventeen percent of surviving patients developed long-term sequelae. The clinico-biologic profile of LCH patients in India is largely similar to international patterns except a higher incidence of lymphoreticular involvement. Majority of the patients respond favorably to therapy and have a good outcome, except a subset of Group I patients who warrant enrollment in clinical trials with innovative therapeutic strategies to improve outcome.

Langerhans' Cell Histiocytosis in a 5‐Year‐Old Girl: Evidence of Periodontal Pathogens

Langerhans' cell histiocytosis (LCH) is a rare disorder characterized by Langerhans' cell proliferation in various organs or tissues. When periodontal tissue is involved, clinical manifestations can vary from gingival recession and pocket formation to severe alveolar bone loss. This case report describes periodontal pathogens found in the pockets of involved primary teeth. A 5-year-old girl with LCH presented with loose teeth. Intraoral examination and radiographs revealed deep pockets and severe bone loss around all primary molars. Bacterial samples were obtained from saliva and subgingival plaque and analyzed for the presence of five periodontopathic bacteria using a polymerase chain reaction (PCR) method. Due to severe periodontal destruction, all primary molars were extracted, and a gingival biopsy was taken from tooth T to confirm the diagnosis of LCH. The biopsy specimen revealed the histologic features of LCH. The patient was diagnosed as having periodontitis as a manifestation of LCH. PCR results of subgingival plaque from LCH-affected molars indicated the presence of Porphyromonas gingivalis, Tannerella forsythensis, Treponema denticola, and Prevotella intermedia. However, Actinobacillus actinomycetemcomitans was absent from these teeth. No tested bacteria were found in the non-affected anterior teeth. The bacteria commonly associated with periodontal disease were detected in subgingival plaque samples from this LCH patient. More microbiological data are required to understand the role of these bacteria in LCH-associated periodontal destruction.

Central nervous system‐related permanent consequences in patients with Langerhans cell histiocytosis

Permanent consequences in Langerhans cell histiocytosis (LCH) are irreversible late sequelae related to the disease that may severely impair the quality of life of survivors. The frequency and pattern of permanent consequences affecting the central nervous system (CNS) remains to be determined. In this single center study, 25 LCH patients observed for a median time of 10 years 3 months underwent a uniform thorough follow-up program including neuropsychological testing and electrophysiological evaluation. Overall permanent consequences were seen in 9 of 25 patients. Intracranial abnormalities were the most frequent including diabetes insipidus (DI) in seven patients, anterior pituitary deficiencies in five patients, and neurodegenerative CNS disease in five patients. No patient had overt neurological symptoms upon neurological evaluation, but psychological testing revealed subtle deficits in short-term auditory memory (STAM) in 14 patients. Brain stem evoked potentials showed abnormalities in four of nine tested patients, all of these four had neurodegeneration on MRI. Psychoneuroendocrine sequelae were found in an unexpectedly high number of patients in this single center study. Long-term follow-up focusing on such sequelae are important in LCH survivors, in order to detect early deficits, to monitor the evolution of the disease, and to provide specific support.

Elevated Serum Levels of the Decoy Receptor Osteoprotegerin in Children with Langerhans Cell Histiocytosis

Langerhans cell histiocytosis (LCH) is characterized by an accumulation of dendritic Langerhans cells in granulomatous lesions in the bone, skin, and other sites in the body. The pathogenesis of the disease remains unknown. We measured serum levels of the decoy receptor osteoprotegerin (OPG), an important regulator of bone metabolism as well as immune responses, in 18 children with single system (SS) or multi-system (MS) forms of LCH and 20 pediatric controls. OPG levels were significantly increased in LCH patients at diagnosis when compared with controls, and pretreatment levels of OPG were elevated in MS compared with SS patients. Moreover, OPG levels in LCH patients were elevated in patients with involvement of risk organs (liver, lungs, hematopoietic system, or spleen) when compared with patients without risk organ involvement, indicative of an association between OPG values and disease severity. We also observed a positive correlation between serum levels of OPG and tumor necrosis factor (TNF)-alpha, a pro-inflammatory cytokine, at the time of onset of disease. These findings show, for the first time, that serum OPG levels are elevated in LCH patients, and suggest that OPG may play a role in the pathogenesis of this enigmatic disease.

Langerhans cell histiocytosis and human herpes virus 6 (HHV‐6), an analysis by real‐time polymerase chain reaction

Patients with Langerhans cell histiocytosis (LCH) usually present to orthopedic surgeons because this disease most commonly affects bone. The pathogenesis of LCH is unknown, although roles for environmental, infectious, immunologic, and genetic causes have been postulated. More specifically, there is limited data suggesting that human herpes virus 6 (HHV-6) may be a potential etiologic agent. Frozen biopsy material was obtained from 13 patients with LCH and 20 patients without the disease. After ensuring histologic adequacy of the material, the tissue was tested for HHV-6 by qualitative and quantitative real-time TaqMan PCR. Four of 13 patients with LCH had evidence of HHV-6 DNA in their tissue while 7 of 20 control patients tested positive for HHV-6 genome. Viral loads are reported for the positive patients; no statistical difference was observed in the presence or quantity of HHV-6 DNA found in either population, suggesting that the prevalence of HHV-6 in the tissue of LCH patients is the same as that found in tissue from individuals without disease.