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Radiographic skeletal survey (R-SS) is the standard imaging technique for the initial staging of Langerhans cell histiocytosis (LCH). Whole-body magnetic resonance imaging (WB-MRI) has been proposed as an effective, radiation-free alternative.We prospectively assessed patients with LCH followed at three tertiary centers in Italy and Austria. Two national study protocols were independently designed, and data were then pooled to increase the power of their findings. R-SS and WB-MRI were performed at diagnosis and repeated at the follow-up to confirm the nature of the identified lesions and to study their evolution.Data from 67 patients were analyzed (52 from Italy and 15 from Austria). Compared to R-SS, WB-MRI identified 29 additional skeletal lesions in 14 patients (including two false-positive lesions). Two skeletal lesions were detected at R-SS and missed at WB-MRI (false negative). Per-lesion sensitivity rates were 78.6% (95% CI: 71.0-85.9) for R-SS and 98.4% (95% CI: 94.4-99.8) for WB-MRI, respectively. Based on WB-MRI findings, six patients would have been upstaged to a higher risk class than staging with R-SS.WB-MRI had a significantly higher detection rate for skeletal lesions compared to R-SS. Clinical and radiology expertise is required to avoid upstaging and overtreatment.

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. Pediatr Blood Cancer 2012; 58: 606–610. © 2011 Wiley Periodicals, Inc.

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. Pediatr Blood Cancer 2007;48:50–56. © 2006 Wiley-Liss, Inc.

Background To study the incidence, clinical patterns, course, and outcome of neonatal Langerhans cell histiocytosis (LCH). Procedure Retrospective analysis of the data of the Austrian/German/Swiss/Netherlands LCH Study Group. The incidence of neonatal LCH was estimated with the data from the population-based German Childhood Cancer Registry. Results The estimated incidence of neonatal LCH (LCH diagnosed within 28 days after birth) in the population-based registry was 1–2/1,000,000. In 61/1,069 trial patients (6%), the first disease manifestations were observed in the neonatal period. However, in only 20 of them, the diagnosis was established within this period. There was a preponderance of multisystem (MS)-LCH 36/61 (59%). Cutaneous changes were the most common initial manifestation in both, single-system (SS)-LCH (92%), and MS-LCH (86%). In 72% of the MS-LCH patients, risk organs (ROs) were involved at diagnosis as well. The probability of survival at 5 years was 94% in SS-LCH and 57% in MS-LCH, which is significantly lower than in older age groups. Conclusions In contrast to the available literature, neonatal LCH is characterized by a clear predominance of MS-LCH. Cutaneous changes are the most common initial manifestation in neonates with both SS-LCH and MS-LCH. Prompt evaluation of disease extent upon diagnosis is mandatory for risk-adapted treatment. The disease course is unpredictable upon diagnosis. Close monitoring for disease progression is mandatory if isolated cutaneous LCH is managed by the “wait and see” approach. Neonates with MS-LCH, especially those with RO involvement at diagnosis, have less favorable prognosis compared to infants and older children, and need systemic therapy. © 2005 Wiley-Liss, Inc.

Background Diabetes insipidus (DI) is the most frequent central nervous system (CNS)-related permanent consequence in Langerhans cell histiocytosis (LCH), which mostly requires life-long hormone replacement therapy. In an attempt to define the population at risk for DI, 1,741 patients with LCH registered on the trials DALHX 83 and DALHX 90, LCH I and LCH II were studied. Results Overall 212 of 1,741 patients (12%) was reported to have DI. In 102 of 1,741 patients (6%) DI was present at diagnosis of LCH. One thousand one hundred eighty three of 1,539 patients without DI at diagnosis had follow up information. One hundred ten of these (9%) later developed DI. The risk of developing DI was 20% at 15 years after diagnosis. Multisystem disease patients at diagnosis carried a 4.6-fold risk for DI compared to single system patients. Craniofacial lesions, in particular in the “ear,” “eye,” and oral region were associated with a significantly increased risk for DI (relative hazard rate, RHR 1.7), independent of the extent of disease. No influence of the duration of therapy could be determined, but the duration of initial disease activity (RHR 1.5) and the occurrence of reactivations (RHR 3.5) significantly increased the risk for DI. Conclusions Patients with multisystem disease and craniofacial involvement at diagnosis, in particular of the “ear,” “eye,” and the oral region carry a significantly increased risk to develop DI during their course. This risk is augmented when the disease remains active for a longer period or reactivates. © 2005 Wiley-Liss, Inc.

TI was reported in 18/1,264 (1.4%) LCH patients. All nine patients with TI at initial LCH presentation were below 2 years of age and had multisystem LCH (9/242, 4%). Images (sonography, CT, MRI) for central review were available in 15 cases. Characteristic findings of TI were thymus enlargement (67%), few to many cysts (80%), and few to many calcifications (100%). Sonographic and MRI findings were in excellent agreement. We recommend adding sonography of the thymus to the standard for initial clinical evaluation of LCH patients below the age of 2 years.

Background Diabetes insipidus (DI) is the most frequent sequela in Langerhans cell histiocytosis (LCH). The clinical relevance and therapeutic impact of brain magnetic resonance imaging (MRI) findings in LCH patients with LCH during the disease course is unclear. Procedure In this retrospective study, we reviewed 113 brain MRIs from 59 DI patients, in 17 of these serial follow up MR-examination findings were correlated to the clinical course and therapy. Results At DI diagnosis, 71% patients showed a thickened stalk, in 24% the stalk was still thickened on MRIs done more than 5 years after DI onset, and in two patients the stalk was already thickened several months before DI onset. The changes of the pituitary stalk thickness were highly variable and did not clearly correlate with the treatment. Regression of pituitary thickness on MRI did not concur with clinical recovery of DI, which persisted in all but one patient with initially partial DI. The occurrence of anterior pituitary hormone deficiencies appeared to be linked to a thickening of the stalk at DI diagnosis. LCH-lesions in the craniofacial bones were seen in 75% DI patients, and 76% of DI patients with follow up MRIs done 5 years or longer after DI diagnosis had parenchymal neurodegenerative brain changes. Conclusions Our study indicates that repeated MR-examinations in DI patients are of limited value for assessing a response to therapy in the pituitary stalk, but are important for the monitoring of craniofacial bone lesions and for the detection of parenchymal CNS disease. © 2004 Wiley-Liss, Inc.