Watchful waiting in children with unifocal osseous Langerhans cell histiocytosis.

Validating a conservative first-line strategy: This research provides robust, multicenter evidence that a watchful-waiting strategy is safe and effective as initial management for children with biopsy-proven, non-CNS-risk, unifocal bone LCH. This can directly inform clinical guideline updates, supporting a shift away from universal upfront systemic chemotherapy for this specific subgroup. It empowers clinicians to recommend initial observation with confidence, thereby avoiding unnecessary treatment-related toxicity, cost, and psychological burden for a majority of patients.

Informing follow-up protocols: The observation that 94% of disease progression events occurred within the first-year post-diagnosis critically informs monitoring schedules. These supports structuring a more intensive clinical and imaging follow-up regimen during the initial 12-month period, with subsequent visits potentially spaced further apart for stable patients. Resources can thus be allocated more efficiently.

Refining the role of PET-CT in staging: The significant association between PET-CT-based staging and superior event-free survival suggests that conventional imaging (plain radiographs and bone scan) may miss multifocal disease in a subset of patients, leading to the misclassification of some multi-system cases as single-site. Therefore, when resources permit, performing a baseline whole-body PET-CT for accurate initial staging should be considered. This allows for more precise risk stratification, ensuring that patients with truly disseminated disease receive appropriate systemic therapy, while those with confirmed unifocal disease can safely proceed with observation.

Guiding diagnostic and counselling priorities: The lack of prognostic impact based on lesion location or common mutation status simplifies clinical decision-making. It indicates that, within this defined cohort, the choice for observation is broadly applicable regardless of the specific bone involved. Furthermore, the high prevalence of anxiety related to disease relapses, particularly among adolescents, underscores the necessity of integrating structured psychosocial support and patient education about the favorable natural history of this disease variant into standard care pathways.

Introduction

Langerhans cell histiocytosis (LCH) is a rare disease characterized by inflammatory lesions composed of CD1a+/CD207+ histiocytes deriving from myeloid precursor cells. As the most prevalent histiocytic disorder, LCH has an estimated incidence of 2.6-8.9 cases per million in children. 1 , 2 The clinical manifestations of LCH demonstrate significant heterogeneity, ranging from self-limiting lesions to life-threatening disseminated disease. Based on disease involvement, LCH is classified into single-system (SS-LCH) and multisystem (MS-LCH) subtypes. 3 Compared to SS-LCH, MS-LCH is associated with lower survival rates (77%-98%), higher reactivation rates (38%-59%), and increased incidence of permanent sequelae (23%-71%). 4–7 Consequently, clinical management and research efforts have predominantly focused on MS-LCH. The LCH-III/IV protocols established by the Histiocyte Society have significantly improved survival outcomes and reduced disease reactivation rates, particularly in MS-LCH patients. 1 , 4 However, there is currently a lack of large-scale studies specifically targeting SS-LCH, leading to considerable variability in treatment strategies for SS-LCH across different regions.

SS-LCH can be further classified into two distinct subtypes: single-system multi-site (SS-m-LCH) and single-system single-site (SS-s-LCH). Compared to SS-s-LCH, SS-m-LCH has a higher probability of reactivation and sequelae, leading to a greater inclination toward chemotherapy. In contrast, the management of SS-s-LCH remains largely dependent on the extent of disease involvement and individual clinical judgment, as current clinical guidelines provide limited evidence-based recommendations for this subtype. Bone involvement represents the most frequent manifestation of SS-s-LCH, accounting for approximately 75% of cases. Clinical presentations typically include localized pain, swelling, and functional impairment, with potential progression to movement disorders in advanced cases. 8 , 9 Notably, unifocal craniofacial bone lesions (excluding the cranial vault) are classified as CNS-risk lesions due to their well-documented association with severe permanent complications, including diabetes insipidus (DI) and neurodegenerative diseases (ND). 3 , 10–15 Similarly, vertebral lesions with spinal cord compression may directly lead to neurological deficits, while odontoid process involvement can result in spinal instability and subsequent neurological compromise, both demonstrating significant neurological risks. 3 , 10–15 Based on these risks, the Histiocyte Society’s LCH-III trial strongly recommends immediate chemotherapy for patients presenting with unifocal CNS-risk bone lesions. 11 , 16–20 However, the therapeutic approach for unifocal non-CNS-risk bone lesions remains highly controversial, with current options encompassing a wide spectrum of interventions, from active treatments such as chemotherapy, intralesional corticosteroid injections, radiation therapy, bisphosphonates, and surgical interventions (curettage or bone grafting) to more conservative approaches including watchful waiting and indomethacin administration. 3 , 6 , 15 , 21–23 Furthermore, due to the rarity of LCH with unifocal bone involvement, there is a lack of data on the safety and efficacy of these treatments in this patient population.

Watchful waiting, defined as the active monitoring of asymptomatic patients without immediate therapeutic intervention, has been established as a viable management strategy for specific neoplasms and premalignant conditions, including low-grade follicular lymphoma, smoldering multiple myeloma, and Barrett’s esophagus with high-grade dysplasia. 24–26 Emerging evidence from small-scale studies suggests the potential applicability of this approach in LCH management. Specifically, a series of case studies involving 47 patients with unifocal bone LCH demonstrated that observation following diagnostic biopsy resulted in favorable outcomes: 46 patients (97.9%) achieved complete or partial lesion resolution without disease recurrence during follow-up periods ranging from 1 to 4 years. 27–29 Other studies indicate that diagnostic biopsy may trigger lesion regression, possibly by mechanically disrupting the pathological microenvironment. This mechanism could explain symptom resolution without further treatment while preventing complications associated with aggressive therapies. 30–32

However, currently, there are no large-scale cohort studies focusing on watchful waiting for unifocal bone LCH involvement. To address these evidence gaps and to resolve ongoing clinical controversies, we conducted a national, multicenter retrospective study to evaluate the clinical outcomes of pediatric patients with unifocal osseous LCH by watchful waiting in China.

Methods

Study design and patients

This multicenter, retrospective study was conducted across seven medical centers within the Chinese Children Histiocytosis Group (CCHG), a nationwide consortium led by Beijing Children’s Hospital, Capital Medical University, which specializes in pediatric histiocytic disorders. The CCHG comprises over 20 Grade-A tertiary hospitals and has established standardized protocols for the diagnosis and management of childhood histiocytic diseases in China.

The study population included patients diagnosed with osseous SS-s-LCH between August 2014 and August 2024 who received no prior LCH-directed therapy. Consistent with current clinical guidelines and published literature, we implemented stringent exclusion criteria: (1) patients with craniofacial bone lesions (excluding vault lesions), classified as CNS-risk lesions due to their association with DI and neurodegenerative complications; (2) cases with vertebral lesions with evidence of spinal cord compression; and (3) patients with odontoid process involvement, both of which are associated with significant neurological risks. 3 , 10–15 The complete inclusion and exclusion criteria are detailed in Table 1 .

Diagnosis and staging investigations of SS-s-LCH

The diagnosis of LCH was established by histopathological biopsy and defined by positive immunohistochemical staining for CD1a and/or CD207 (langerin). Additional immunohistochemical markers, including S100 and BRAF, were also assessed. Furthermore, whole-exome sequencing (WES) was performed on biopsy tissue from all patients, but peripheral blood cfDNA analysis was only completed in a subset of patients, as this test was not available in some participating medical centers; methodological details are provided in the Supplementary Materials . Subsequently, SS-s-LCH was confirmed through systematic laboratory and radiographic investigations, in accordance with the LCH-III protocol of the Histiocyte Society ( Table S1 ). 2 , 3 , 16 , 19 , 33 PET-CT was recommended for all patients aged 3 years and older. The final decision to undergo PET-CT, however, was made by the parents or guardians after considering financial burden and potential radiation exposure. When performed, the PET-CT scan covered the region from scalp to toes. Patients who were upstaged to MS-LCH or SS-m-LCH based on PET-CT findings were excluded from the watchful waiting cohort and received standard therapy according to their disease classification.

Watchful waiting, treatment, and evaluation

In this study, watchful waiting was adopted as the primary management strategy for patients with osseous SS-s-LCH at the participating medical centers. Watchful waiting was defined as active monitoring without administration of LCH-specific therapies. All patients were managed exclusively with this approach and underwent regular follow-up assessments. For symptomatic relief, temporary immobilization with supportive measures, such as brace fixation, was provided under the guidance of orthopedic specialists.

Follow-up frequency was at least twice per year for the first year, at least once per year from the second to fifth year, and no further regular follow-up was required after the fifth year. Each follow-up evaluation included a comprehensive assessment of disease status, quality of life, and related sequelae. Disease status was categorized as improvement, stabilization, or progression, based on laboratory parameters and radiographic findings according to Histiocyte Society protocols. 34 Improvement was defined by both symptomatic relief and radiographic evidence of reduced bone destruction at the primary site, without development of new lesions. Disease progression was defined by either radiographic worsening at the primary lesion site or development of new LCH lesions. Cases not meeting criteria for either improvement or progression were classified as stabilization.

Quality of life was assessed using the EQ-5D-5L questionnaire and Karnofsky Performance Status (KPS). 35 All patients completed the EQ-5D-5L, which evaluates 5 domains: mobility, self-care, daily activities, pain/discomfort, and anxiety/depression, with responses graded on a 5-level scale. KPS scoring, ranging from 0 (death) to 100 (fully active), was specifically administered to patients with disease progression to assess physical functioning. For patients unable to attend in-person visits, assessments were conducted via telephone. Parental or guardian proxy reporting was utilized for younger children unable to complete the questionnaires independently. Detailed assessment criteria are provided in Tables S2 and S3 .

LCH-specific therapy was immediately initiated for patients demonstrating disease progression with either primary lesion expansion or new site involvement. Treatment modalities included corticosteroids, etoposide, 6-mercaptopurine, vinblastine, cytarabine, cladribine, indomethacin, MEK inhibitors, or BRAF inhibitors. Treatment response was categorized according to LCH-III criteria as active disease-worse (AD-W), active disease-stable (AD-S), active disease-better (AD-B), or no active disease (NAD). 4

Outcome

Among all patients, the primary outcome of this study was 3-year event-free survival (EFS). Event included disease progression, fracture in the primary lesion, and death. The secondary outcomes included the evaluation of the primary site, quality of life assessments, and assessment of permanent sequelae in all patients, as well as treatment response in patients who experienced events and subsequently received chemotherapy.

Statistics

Descriptive data are presented as the means ± standard deviation for variables with a normal distribution and the medians (minimum–maximum) for variables without a normal distribution. For categorical variables, number and percentage are presented. Characteristics were compared using the Wilcoxon rank sum test for continuous variables. Kaplan-Meier curves were used to analyze survival, and the log-rank test was used to compare the differences in survival among patient subgroups. Multivariate Cox proportional-hazards model was used to adjust confounding factors associated with events. All statistical analyses were conducted using SPSS version 23.0 software (IBM, Armon, NY, USA). A two-sided P value of .05 was used to determine the statistical significance.

Results

Patient characteristics

From August 2014 to August 2024, a total of 134 patients were included in this study ( Table 1 ), including 51 females and 83 males, with a median age of 5.5 years (range: 0.1-16.1 years). The median follow-up duration was 36.0 months (range: 4.1-124.0 months).

At the time of initial diagnosis, all patients underwent conventional imaging examinations, while only 42 patients received additional PET-CT scans. Bone involvement was categorized into three groups: cranial bones (n = 37), vertebrae (n = 33), and other bones (n = 64). Among the 80 patients with sufficient biopsy material for genetic analysis, 34 (42.5%) harbored BRAF mutations, 19 (23.8%) had MAP2K1 mutations, and 27 (33.8%) exhibited no detectable mutations ( Table 2 ). Comprehensive patient details for the entire cohort (n = 134) are provided in the Supplementary Database .

Survival

All patients were diagnosed with unifocal osseous LCH and were managed with watchful waiting treatment ( Figure S1 ).

At the final follow-up, 118 out of 134 patients remained event-free, yielding an EFS rate of 88.1% (95% confidence interval [CI]: 81.5-92.5). The overall EFS is illustrated in Figure 1A . The 1-year, 2-year, and 3-year EFS rates were 88.8% (95% CI: 82.4-93.1), 88.1% (95% CI: 81.5-92.5), and 88.1% (95% CI: 81.5-92.5), respectively. Among the 118 event-free patients, 82 achieved spontaneous resolution of the primary lesion. The 3-year EFS rates for patients with skull involvement, vertebral involvement, and other bone involvement were 83.8% (95% CI: 68.9-92.4), 81.8% (95% CI: 65.6-91.4), and 93.8% (95% CI: 85.0-97.5), respectively. The Kaplan-Meier curves are shown in Figure 1A . There was no significant difference in the 3-year EFS among the different involvement groups ( P = .196). The 3-year EFS rate for patients who underwent additional PET-CT was 97.6% (95% CI: 87.7-99.6), while that for patients who did not was 83.7% (95% CI: 74.8-89.9), with a P value of .025 ( Figure 1B ).

Clinical characteristics and outcomes of patients with disease progression

The clinical characteristics of the 16 patients who experienced disease progression are detailed in Table 3 . The median time to progression was 4.7 months (range: 0.6-23.6 months). Disease progression manifested as new LCH involvement in 14 patients (87.5%) and primary lesion expansion in 2 patients (12.5%). Among patients with new lesions, bone was the most frequently involved site (11/14), followed by pituitary (2/14) and skin (1/14).

Molecular profiling was performed in 9 patients with progressive disease. Somatic mutations were detected in biopsy samples from 3 patients (BRAF V600E, n = 1; MAP2K1, n = 2) and in peripheral blood from additional patients (detailed in Table 3 ). Neither tissue nor peripheral blood mutation status showed a significant correlation with disease progression ( Figure 1D and 1E ).

At final follow-up, 13 patients had completed treatment (11 first-line, 2 second-line), 2 remained on treatment with AD-B status, and 1 had not initiated therapy. Notably, none of the 13 treated patients experienced disease reactivation (median follow-up from treatment completion: 43.4 months; range: 2.0-86.9 months).

The KPS scores of patients who experienced disease progression remained above 90, indicating that they maintained satisfactory physical function after watchful waiting and subsequent treatment, except Patient #2. Patient #2, who was initially diagnosed with frontal bone involvement, developed skin lesions at 3.1 months. Despite achieving AD-B with vindesine plus corticosteroid therapy, the patient succumbed to fulminant myocarditis during a chemotherapy interval, deemed unrelated to LCH or treatment toxicity. Two patients demonstrated absent posterior pituitary bright spots on T1-weighted MRI without clinical evidence of DI or ND. Both cases involved cranial bones (occipital and parietal), with no detectable peripheral blood mutations. Patient #12, who progressed to multifocal vertebral involvement, reported minimal discomfort during neck flexion. No severe sequelae were observed among patients with disease progression, except for the aforementioned unrelated mortality.

Quality of life

The quality of life assessment revealed minimal long-term impact. Among 134 patients, 122 completed the EQ-5D-5L Quality of Life Assessment, demonstrating minimal impairment across all evaluated domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression ( Table S3 ). Pain/discomfort was the most frequently reported issue (21/122, 17.2%). While all reports were of mild severity, only 7 of these 21 patients experienced minor limitations in daily activities such as bending, running, or nodding. In addition, 15 patients had slight problems in anxiety, all of whom were adolescents at diagnosis.

Discussion

Langerhans cell histiocytosis is a rare systemic disorder characterized by the proliferation of CD1a+/Langerin+ dendritic cells and multisystem involvement. Although previous studies have suggested favorable outcomes with watchful waiting in unifocal osseous LCH, their clinical applicability has been limited by small sample sizes, leaving the optimal management strategy unresolved.

In this national, multicenter study of 134 pediatric patients with osseous single-system, single-site LCH managed with watchful waiting, the 3-year EFS rate was 88.1% (95% CI: 81.5-92.5). Notably, spontaneous resolution of the primary bone lesion occurred in 82 patients (61.2%). When patients were stratified according to the site of involvement (cranial, vertebral, or other bones), the 3-year EFS rates were 83.8%, 81.8%, and 93.8%, respectively, with no significant difference between groups ( P = .196). These findings support that watchful waiting should be a practical initial approach for osseous SS-s-LCH. Notably, subsequent treatment remained effective for disease progression during observation, with no severe sequelae observed. Among 16 patients experiencing progression, 13 completed chemotherapies without subsequent reactivation (median follow-up post-treatment: 43.4 months; range: 2.0-86.9 months). Importantly, no LCH-related severe sequelae were observed regardless of disease progression.

Notably, while overall quality of life was well-preserved, we identified a significant psychological burden in adolescent patients (10-18 years old). The prevalence of mild anxiety symptoms in this subgroup was 60% (15/25), which markedly exceeds the reported range in the general adolescent population (3.6%-18.0%). 36 , 37 Strikingly, and in contrast to the academic stress commonly cited in the general population, all affected adolescents attributed their anxiety primarily to the fear of disease recurrence. In conclusion, early identification of patients at risk of disease-related events represents a key area for future investigation, with particular emphasis on mental health monitoring and support in adolescent patients.

In addition, the frequency of follow-up also remained questions. It is essential to conduct scheduled re-assessments by experienced physicians during watchful waiting and to make appropriate decisions based on evaluation. Previous studies involving adult LCH patients with unifocal involvement recommended reassessment three months after the initial evaluation and/or biopsy, followed by assessments every 6 months for at least 2 years after diagnosis. 30 In this study, the great majority of disease progression (93.75%, 15/16) occurred within 12 months since the initial diagnosis of unifocal osseous involvement; only one patient (6.25%, 1/16) experienced disease progression in 23.6th month. This finding indicated that monitoring examinations should be more frequent within the first year after the initial diagnosis of LCH, and interval gradually extended afterwards based on the assessment of individual patient. In particular, early detection and prompt treatment of new pituitary involvement are essential to prevent potential sequelae.

The choice between surgical curettage and needle biopsy remains controversial. A series of studies suggested that bone lesions could resolve following curettage or even simple biopsy, possibly by triggering a healing process even without additional treatment. Nevertheless, there still lacks sound evidence to support this assumption. In our cohort, 59 patients underwent needle biopsy and 75 received surgical curettage, with no significant differences in EFS rate ( P = .653) or primary lesion improvement ( P = .815) between groups ( Figure 1C ). Importantly, surgical curettage of unifocal bone lesions, while carrying additional risks of long-term deformity and iatrogenic injury, did not demonstrate superior outcomes in terms of recurrence rates compared to needle biopsy. From the perspective of potentially maximal benefit for patients, needle biopsy may represent a preferred option. These findings underscore the importance of individualized decision-making through multidisciplinary collaboration between orthopedic surgeons and hematologists. 3 , 29

Furthermore, our findings further reinforce the diagnostic utility of 18F-fluorodeoxyglucose-PET-CT (FDG-PET/CT) in clinical management of LCH. Consistent with previous evidence, PET-CT demonstrates high sensitivity (100%) and specificity (83%) in differentiating single-system from multi-system LCH, while also enabling the identification of metabolically active lesions that may be overlooked by conventional imaging modalities. 38 , 39–43 In our study cohort, FDG-PET/CT confirmed unifocal osseous involvement in 42 patients, who subsequently achieved excellent clinical outcomes with a 3-year EFS rate of 97.6%, demonstrating significantly lower progression risk ( P = .025) ( Figure 1B ). This observation supports the important role of FDG-PET/CT in refining risk stratification at the time of initial diagnosis, which is critical for guiding individualized treatment strategies. However, as highlighted in the LCH-III consensus guidelines, FDG-PET/CT is still limited by its high cost, substantial radiation exposure, and the frequent requirement for sedation in young children—factors that preclude its universal adoption as a first-line staging tool for all pediatric LCH patients. 3 Thus, the use of FDG-PET/CT should be guided by clinical suspicion of extensive or progressive disease, availability of imaging resources, and a rigorous risk–benefit assessment. In resource-limited settings or when FDG-PET/CT is unavailable, conventional skeletal survey serves as a rapid, cost-effective, and low-radiation alternative for the initial evaluation of bony involvement and subsequent long-term follow-up. Future prospective studies are warranted to establish clearer indications for FDG-PET/CT in pediatric LCH, particularly in identifying high-risk patient subgroups that may derive the greatest benefit from its superior metabolic resolution.

Analysis revealed no significant association between baseline tissue or peripheral blood mutations and disease progression in unifocal osseous LCH ( Figure 1D , P = .068; Figure 1E , P = .236). While MAPK pathway mutations are well-established drivers of LCH pathogenesis and correlate with relapse, refractory disease, and risk organ involvement in MS-LCH patients, their prognostic significance in SS-LCH remains unclear. 2 , 44–47 Notably, the only statistically significant finding in the present study was an observed difference between patients with BRAF mutations (including BRAF V600E, BRAF V600D, and BRAF indel variants) and those with wild-type BRAF in pathological biopsy specimens ( P = .019). In contrast, no statistically significant differences were detected among all other comparative analyses performed in this cohort. However, due to the extremely low positivity rate of gene mutations in the peripheral blood of unifocal osseous LCH patients and the limited number of positive cases, these findings may not be sufficient to draw a definitive conclusion. Consequently, further research is warranted to elucidate the underlying mechanisms.

Several study limitations warrant consideration. First, this study is a retrospective study, which may cause bias in the results. Secondly, this study did not include measurements of the primary lesions, which limited our ability to establish a threshold value for distinguishing between observation and treatment. Third, previous studies indicated that disease reactivations occurred in approximately one-third of patients within 5 years in LCH patients. 2 , 7 In this study, the median follow-up time of all patients was 36.0 months (range 4.1 months-124.0 months), raising concern about whether the follow-up duration was sufficient.

In conclusion, watchful waiting might represent a safe, effective strategy for LCH patients with unifocal osseous involvement, demonstrating favorable outcomes with minimal complications. Besides, needle biopsy may represent a preferred option of SS-s osseous LCH patients. However, it still requires validation through further research.

Supplementary Material

Acknowledgments

The authors thank the patients and their families for contributing to this study.

Contributor Information

Chenxin Zhou, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing 100045, China.

Haixia Yang, The Affiliated Children’s Hospital of Xiangya School of Medicine, Central South University (Hunan children’s hospital), Changsha 410007, China.

Shilin Liu, Hematology Oncology Department, Shenzhen Children’s Hospital, Shenzhen 518026, China.

Wenyuan Shi, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing 100045, China.

Baosheng Sun, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing 100045, China.

Yunze Zhao, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing 100045, China.

Wei Liu, Hematology Oncology Department, Children’s Hospital Affiliated to Zhengzhou University, Zhengzhou 450012, China.

Lanlan Tang, Pediatric Hematology Department, Xiangya Hospital of Central South University, ChangSha 410008, China.

Rong Liu, Hematology Department, Children’s Hospital Capital Institute of Pediatrics, Beijing 100020, China.

Jian Ge, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing 100045, China.

Dong Wang, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing 100045, China.

Jiafeng Yao, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing 100045, China.

Zishi Fang, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing 100045, China.

Wenqian Wang, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing 100045, China.

Xue Tang, Pediatric Hematology Department, West China Second University Hospital, Sichuan University, Chengdu 610041, China.

Haiyan Luo, The Affiliated Children’s Hospital of Xiangya School of Medicine, Central South University (Hunan children’s hospital), Changsha 410007, China.

Linlin Liu, Hematology Oncology Department, Children’s Hospital Affiliated to Zhengzhou University, Zhengzhou 450012, China.

Jing Cao, Hematology Department, Children’s Hospital Capital Institute of Pediatrics, Beijing 100020, China.

Tianyou Wang, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing 100045, China.

Ju Gao, Pediatric Hematology Department, West China Second University Hospital, Sichuan University, Chengdu 610041, China.

Rui Zhang, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing 100045, China.

Author contributions

Chenxin Zhou (Conceptualization, Data curation, Formal analysis, Investigation, Visualization, Writing—original draft), Haixia Yang (Data curation, Investigation, Writing—original draft), Shilin Liu (Data curation, Formal analysis, Investigation), Wenyuan Shi (Data curation, Formal analysis, Funding acquisition), Baosheng Sun (Data curation, Investigation), Yunze Zhao(Data curation, Investigation), Wei Liu (Data curation), Lanlan Tang (Data curation), Rong Liu (Data curation), Jian Ge (Data curation, Investigation, Methodology), Dong Wang (Data curation), Jiafeng Yao (Data curation), Zishi Fang (Data curation), Wenqian Wang (Data curation), Xue Tang (Data curation), Haiyan Luo (Data curation), Linlin Liu (Data curation), Jing Cao (Data curation), Tianyou Wang (Conceptualization, Supervision, Writing—review & editing), and Ju Gao (Writing—review & editing), Rui Zhang (Conceptualization, Writing—review & editing).

Supplementary material

Supplementary material is available at The Oncologist online.

Funding

This work was supported by the National Natural Science Foundation of China (No.82070202 and 82141119), the Beijing Natural Science Foundation (No. 7232058, 7242053), the Capital’s Funds for Health Improvement and Research (2022-2-1141), and Funding for Reform and Development of Beijing Municipal Health Commission.

Conflicts of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Data availability

The original data and protocols are available to other investigators upon request by contacting the corresponding author.

The member of the Chinese children histiocytosis group (institutions are listed in alphabetical order)

Children’s Hospital of Chongqing Medical University; Children’s Hospital of Hebei Province; Henan Children’s Hospital (Zhengzhou Children’s Hospital); Hunan Children’s Hospital, Children’s Hospital Affiliated to Xiangya Medical College, Central South University; Inner Mongolia Children’s Hospital; National Center for Children’s Health, Capital Medical University; National Children’s Medical Center, Beijing Children’s Hospital, Capital Medical University; National Children’s Medical Center, Children’s Hospital of Fudan University; National Children’s Medical Center (Shanghai), Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine; Nanjing Children’s Hospital, Affiliated to Nanjing Medical University; Shanghai Children’s Hospital; Shenzhen Children’s Hospital; Shanxi Children’s Hospital; Shengjing Hospital of China Medical University; Shandong Provincial Hospital Affiliated to Shandong First Medical University; Sun Yat-sen Memorial Hospital, Sun Yat-sen University; Soochow University Affiliated Children’s Hospital; The Affiliated Hospital of Qingdao University; The Children’s Hospital, Zhejiang University School of Medicine; The First Affiliated Hospital of Zhengzhou University; The First Bethune Hospital of Jilin University; Third Xiangya Hospital of Central South University; Tianjin Children’s Hospital; Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Union Hospital, Tongji Medical College, Huazhong University of Science and Technology; West China Second University Hospital, Sichuan University; Wuhan Children’s Hospital, Tongji Medical College, Huazhong University of Science and Technology; Xi’an Children’s Hospital; Xinhua Hospital, Shanghai Jiao Tong University School of Medicine.

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Associated Data

Supplementary Materials

Data Availability Statement

The original data and protocols are available to other investigators upon request by contacting the corresponding author.