GREEK PEDIATRIC LANGERHANS CELL HISTIOCYTOSIS NATIONAL REGISTRY RESULTS OVER TWO DECADES

GREEK PEDIATRIC LANGERHANS CELL HISTIOCYTOSIS NATIONAL REGISTRY RESULTS OVER TWO DECADES | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 21 October 2025 V1 Latest version Share on GREEK PEDIATRIC LANGERHANS CELL HISTIOCYTOSIS NATIONAL REGISTRY RESULTS OVER TWO DECADES Authors : Marina Servitzoglou , Efthimia Rigatou , Loizos Petrikkos 0000-0002-8313-9141 , Eugenia Papakonstantinou 0000-0001-5620-7885 , Emmanuel Hatzipantelis , Iordanis Pelagiadis , Helen Dana , … Show All … , Dimitrios Doganis , Natalia Tourkantoni , Kyriaki Routzouni , Athanasios Tragiannidis 0000-0003-4294-2605 , Maria Labrou , Helen Vasiliatou Kosmidis 0000-0001-8965-6679 , Eftichia Stiakaki , Sophia Polychronopoulou , Antonis Kattamis , Margaret Baka , and Vassilios Papadakis 0000-0002-1821-7799 [email protected] Show Fewer Authors Info & Affiliations https://doi.org/10.22541/au.176102684.42938349/v1 291 views 101 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Objective: To document characteristics and outcome in children with Langerhans cell histiocytosis (LCH) in Greece. Methods : A retrospective review of patients with biopsy-proven LCH treated in pediatric-hematology-oncology units was undertaken. Results: Between 2000-2019, LCH was diagnosed in 169 patients (62.7% males) with median age 4.76 years (37.8% <2 years old). One-hundred-thirty-three (78.7%) had single-system (SS) disease; bone 110/133 (82.7%), 4 with diabetes insipidus (DI): 67 (50.4%) were only observed and 5 (7.5%) relapsed. With median follow-up-time (MFupT) 4.2 years (range, 0.1-19.7), all are alive in complete remission (CR), with overall survival (OS) 100% and event-free survival (EFS) 92.5%. Seventy-one (53.4%) patients with SS-disease received systemic chemotherapy (66/71 as initial treatment). At MFUpT time of 6.51 years (range, 0.1-19.7), OS and EFS were 98.4% and 85.7%, with 2 deaths (pneumothorax, lymphoma). Multi-system (MS) disease (2-5 systems) had 36 patients (21.3%), median-age 1.7 years (range, 0.04-10.35 / 58.3% <2 years), 28/36 (77,8%) had bone involvement and 44,4% (16/36) Risk-Organ involvement, while 10/36 (27.8%) presented with DI. Most MS-patients (91.7%) received Prednisolone/Vinblastine for a median duration of 12 months (range, 1-43); OS and EFS were 97.2% and, 75.0%, with MFUpT 6.39 years (range, 0.5-20.2). Twenty-seven patients out of 51 tested, were found BRAF-V600E+ (52.9%); the probability of relapse was significantly higher in BRAF-600E mutated patients (p=0,014). Discussion: Disease and outcome data of the Greek LCH National Registry cohort are comparable with international data, with favorable results. This work formed the basis for LCH-IV Protocol national participation, supported by Histiocytosis Hellas. TITLE PAGE GREEK PEDIATRIC LANGERHANS CELL HISTIOCYTOSIS NATIONAL REGISTRY RESULTS OVER TWO DECADES AUTHORS Marina Servitzoglou 1 , Efthymia Rigatou 2 , Loizos Petrikkos 3 , Evgenia Papakonstantinou 4 , Emmanouil Hatzipantelis 5 , Iordanis Pelagiadis 6 , Helen Dana 7 , Dimitrios Doganis 1 , Natalia Tourkantoni 2 , Kyriaki Routzouni 8 , Athanasios Tragiannidis 5 , Maria Labrou 4 , Helen Kosmidis 7 , Eftichia Stiakaki 6 , Sophia Polychronopoulou 3 , Antonios Kattamis 2 , Margaret Baka 1 , Vassilios Papadakis 3 AFFILIATIONS 1 Oncology Department, “A & P Kyriakou” Children’s Hospital, Athens, Greece 2 Division of Pediatric Hematology - Oncology, 1st Department of Pediatrics, National & Kapodistrian University of Athens, «Agia Sofia» Children’s Hospital, Athens, Greece 3 Department of Pediatric Hematology-Oncology (T.A.O.), “Agia Sofia” Children’s Hospital, Athens, Greece 4 Padiatric Hematology-Oncology Department of, Ippokratio General Hospital, Thessaloniki, Greece 5 Division of Pediatric & Adolescent Hematology-Oncology, 2nd Department of Pediatrics, Aristotle University of Thessaloniki, AHEPA General Hospital, Thessaloniki, Greece 6 Department of Pediatric Hematology-Oncology, University Hospital of Heraklion, Heraklion, Crete, Greece 7 Pediatric & Adolescent Oncology Clinic, ”Mitera” Hospital, Athens, Greece 8 Data Manager, Hellenic Society of Pediatric Hematology-Oncology CORRESPONDING AUTHOR Vassilios Papadakis MD PhD Head of the Department of Pediatric Hematology- Oncology (TAO) 8 Levadias Str, Goudi, Athens 11527 Greece Agia Sofia Children’s Hospital, Marianna V Vardinoyannis- ELPIDA Oncology Hospital Athens 11527, Greece [email protected] |, [email protected] tel. +30 210 745 2020 Mobile: +30 693 229 4328 fax +30 210 6800 125 Word Count : a) Abstract : 246 b) Main Text 3426 –The number of Tables (1), Figures (2), and Supporting Information files (0); – Short running title Greek National Registry LCH results – Keywords Langerhans cell histiocytosis; child; registry; outcome . – Abbreviations key CI Confidence Interval CNS Central Nervous System CR Complete Remission EFS Event-free Survival DI Diabetes Insipidus LCH Langerhans Cell Histiocytosis MS Multi-System MFupT Median-Follow-up Time ND Neurodegenerative Disease OS Overall Survival RO- Risk Organ Negative RO+ Risk Organ Positive SD Standard deviation SS Single System ABSTRACT TITLE GREEK PEDIATRIC LANGERHANS CELL HISTIOCYTOSIS NATIONAL REGISTRY RESULTS OVER TWO DECADES Objective: To document characteristics and outcome in children with Langerhans cell histiocytosis (LCH) in Greece. Methods : A retrospective review of patients with biopsy-proven LCH treated in pediatric-hematology-oncology units was undertaken. Results: Between 2000-2019, LCH was diagnosed in 169 patients (62.7% males) with median age 4.76 years (37.8% <2 years old). One-hundred-thirty-three (78.7%) had single-system (SS) disease; bone 110/133 (82.7%), 4 with diabetes insipidus (DI): 67 (50.4%) were only observed and 5 (7.5%) relapsed. With median follow-up-time (MFupT) 4.2 years (range, 0.1-19.7), all are alive in complete remission (CR), with overall survival (OS) 100% and event-free survival (EFS) 92.5%. Seventy-one (53.4%) patients with SS-disease received systemic chemotherapy (66/71 as initial treatment). At MFUpT time of 6.51 years (range, 0.1-19.7), OS and EFS were 98.4% and 85.7%, with 2 deaths (pneumothorax, lymphoma). Multi-system (MS) disease (2-5 systems) had 36 patients (21.3%), median-age 1.7 years (range, 0.04-10.35 / 58.3% (16/36) Risk-Organ involvement, while 10/36 (27.8%) presented with DI. Most MS-patients (91.7%) received Prednisolone/Vinblastine for a median duration of 12 months (range, 1-43); OS and EFS were 97.2% and, 75.0%, with MFUpT 6.39 years (range, 0.5-20.2). Twenty-seven patients out of 51 tested, were found BRAF-V600E+ (52.9%); the probability of relapse was significantly higher in BRAF-600E mutated patients (p=0,014). Discussion: Disease and outcome data of the Greek LCH National Registry cohort are comparable with international data, with favorable results. This work formed the basis for LCH-IV Protocol national participation, supported by Histiocytosis Hellas. 1 INTRODUCTION Langerhans cell histiocytosis (LCH) is the most common histiocytosis. Since the initial identification of BRAFV600E mutations in more than half of the patients with LCH 1 , several groups subsequently confirmed the activation of MAPK pathway in the vast majority of patients. 1-4 The incidence of LCH is better defined in children than in adults. An annual incidence of 4.6 cases per million children below 15 years of age has been reported, with a broader range of 2,6 to 9 cases, in different population studies. 5-8 In adults, the incidence is reported at 0,07 cases per million per year for disseminated disease. 9,10 The incidence of LCH in adults might be underestimated. LCH has been associated with other neoplasms, such as lung and thyroid cancer or leukemia, regardless of age at initial presentation. 4,11-15 Especially in synchronous LCH with acute lymphoblastic leukemia (ALL) cases, the presence of common mutations or identical T-cell receptor or immunoglobulin rearrangement indicates a clonal relationship between the diseases. 16,17 LCH has a wide clinical spectrum. Manifestations can vary from a single lesion, not requiring any treatment, to a multisystem, life-threatening disease. 18-20 The skeleton is the most frequently affected organ (about 80% of cases). Diabetes insipidus is a characteristic chronic sequela of LCH. Involvement of maxillofacial bones is a predisposing factor for DI, which can present prior, concurrently or after LCH diagnosis. 21-23 The refinement and intensification of current therapeutic protocols has progressively improved the outcome and the quality of life of these patients. 8,23 Aim The aim of this study was to describe patient and disease characteristics, treatment approach and outcome in children and adolescents with Langerhans cell histiocytosis (LCH) in Greece on a national basis, as prior reports related to local departments’ results. 24 This is the first patient registry at a national level towards the official participation of Greece in the LCH-IV protocol, supported by Histiocytosis Hellas (https://www.histioartemis.org/en/). 2 / METHODS 2.1 / Patients and study design All seven Pediatric Hematology-Oncology Units across Greece, under the auspices of the Hellenic Society of Pediatric Hematology-Oncology (HeSPHO, https://eepao.gr/) participated in this national retrospective chart-review study which included children diagnosed with biopsy-proven LCH. Anonymized demographics, LCH site/ organ involvement, categorization as Single System (SS) or Multi-System (MS), risk-organ involvement (RO+) or not (RO-), CNS-risk lesions present or not, BRAF-V600E status, initial therapeutic approach, treatment delivered, response and outcome assessment, treatment and outcome of possible relapse, alive/death status, cause of death and major co-morbidities. The categorization used (SS, MS. CNS risk, RO+/-) followed the current implementation of LCH treatment protocols. Disease state was defined as “non-active” when all symptoms or disease activity signs were resolved. Bone healed lesions could have residual deformities or no abnormality on imaging. Patients with non-active disease were considered in complete remission (CR). A patient with active disease intermediate or worse in non-risk organs, and those with active disease better in risk organs following the initial 6- or 12-week treatment period (depending on the treatment protocol- era of treatment) was considered to have resistant disease, as defined in the LCH-IV protocol (https://clinicaltrials.gov/study/NCT02205762). Any patient with non-active disease in CR developing active disease in pre-existing or new LCH lesions was considered as relapse. Informed consent was obtained from all participants for treatment and patient data registration, the documents and the procedure though, could vary according to each Institute’s policy and era. A single, unified dataset was compiled, and additional queries were sent for further data clearing and validation. Median follow-up time (MFupT) was defined as the time from diagnosis to event (resistant disease, relapse or death) or time of last follow-up. Only 169 patients with adequate complete data sets from the initial cohort of 178 patients were included for further analysis. 2.2 / Statistical analysis Initial statistical analysis was based on descriptive statistics. For categorical variables absolute and relative frequencies were provided, while continuous variables were described by n, mean, standard deviation (SD), minimum, median, and maximum. Overall survival (OS) and event free survival (EFS) were calculated with Kaplan-Meier estimator while the confidence intervals (CI) were treated under the log-log method. Log-rank test was employed for the comparison of survival curves, and the proportionality of hazards was evaluated by Schoenfeld residuals. For association between categorical variables or between categorical and continuous variables, Chi-square test and t-test were used accordingly. Seasonality of LCH diagnosis was approached separately by months, seasons, and quantiles. The statistical significance of the seasonality was investigated by Chi-Square tests; expected values were calculated by dividing the number of diagnosed patients by 12, 4 and 4, for months, seasons and quantiles, respectively. Data analysis was performed using R V4.0.3, all tests were two-sided, and the level of significance was set to α = 0.05. 3 / RESULTS Between January 2000 and December 2019, 169 pediatric and adolescent patients were diagnosed with biopsy proven LCH, in all seven Pediatric Oncology Units in Greece. 3.1 / Age, Sex and Disease All patients The mean and median age at diagnosis was 5.59 and 4.76 respectively (SD:4.27 years; range: 0–20.51 years, 82.8% 18 years, 17,2% >10 years). Nearly one third (47/169; 37.8%) of patients were below 2 years old at diagnosis. The majority of patients were males (106/169 patients; 62.7%). Patient characteristics are given in the Table. SS and MS disease was diagnosed in 133 (78.7%) and 36 (21.3%) patients, respectively. Median age at diagnosis for patients with SS and MS disease was 5.88 years (SD:4.31; range, 0-20.51 years) and 1.71 years (SD:2.51; range, 0.04-10.33 years) respectively, and there was a statistically significant difference (p=<0.001). Skeleton was the most frequently involved system (138/169, 81.6%) followed by skin (30/169, 17.8%), lymph nodes (13/169, 7.7%), CNS/DI (14/169, 8.2%, 8 of those with DI at diagnosis), liver (9/169, 5.3%), hematopoietic system (7/169, 4.1%), lung (7/169, 4.1%), spleen (6/169, 3.6%), thyroid (1/169, 0.6%) and other (5/169, 3.0%). For a MFupT of 6.39 years (range, 0 – 20.2 years) EFS and OS were 82.2% and 98.2%, respectively, with all 3 deaths occurring during the first 8 months following diagnosis: one in relation to pneumothorax, one due to secondary lymphoma and the third due to multi-organ system failure post CMV infection (Figure 1, A and B). There was no statistically significant difference in EFS between patients with MS and SS disease (p=0.3074) (Figure 2, A). Sex, age younger than 2 years at diagnosis, Risk Organ+ and bone CNS risk+ were not predictive factors for worse EFS. A definite trend for higher EFS was observed for patients diagnosed from 2010 to 2019, compared to the earlier period 2000 – 2009, but that was not statistically significant (p=0.0862). Similarly, survival has improved with the use of the more recent LCH-IV protocol (p=0.0164) (Figure 2, C). 3.2 / LCH incidence and seasonal distribution Based on our data for the years 2012 – 2019, when the patient study enrollment was universal for all 7 departments, the incidence of LCH in the Greek general population aged up to 14 years was 7.38 new cases per 10 6 children of the general population (as per the year 2016 census-based denominator). Relating to the distribution of new diagnoses throughout the year, there was a trend for more new diagnoses during the fourth quadrant of the year (October, November and December), but this did not reach statistical significance (p=0.075). 3.3 / Patients with Single System (SS) Disease One hundred thirty-three children (87 males, 65.4%) presented with SS disease at a mean and median age of 6.38 and 5.88 years, respectively (range, 0 – 20.51). System involved was: bone in 110 (82.7%) patients, skin 16 (12.0%), hypothalamus/pituitary 3 (2.3%), other systems in 4 (3.0). CNS– risk lesions were reported in 46 (34.6%) patients. Four had diabetes insipidus at diagnosis. No neurodegenerative disease was recorded. For 67 of 133 (50.4%) children, a strategy of watchful observation was initially adopted. Relapse was reported in 5 of those 67 (7.5%) patients, one of them had a second relapse. All children are alive, in CR. Consequently, OS and EFS for children with SS-disease and a watchful observation approach were 100% and 92.5%, respectively, with a MTFup of 4.2 years (range: 0,1 – 19,7) (Figure 1 C, D). Sixty-six SS patients received systemic chemotherapy as initial treatment, 13 (19.7%) of them have relapsed. Two of them (2.8%) died: one in relation to pneumothorax and another child due to secondary lymphoma. From the entire cohort of SS patients, 71 (53.4%) patients received systemic chemotherapy (66 as initial approach and 5 following initial observation at relapse). All of them received Prednisolone / Vinblastine. Survival rates of OS and EFS, for the entire cohort of SS patients were 98.4% and 85.9%, respectively, with a MTFup of 6.51 years (range: 0.1-19.7). Two patients developed second malignancy, both with single site bone disease at diagnosis. The first was a 1-month-old male infant with a soft palate mass, who did not initially receive any treatment, but 6 months later he presented with B-common ALL. The second patient, a 5-year-old male presented with unilateral femoral LCH, treated with a 12-month regime of Prednisone / Vinblastine and was diagnosed with papillary thyroid carcinoma 11 years later. They remain in full remission of the secondary neoplasms. 3.4 / Patients with Multi System (MS) Disease Thirty-six patients (21.3%) presented with MS disease. Mean and median age at diagnosis was 2.69 and 1.70 years respectively (range: 0.04-10.33). More than half of them (21/36, 58.3%) were less than 2 years old at diagnosis. Patients with MS were statistically significantly younger at diagnosis comparing to those with SS disease (mean age at diagnosis: 2.69 years versus 6.38 years, respectively, p<0.001). The patients had up to 5 systems involved. Specifically, 21 patients had 2 systems involved, 7 had 3, 6 had 4 and 2 patients had 5 systems involved. The hematopoietic system, liver and spleen were involved in 6, 9 and 6 patients, respectively. The majority of patients had bone localization (28/36, 77.8%); CNS-Risk localization had 21/28 (75%) children. Sixteen patients (16/36, 44.4%) were RO+ (had at least one risk organ involved). Ten patients (27.8%) developed DI. DI was significantly more frequent in the MS patient cohort, compared to SS population (p<0.001). The majority (33/36 children, 91.7%) were treated with 2 drugs (Prednisolone/ Vinblastine), 1 patient with 3 drugs (Prednisolone/ Vinblastine/ Etoposide) and 2 patients with Prednisolone only. Median treatment duration was 12 months (range, 1 to 43 months). Upon completion of treatment, 2/36 children had resistant disease and 3/36 active stable disease. First relapse was observed in 9 patients (24.3%), whilst 6 of them had second and 3 third relapse. One patient succumbed due to multi-organ system failure post CMV infection, following cladribine treatment. One patient is alive in CR, after stem-cell transplantation. The survival rates of OS and EFS, for the entire cohort of MS patients were 97.2% and 75.0% respectively, with a MTFup of 6.39 years (range 0.5 – 20.2 years) (Figure 1 E, F). 3.5 / BRAF-600E Status The presence of BRAF-600E mutations by immunohistochemistry was evaluated in 51 patients (30.2%). In 27 of them (52.9%) the mutation was detected and in relation to patients with SS and MS disease, 21/39 (53.8%) and 6/12 (50.0%) tested positive, respectively. Among the 21 BRAF-V600E positive patients with SS disease, 5 have relapsed, all after receiving upfront chemotherapy. Regarding patients with MS disease, all 6 with BRAF-600E mutation have relapsed. Of those, 3/6 are alive in CR2 and 3/6 had resistant or multiple relapsed LCH. The probability of relapse was significantly higher in BRAF-600E mutated patients (p=0.014) (Figure 2, B). 3.6 / Diabetes insipidus Fourteen patients had evidence of DI, 4 with SS and 10 with MS. Their median age at diagnosis was 4.49 years, 3/14 patients were below had skeletal involvement and among them, 7 had CNS risk cranial bone involvement. DI upon diagnosis as initial symptom was found in 8/14 patients, 4/8 had CNS risk bone involvement. In one patient DI preceded 2 years before LCH diagnosis. Regarding the remaining 5 patients who developed DI during the course of the disease: 4/5 had multisystem disease and 3/5 had CNS risk bone involvement. Ten out of 14 patients with DI were treated with systemic chemotherapy due to multisystem disease. All 10 patients received prednisolone/Vinblastine, one with additional VP16. Median duration of treatment was 12 months. In a MTFup of 3.2 years, all children are alive with permanent DI. Relapse of LCH has occurred in 3/14 patients with DI in a median time of 32 months from diagnosis. Notably, in all (3/3) relapsed patients, DI was not the initial symptom at diagnosis, but it occurred during the course of the disease. Moreover, 2/3 of relapsed patients had multisystem disease and CNS Risk bone lesions. Of 3 relapsed patients one is lost to follow up and one had additionally hypothyroidism. Neurodegenerative disease has not been documented clinically or by imaging/ MRI in any patient of the entire cohort. 4 / DISCUSSION The current study is the first national comprehensive attempt to collect and analyze clinical and epidemiological data of young patients with LCH, from the seven Greek Pediatric Hematology-Oncology Units. Our cohort comprised of 169 children and adolescents with age up to 16 years, and was observed over a period of 19 years. The official limit for pediatric hospital admission during this period was 14 years of age. The estimated incidence for LCH was 7.38 per 10 6 children, which is rather in the upper limit of the incidence range reported in various population studies. 5-8,20,25 The number of new LCH diagnoses was comparatively higher during the last quarter of the year. The increased incidence of LCH in the cold months, during autumn and winter, was initially described in the study of Stalemark et al (2008), though it has not been consistently reported in others. 25,26 The pathophysiologic mechanism for the possible seasonal variability in LCH incidence has not been clarified. There was a male predominance in children diagnosed with LCH (male:female 1.7:1) similar to other population studies. 5,25,27 The vast majority of our patients (78.7%) were diagnosed with SS disease. Skeleton was, as anticipated, the most frequently affected system (82.7%). 5,7,28 The median age at diagnosis was 4.76 years for the entire cohort. Nevertheless, there was a significant difference in the median age at diagnosis between the 2 subgroups (5.9 years for the SS versus 1.7 years for the MS patients), as children with MS were much younger at diagnosis. Similarly, 34.6% of patients with SS had CNS-risk lesions versus 77.8% with MS. Diabetes insipidus was reported in 3% versus 27.8% of patients with SS and MS LCH, respectively. In the MS subgroup, 55.8% of patients had at least one high risk system involved. The overall EFS and OS for the entire cohort were excellent, 82.2% and 98.2% respectively. These results are comparable with those in previous studies. 8,23 Age did not prove to be a prognostic factor in our population, as EFS was similar in children below and over 2 years of age. Younger children have a higher probability of presenting with MS and RO+ disease, but according to the Histiocyte Society LCH-II study results, it is high-risk organ involvement that can affect response to treatment and subsequent, long-term prognosis at this age group. 23 Interestingly, the OS is completely comparable and particularly high for both subgroups of patients (98.5% and 97.2% for SS and MS LCH, respectively). The intensification and prolongation of treatment for high-risk disease, the addition of reinduction phase in children with incomplete response by the end of initial induction, in combination with prompt shift to refined, effective salvage therapy in case of resistant disease have significantly ameliorated overall survival rates in patients with LCH. The EFS was also not significantly different between patients with SS and MS LCH in our cohort (85.9% and 75%, respectively). Disease reactivation occurred in 16.6% of our patients in a median follow-up time of 7,1 years (range: 0-20.2), a finding which is not in accordance with previous data reporting probability of relapse up to 50%, depending on extent of disease. In detail, the percentage of reactivation is reported to be about 10 – 17% for unifocal but 35% for multifocal SS LCH, rising to 46% for MS LCH and 54% for RO+ disease, with most events occurring in the first 5 years from diagnosis. 29,30 Children who have been treated with older protocols (LCH-II and III) had higher possibility of recurrence compared to those treated with LCH-IV (p=0.0164), although the later patient group also had shorter follow-up time. The lower number of patients with disease recurrence in our cohort may be, in fact, attributed to the high percentage of children treated according to the current protocols (LCH-III, LCH-IV) which include more intensive strategies for initially resistant disease. Literature has confirmed the benefit of treatment intensification over LCH survival rates. 8,23,31,32 BRAF-V-600E was evaluated by immunostaining in approximately one-third of our patients and 52.9% of them were tested positive (53.8% in SS and 50% in MS), a percentage comparable with those reported in previous studies. 1,33-35 It should be mentioned, though, that the sample evaluated is not representative of our entire cohort, because BRAF status testing has been routinely performed only in the last years and usually by immunostaining only. Children positive for BRAF-V-600E mutation had higher risk of relapse (p=0.014), as anticipated. As prior literature has revealed, BRAF-V-600E mutation occurs more often in RO+ and MS LCH, neurodegenerative syndrome, pituitary infiltration and also correlates with resistant or recurrent disease. 34,35 Probably due to the small sample of children with MS tested for BRAF-V-600E, this correlation has been confirmed only in children with SS LCH (p=0.0276). Targeted therapy has not been administered in any of our patients in this cohort. The incidence of diabetes insipidus in our cohort was 8.3%, with most cases occurring in patients with MS disease. The intensification and prolongation of chemotherapy in patients with CNS or bone CNS-risk LCH has reduced their long-term risk for DI development and other endocrinopathies, which has been reported up to 40%, in earlier years, from French and Japanese cohorts. 8,23,36-39 In our cohort, presentation of DI was reported synchronous with LCH diagnosis in all 8 cases. The diagnosis of DI can also precede the presentation of additional LCH lesions, which can develop even 10 years after the initial symptom. 40 In our cohort, 1 patient had DI 2 years before the diagnosis of LCH. The percentage of second neoplasms in our cohort (2/169; 1.2%) is in accordance with the increasing literature data, originating from analysis of international databases, suggesting an association of LCH with other malignancies, mostly leukemias or lymphomas in children. 15 The fact that LCH diagnosis can be antecedent or concurrent with other neoplasms suggests that this association is not only treatment related but could also be attributed to inherent predisposition. A neurodegenerative syndrome has been described in patients with LCH, with incidence varying from 2% to 20%. 21,41 Risk factors for ND are pituitary, skin and base skull bone involvement. Additionally, patients with BRAF mutation are more likely to develop ND-LCH. 42 The fact that no patient has been diagnosed with ND in our cohort, neither at diagnosis nor later, can also be attributed to the very limited use of brain MRI screening for asymptomatic patients and no routine use of specific clinically useful screening tests for neurodegeneration during the follow-up of the patients, besides routine clinical evaluation. Nevertheless, no patient with significant disabling ND was reported. Conclusion The results of the Greek National LCH Registry regarding survival rates, both EFS and OS are comparable with international rates This data confirm that an optimal outcome is achieved when appropriate stratification of patients and subsequent rationalization of treatment are applied, according to the current LCH protocols. Estimated incidence of LCH in the Greek pediatric population is relatively high, in the upper limit of the incidence range compared to other population studies. A lower incidence of DI and ND is noted in our cohort. The official Greek national participation into the LCH-IV Protocol has started in 2021, with the kind support of Artemis Association/ Histiocytosis Hellas (https://www.histioartemis.org/en/). CONFLICT OF INTEREST STATEMENT There is no conflict of interest for all authors relating to this work. ACKNOWLEDGEMENTS This work was supported by the Hellenic Society of Pediatric Hematology and Oncology (HeSPHO). We are deeply grateful to all physicians, nurses and other staff of the seven Greek Pediatric Hematology-Oncology Units for their dedicated care of all patients with LCH. TABLE AND FIGURE LEGENDS Tables Table: Patient, disease and treatment characteristics Figures Figure 1 Event free survival and overall survival for all patients, and patients with single system and multisystem disease. Figure 2 : Patient survival. A. EFS of MS vs. SS patients; B: EFS of BRAF-V600E positive vs. negative patients: C: EFS of all patients according to treatment protocol used. REFERENCES 1. Badalian-Very G, Vergilio JA, Degar BA, et al. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood 2010;116:1919-23.2. Berres ML, Lim KP, Peters T, et al. BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups. J Exp Med 2014;211:669-83.3. Nelson DS, van Halteren A, Quispel WT, et al. MAP2K1 and MAP3K1 mutations in Langerhans cell histiocytosis. Genes Chromosomes Cancer 2015;54:361-8.4. Gulati N, Peckham-Gregory E, Parsons DW, Allen CE. Genomic Alterations in Langerhans Cell Histiocytosis. 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Incidence and risk factors for clinical neurodegenerative Langerhans cell histiocytosis: a longitudinal cohort study. Br J Haematol 2018;183:608-17.42. Mittheisz E, Seidl R, Prayer D, et al. Central nervous system-related permanent consequences in patients with Langerhans cell histiocytosis. Pediatr Blood Cancer 2007;48:50-6.ss Supplementary Material File (figure 1.docx) Download 114.94 KB File (figure 2.docx) Download 111.48 KB File (table 1.docx) Download 18.79 KB Information & Authors Information Version history V1 Version 1 21 October 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords chemotherapy langerhan's cell histiocytosis long term survival Authors Affiliations Marina Servitzoglou Oncology Department View all articles by this author Efthimia Rigatou National & Kapodistrian University of Athens View all articles by this author Loizos Petrikkos 0000-0002-8313-9141 Children’s Hospital View all articles by this author Eugenia Papakonstantinou 0000-0001-5620-7885 Ippokratio General Hospital View all articles by this author Emmanuel Hatzipantelis Aristotle University of Thessaloniki View all articles by this author Iordanis Pelagiadis University Hospital of Heraklion View all articles by this author Helen Dana Mitera" Hospital View all articles by this author Dimitrios Doganis Oncology Department View all articles by this author Natalia Tourkantoni National & Kapodistrian University of Athens View all articles by this author Kyriaki Routzouni Hellenic Society of Pediatric Hematology-Oncology View all articles by this author Athanasios Tragiannidis 0000-0003-4294-2605 Aristotle University of Thessaloniki View all articles by this author Maria Labrou Ippokratio General Hospital View all articles by this author Helen Vasiliatou Kosmidis 0000-0001-8965-6679 Mitera" Hospital View all articles by this author Eftichia Stiakaki University Hospital of Heraklion View all articles by this author Sophia Polychronopoulou Children’s Hospital View all articles by this author Antonis Kattamis National & Kapodistrian University of Athens View all articles by this author Margaret Baka Oncology Department View all articles by this author Vassilios Papadakis 0000-0002-1821-7799 [email protected] Children’s Hospital View all articles by this author Metrics & Citations Metrics Article Usage 291 views 101 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Marina Servitzoglou, Efthimia Rigatou, Loizos Petrikkos, et al. GREEK PEDIATRIC LANGERHANS CELL HISTIOCYTOSIS NATIONAL REGISTRY RESULTS OVER TWO DECADES. Authorea . 21 October 2025. DOI: https://doi.org/10.22541/au.176102684.42938349/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . 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