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Skeletal involvement is generally, but not universally, characteristic of Langerhans cell histiocytosis (LCH). We investigated whether the presence of bone lesions at diagnosis is a prognostic factor for survival in LCH. Nine hundred and thirty-eight children with multisystem (MS) LCH, both high (386 RO+) and low (RO-) risk, were evaluated for bone lesions at diagnosis. Risk organ (RO+) involvement was defined as: haematopoietic system (haemoglobin <100 g/l, and/or white blood cell count <4·0 × 10(9) /l and/or platelet count <100 × 10(9) /l), spleen (>2 cm below the costal margin), liver (>3 cm and/or hypoproteinaemia, hypoalbuminaemia, hyperbilirubinaemia, and/or increased aspartate transaminase/alanine transaminase). Given the general view that prognosis in LCH worsens with increasing extent of disease, the surprising finding was that in MS+RO+ LCH the probability of survival with bone involvement 74 ± 3% (n = 230, 56 events) was reduced to 62 ± 4% (n = 156, 55 events) if this was absent (P = 0·007). An even greater difference was seen in the subgroup of patients with both liver and either haematopoiesis or spleen involvement: 61 ± 5% survival (n = 105; 52 events) if patients had bony lesions, versus 47 ± 5% (n = 111; 39 events) if they did not (P = 0·014). This difference was retained in multivariate analysis (P = 0·048). Although as yet unexplained, we conclude that bone involvement at diagnosis is a previously unrecognized favourable prognostic factor in MS+RO+ LCH., (© 2014 John Wiley & Sons Ltd.)

Langerhans cell histiocytosis (LCH)-III tested risk-adjusted, intensified, longer treatment of multisystem LCH (MS-LCH), for which optimal therapy has been elusive. Stratified by risk organ involvement (high [RO+] or low [RO-] risk groups), > 400 patients were randomized. RO+ patients received 1 to 2 six-week courses of vinblastine+prednisone (Arm A) or vinblastine + prednisone + methotrexate (Arm B). Response triggered milder continuation therapy with the same combinations, plus 6-mercaptopurine, for 12 months total treatment. 6/12-week response rates (mean, 71%) and 5-year survival (84%) and reactivation rates (27%) were similar in both arms. Notably, historical comparisons revealed survival superior to that of identically stratified RO+ patients treated for 6 months in predecessor trials LCH-I (62%) or LCH-II (69%, P < .001), and lower 5-year reactivation rates than in LCH-I (55%) or LCH-II (44%, P < .001). RO- patients received vinblastine+prednisone throughout. Response by 6 weeks triggered randomization to 6 or 12 months total treatment. Significantly lower 5-year reactivation rates characterized the 12-month Arm D (37%) compared with 6-month Arm C (54%, P = .03) or to 6-month schedules in LCH-I (52%) and LCH-II (48%, P < .001). Thus, prolonging treatment decreased RO- patient reactivations in LCH-III, and although methotrexate added no benefit, RO+ patient survival and reactivation rates have substantially improved in the 3 sequential trials. (Trial No. NCT00276757 www.ClinicalTrials.gov).

Background: Hypothalamic-pituitary (HP) disease is the most common CNS manifestation of Langerhans cell histiocytosis (LCH) frequently leading to diabetes insipidus (DI) and anterior pituitary hormone deficiencies (APD). On MRI, loss of the normal posterior pituitary signal and thickening of the pituitary stalk have been described, as well as neurodegenerative signal changes associated with neuropsychological disabilities in some patients. The influence of therapy on the long-term course of HP tumors and neurodegeneration (ND) is not well-understood., Procedure: In this retrospective survey we focused on patients with LCH and HP disease with clinical and MRI data available at diagnosis of HP disease and at least three follow up investigations. We collected clinical and MRI follow-up information for central review and analysis., Results: We identified 22 patients with HP tumors (HPT) registered at the LCH study center. Many different treatment regimens were applied for variable periods, with more than one regimen in most patients. Regression of the tumor was seen in the majority, but all patients had APD or ND on MRI at last follow up. In none of the patients APD and ND regressed or resolved. A deterioration of radiological ND was noted in 17 patients leading to overt clinical neuropsychological impairment in five., Conclusions: Patients with HPT appear to be at high risk to develop permanent neuroendocrine consequences. Coordinated studies for patients with LCH and HP disease including thorough MRI monitoring and neuropsychological tests are needed., (Copyright © 2011 Wiley Periodicals, Inc.)

Background: Patients with Langerhans cell histiocytosis (LCH) may develop neurodegeneration and other central nervous system (CNS) dysfunctions revealed by brain magnetic resonance imaging (MRI). We estimated the incidence and pattern of pathological brain MRI findings in a well-defined, population-based cohort of children with LCH., Methods: Among children under 15 years of age diagnosed with LCH in the Stockholm County during 1992-2001, brain MRI was performed at a single center in children with clinical and/or laboratory signs of CNS involvement, including endocrine dysfunction., Results: Out of the 29 children (16 males, 13 females) diagnosed with LCH, brain MRI was performed based on clinical indications in 16 children (55%) with either abnormal endocrine findings (n = 6), such as diabetes insipidus (n = 5), low IGF-1 (n = 1), or panhypopituitarism (n = 1), or clinical CNS symptoms (n = 10). CNS MRI abnormalities were demonstrated in eight children (28%), at a median time of 3.5 years after LCH diagnosis (range 1-11.4 years). Altogether 7 of the 29 children (24%) had MRI findings associated with neurodegeneration, corresponding to a minimal incidence of 2.1/10(6) children per year. Neurodegenerative abnormalities tended to be more frequent in patients with craniofacial involvement (P = 0.12)., Conclusions: The minimal annual incidence rate of neurodegenerative associated radiographic findings in LCH is estimated at 2.1/10(6) children (24% of all children with LCH). An important question is whether all patients with LCH, or certain forms of LCH, should be recommended for a late follow-up examination including MRI. In patients with CNS-LCH, neurological, neuropsychological, neurophysiological, neurochemical and neuroradiological follow-up assessment is suggested., (Copyright © 2010 Wiley-Liss, Inc.)

Objective: To assess multisystem Langerhans cell histiocytosis reactivation and its impact on morbidity and mortality., Study Design: Retrospective analysis of 335 patients with MS-LCH and documented complete disease resolution (NAD1)., Results: The probability of a reactivation within 5 years of NAD1 was 46%. The first reactivation occurred within 2 years after NAD1 in most of the patients. Of 134 events, 35% were confined to skeleton, 24% were single-system nonbony lesions, 24% were multisystem reactivations without risk-organ involvement, and 10% with risk-organ involvement. In 7%, the location was unspecified. Only 3 deaths (2.2%) were documented within the context of a first reactivation. Second disease resolution (NAD2) was achieved in 85% of the cases. The probability of a second reactivation within 5 years of NAD2 was 44%. The risk for permanent consequences in patients with reactivations was higher, compared with patients without reactivation (RHR 2.2, P = .046)., Conclusions: Reactivation is a frequent and early event in MS-LCH, but involvement of risk organs at reactivation is rare and mortality is minimal. However, reactivations increase the risk for permanent consequences by about 2-fold. Prospective trials targeting reduction of acute morbidity and permanent disabilities through nontoxic treatment of the reactivations are warranted.

Objective: To explore the frequency and course of neurodegenerative central nervous system (CNS) disease in Langerhans cell histiocytosis (ND-LCH)., Study Design: We studied 83 patients with LCH in whom magnetic resonance imaging (MRI) of the brain was performed at least twice for various clinical indications. We defined radiologic ND-LCH as an MRI pattern comprising bilateral symmetric lesions in the dentate nucleus of the cerebellum or basal ganglia., Results: Forty-seven of 83 patients (57%) had radiologic ND-LCH, at a median of 34 months (range 0-16 years) from the diagnosis of LCH. The MRI findings deteriorated in 31/47 (66%) patients over a median of 3 years (range 2 months to 12 years 6 months) and did not reverse in any patient. In 12 patients with radiologic ND-LCH (25%), clinical ND-LCH with overt symptoms were found 3 to 15 years (median 6 years) after initial LCH diagnosis. These symptoms included intention tremor, cerebellar ataxia, dysarthria, dysdiadochokinesis, concentration deficits, psychomotor retardation, severe headaches, and psychosis., Conclusion: We conclude that radiologic ND-LCH is serious, not uncommon in patients studied by MRI, irreversible, and may be followed by severe clinical ND-LCH many years after the initial diagnosis of LCH.

Multisystem Langerhans cell histiocytosis (MS-LCH) is associated with high mortality when patients have risk organ involvement (RO(+)) or are younger than 2 years. In an international randomized trial, LCH-II, we intensified their treatment: arm A consisted of 6 weeks of daily prednisone and weekly vinblastine followed by 18 weeks of daily 6-mercaptopurine with vinblastine/prednisone pulses; etoposide was added in arm B. Considering all 193 randomized risk patients, there were similar outcomes: rapid (6 weeks) response (arm A vs arm B: 63%/71%), 5-year survival probability (74%/79%), disease reactivation frequency (46%/46%), and permanent consequences (43%/37%). However, (1) patients younger than 2 years without RO involvement (RO(-)) had 100% survival and uniformly high (> 80%) rapid response, (2) RO(+) patients not responding within 6 weeks had highest mortality, and (3) importantly, the more intensive arm B reduced mortality in RO(+) patients (relative hazard rate, accounting for differences in risk organ involvement, of 0.54; 95% CI = 0.29-1.00). Finally, comparison of RO(+) patients in LCH-I and LCH-II confirmed that increasing treatment intensity increased rapid responses (from 43% in arm A LCH-I to 68% in arm B LCH-II; P = .027) and reduced mortality (from 44% in arm A LCH-I to 27% in arm B LCH-II; P = .042). We conclude that intensified treatment significantly increases rapid response and reduces mortality in risk MS-LCH. This trial was registered at http://www.controlled-trials.com as no. ISRCTN57679341.

Background: 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., Methods: Fifty-seven marrow samples of LCH patients were studied by conventional cytology, immunocytochemistry (ICC) and flow cytometry (FCM)., Results: 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., Conclusions: The combination of conventional aspirate cytology with ICC (CD1a staining) appears to be the most reliable tool for bone marrow assessment in LCH., ((c) 2007 Wiley-Liss, Inc.)

Background and Purpose: MR imaging signal intensity abnormalities in the cerebellum, the pons, and the basal ganglia, compatible with a neurodegenerative process (ND) were reported in up to 10% of patients with Langerhans cell histiocytosis (LCH). Although the imaging features of ND-LCH have been extensively described, the temporal course of ND-LCH has not been assessed as of yet. The purpose of this study was to describe the long-term course of MR imaging signal intensity abnormalities in ND-LCH on T1- and T2-weighted images., Materials and Methods: In this retrospective study, 9 patients with ND-LCH with an observation time of at least 5 years were included. Three or more MR imaging studies per patient, performed in 3-year intervals (+/-11 months), were reviewed. Signal intensity abnormalities on T1- and T2-weighted images in the cerebellum, the pons, and basal ganglia were scored for their signal intensity quality and their extension. In addition, the severity of cerebellar atrophy was scored., Results: The signal intensity alterations were not resolved in any of the patients. Instead, a progression of the signal intensity alterations either in the cerebellum or basal ganglia was observed in all of the patients but did not correlate with a clinical deterioration. Overt and severe neurologic symptoms were reported in only 2 patients in whom some form of atrophy was noted., Conclusions: ND-LCH appears to be a slowly progressive process. The increase of signal intensity abnormalities in the cerebellum and basal ganglia does not correlate with neurologic deterioration. MR imaging appears to be a sensitive technique to detect and monitor radiologic ND-LCH.

Background: 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., Procedure: 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., Results: 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., Conclusion: 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., ((c) 2006 Wiley-Liss, Inc.)

Central diabetes insipidus (CDI) is a rare disorder that may be caused by a variety of diseases. In pediatric and adolescent patients the most common causes for CDI are Langerhans cell histiocytosis (LCH) and germinoma. To avoid a potentially hazardous biopsy of the hypothalamic pituitary region it is recommended to evaluate patients with CDI carefully to identify potential extracranial lesions. Since LCH is the most common systemic disease that may cause CDI, special focus is paid to the identification of LCH lesions. We report on a 9(1/2) year old girl who presented with central diabetes insipidus and a thickening of the pituitary stalk on magnetic resonance imaging. Diagnostic workup revealed a history of recurrent ear infections and a compressed 6th thoracic vertebral body on radiographs. Based on these findings LCH was anticipated. Upon growth of the pituitary stalk lesion the patient was treated with LCH standard chemotherapy. After an initial shrinkage of the lesion, a further growth of the pituitary stalk lesion was observed and the tumor was resected. Histopathology revealed germinoma. This case underscores the importance of a istopathologically proven diagnosis in patients with HPR tumors before the initiation of a specific therapy, even if the clinical findings are highly suggestive.

Langerhans' cell histiocytosis-associated neurodegenerative syndrome is an enigmatic manifestation, most often localized in the cerebellum and the basal ganglia. Its pathophysiologic basis is poorly understood, and effective treatment strategies are currently missing. Modern imaging modalities offer the possibility of shedding further light on this puzzling disease in a noninvasive way. We report on a 12-year-old boy with a Langerhans' cell histiocytosis-associated neurodegenerative syndrome who underwent a thorough evaluation with different modern imaging methods in addition to routine brain magnetic resonance imaging (MRI) to analyze their informative value for this condition. Additional imaging included positron emission tomography using [18F]fluorodeoxyglucose (FDG-PET), single photon emission computed tomography using [123I]2beta-carbomethoxy-3beta-(4-iodophenyl)tropane and [123I]iodobenzamide, and magnetic resonance spectroscopy. The potential relevance of each method for neurodegenerative Langerhans' cell histiocytosis is discussed based on the results obtained, and a review of the literature is made. The case underlines the fact that MRI undoubtedly possesses the major role in the diagnostic evaluation and monitoring of Langerhans' cell histiocytosis-associated neurodegenerative syndrome. FDG-PET and magnetic resonance spectroscopy findings were in good correlation with the MRI results. In particular, magnetic resonance spectroscopy could provide a valuable diagnostic tool in addition to MRI in the early detection and evaluation of the neurodegenerative component of this disease.

Background and Objectives: Central diabetes insipidus (CDI) is a rare disorder associated with various underlying diseases. Among the systemic diseases that may cause CDI, Langerhans cell histiocytosis (LCH) is the most common. Therefore, in patients with endocrinologically proven CDI, a comprehensive diagnostic evaluation is crucial to identify possible extracranial sites of LCH. The goal of the diagnostic evaluation is to yield histopathological proof of the underlying disease. If possible, this histopathological proof should be provided by a biopsy of extracranial lesions to avoid a potentially hazardous biopsy of the pituitary stalk., Study Design: In this retrospective study we included 54 patients registered at the LCH study reference center in whom the onset of CDI preceded the diagnosis of LCH, and we investigated their presentation and course to define a clinical pattern characteristic for LCH., Results: In 49/54 patients (91%) the detection and biopsy of extracranial lesions led to the diagnosis of LCH. The most frequently involved organs were bones, skin, and lungs; 86% of the patients with bone lesions had skull lesions. In 18% of the patients extracranial lesions were already found at presentation of CDI, in another 51% of the patients extracranial lesions were found within 1 year from onset of CDI., Conclusions: These observations underline that a comprehensive search for extracranial lesions at presentation and during the first year thereafter may help to achieve a specific diagnosis without a pituitary stalk biopsy., (Copyright 2004 Wiley-Liss, Inc.)