Clinical characteristics, genomic profiling, treatments, and outcomes of Langerhans Cell Sarcoma

Clinical characteristics, genomic profiling, treatments, and outcomes of Langerhans Cell Sarcoma | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Clinical characteristics, genomic profiling, treatments, and outcomes of Langerhans Cell Sarcoma Min Lang, Xiao-juan Zheng, Long Chang, Dao-bin Zhou, Wei Zhang, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7445461/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 20 Jan, 2026 Read the published version in Orphanet Journal of Rare Diseases → Version 1 posted 6 You are reading this latest preprint version Abstract Background: Langerhans cell sarcoma (LCS), an exceptionally rare and aggressive neoplasm, remains poorly characterized due to its scarcity. To address this knowledge gap, we conducted a retrospective analysis of 13 LCS patients. This retrospective study included patients ≥18 years old with biopsy proven LCS from October 2015 to April 2025. Results: The median age at diagnosis was 59 years (range: 33-71). The mostcommonly affected organs were the subcutaneous soft tissue (61.5%), followed by lymph nodes (53.8%), skin (30.8%), and bone (23.1%). CBL was the most common mutation, detected in four patients (33.3%). Notably, first-line treatment options included surgery and chemotherapy, with an overall response rate of 53.8%. Among all the relapsed or refractory patients, three eventually received targeted therapies (two trametinib and one niraparib), demonstrating promising efficacy with all patients achieved partial remission. With a median follow-up of 18.2 months (range: 2.6-93.1), the estimated 2-year overall survival rate was 92.3%, while the estimated 2-year progression-free survival rate stood at 32.9%. Conclusions: In our cohort of LCS, we found that prognosis of LCS was poor. Genetic sequencing and the use of targeted therapies may offer a survival advantage for patients with LCS. Langerhans cell sarcoma target therapy prognosis Figures Figure 1 Figure 2 Figure 3 Introduction Langerhans cell sarcoma (LCS) is a rare malignant histiocytosis characterized by multi-organ involvement and an aggressive clinical course, which belongs to the M group in the 2016 World Health Organization (WHO) classification of histiocytic disorders 1 . The overall incidence of the disease was 0.2 per 10,000,000 and did not differ by race or sex 2 . Histopathologically, LCS is identified by the presence of cytologically malignant histiocytoid cells with longitudinally grooved nuclei, prominent nucleoli, and a Langerhans cell phenotype by immunohistochemistry with expression of CD68, CD1a, and CD207 (Langerin). While LCS and Langerhans cell histiocytosis (LCH) share overlapping immunohistochemical profiles, diagnostic differentiation requires assessment of elevated Ki-67 proliferation index and cytologic atypia in LCS 3 . Due to lack of pathologically confirmed cases in the literature, there is a paucity of data in LCS. Little is known about the molecular data in people with LCS. One study of malignant histiocytosis (MH) included eight patients with LCS and identified genetic mutations, such as KRAS , TP53 , NRAS , BRAF , MAP2K1 , and PTPN11 4 . Since the existing treatment-specific information are derived from case reports and registry-based studies, the standard of treatment has not been established. There is currently no consensus on treatment options for LCS, surgery has a role in localized disease, treatments such as conventional lymphoma therapy protocols using the cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen and soft tissue sarcoma regimen (doxorubicin, ifosfamide, and dacarbazine) have been used, while further research is required to obtain a consensus on chemotherapeutic regimen. Targeted therapies, such as MEK inhibitors, have shown promising results in patients with specific genetic mutations 5 . Above all, to fill the knowledge gap of LCS, this study integrated clinical evaluation, molecular landscape profiling, and longitudinal outcome analysis in a LCS cohort of 13 patients. Methods Patients This retrospective study included patients diagnosed with LCS from October 2015 to April 2025. We included patients ≥ 18 years old with biopsy proven LCS by two specialized pathologists in this analysis. The histological findings were consistent with LCS on the basis of the WHO classification of hematopoietic neoplasms 6 . The study was conducted in accordance with the ethical standards of the 1964 Declaration of Helsinki and its subsequent amendments. Ethical approval and waivers of informed consent were obtained from the Peking Union Medical College Hospital Ethics Committee and National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital. Data collection In this study, patient demographics, disease characteristics and treatments were collected through electronic medical records. Baseline characteristics included the gender of the patient, age at diagnosis, disease onset location and clinical manifestations. Laboratory examination including complete blood count, liver and renal function. Radiological data, including thoracic and abdominal computed tomography (CT) and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), were collected. Patients with available samples, tissues from the lesions underwent capture-based RNA sequencing for fusion gene and single nucleotide variant detection (Supplementary Table 1) or DNA target gene sequencing of 183 genes as previously described 7 (Supplementary Table 2). Treatment and outcomes The treatment regimens included chemotherapy, targeted therapy and surgical interventions. Therapeutic effect evaluation using the PET Response Criteria in Solid Tumors (PERCIST 1.0) 8 or the Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) 9 , with outcomes classified as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Patient outcomes were collected by clinical follow-up and telephone follow-up, and the last follow-up was on May 1, 2025. If the patient was not contacted at the last follow-up, we analyzed the patients' conditions between diagnosis and the last follow-up record. Progression-free survival (PFS) was defined as the duration from diagnosis of LCS to the date of disease progression or death from any cause or last follow-up for patients with no recorded date of progression or death. Overall survival (OS) was defined as the duration from the diagnosis of LCS to the date of death from any cause or last follow-up. Statistical analysis Descriptive statistics were used to summarize the demographic profile and disease characteristics of the patients. Categorical variables were compared using Fisher’s exact test, while continuous variables were compared with the Mann-Whitney U test. PFS and OS were estimated using the Kaplan-Meier method, with log-rank tests to compare differences between groups. Univariate and multivariate Cox regression models were used to compare variables of interest. p < 0.05 was considered statistically significant. Statistical analyses were performed using R software (version 3.6.3) and the R package ComplexHeatmap (RRID:SCR_017270), and SPSS 25.0 (SPSS Inc., Chicago, Illinois, USA, RRID:SCR_002865). Results Demographics and disease characteristics The study included 13 patients, including 5 males and 8 females. The median age at diagnosis was 59 years (33–71), and the median duration from symptom onset to diagnosis was 16.9 months (1.0-152.9). All the patients underwent full body CT scans at diagnosis, and the proportion of patients underwent FDG-PET was 84.6% (n = 11). Clinical manifestations leading to diagnosis were dominated by mass causing symptoms (10 cases), with additional symptoms such as pain, itching, rash, loosening of tooth and diabetes insipidus presented in one patient each. The most commonly affected organs were the subcutaneous soft tissue (61.5%), followed by lymph nodes (53.8%), skin (30.8%), bone (23.1%), pituitary gland, spleen, oral mucosa and gum in one patient each. Five patients had a single lesion, with three cases affecting subcutaneous soft tissue, one case affecting the skin, and one affecting the gum; the remaining eight patients had multiple lesions. The Ki-67 index of the lesion tissues in all patients was ≥ 60%. The clinical and pathological characteristics of each patient are presented in Table 1 . Table 1 ID Sex Age (years) Time to diagnosis (months) Site of lesion Ki-67 index Genomic profiling First-line treatment Response evaluation PFS (months) Survival state OS (months) LCS-01 Female 71 2.2 Bone, subcutaneous soft tissue, lymph nodes, spleen 60% KRAS、IGHD、KMT2D、TNFAIP3 CHOP PD 2.6 Death 2.6 LCS-02 Male 61 22.1 Skin, lymph nodes 80% CBL、PTPN11 CHOP、brentuximab vedotin、cladribine PD 12.3 Survive 14.6 LCS-03 Female 59 24.0 Subcutaneous soft tissue 60% Negative Surgery CR 79.3 Survive 79.3 LCS-04 Female 70 36.0 Subcutaneous soft tissue, lymph nodes 80% CBL Surgery PD 76.7 Survive 93.1 LCS-05 Male 49 16.9 Gum 80% Negative Cytarabine PD 11.4 Survive 33.5 LCS-06 Female 64 86.3 Subcutaneous soft tissue, lymph nodes 80% Negative Cytarabine、cladribine PR 6.0 Survive 7.3 LCS-07 Female 41 5.0 Subcutaneous soft tissue 80% CBL、TP53 Cytarabine PR 10.1 Survive 10.1 LCS-08 Male 33 16.4 Bone, skin, subcutaneous soft tissue, lymph nodes 60% SCN1A Cytarabine、idarubicin PR 11.7 Survive 11.7 LCS-09 Female 43 19.0 Skin, lymph nodes 60% EZH2 CHOP PD 4.6 Survive 6.9 LCS-10 Male 61 13.0 Bone, pituitary gland, oral mucosa 80% Untested Cytarabine、MTX CR 20.8 Survive 86.8 LCS-11 Male 37 2.2 Subcutaneous soft tissue 70% KRAS、PTPN11、MAP2K1 Cytarabine、idarubicin CR 42.6 Survive 43.9 LCS-12 Female 61 152.9 Skin 70% TP53、ABL2、ARID2、BRCA2、CREBBP、DNMT3A、EZH2、FCGR2B、ATM::WNK2 fusion CHOP PD 10.8 Survive 25.0 LCS-13 Female 56 1.0 Subcutaneous soft tissue, lymph nodes 60% CBL、TP53、PTPN11、NTRK3、CDH1、SPOP、TTF1、CHEK2、TSC1 deletion Surgery, radiotherapy CR 17.2 Survive 18.2 Clinical characteristics of LCS patients. LCS:Langerhans cell sarcoma; OS:overall survival; PFS:progression-free survival; CHOP:cyclophosphamide, doxorubicin, vincristine, and prednisone; MTX:methotrexate; CR:complete response; PR:partial response; PD:progressive disease Genomic profiling Among 13 patients with LCS, targeted DNA sequencing of lesion tissues was successfully performed in 12 cases, supplemented by RNA sequencing in one case. Three patients (25.0%) showed no detectable alterations. The alterations were categorized into three groups: MAPK/PI3K pathway alterations (6/12, 50%), comprising recurrent CBL mutations (n = 4, 33.3%), PTPN11 mutations (n = 3, 25.0%), KRAS mutations (n = 2, 16.7%), and single instances of MAP2K1 mutation and TSC1 deletion (each 8.3%); epigenetic regulator alterations, including EZH2 mutations (n = 2, 16.7%) and single alterations in KMT2D , ARID2 , CREBBP and DNMT3A (each 8.3%); and other alterations such as TP53 mutations (n = 3, 25.0%) along with single cases of IGHD , TNFAIP3 , SCN1A , ABL2 , BRCA2 , FCGR2B , NTRK3 , CDH1 , TTF1 , SPOP and CHEK2 mutations, plus one ATM::WNK2 fusion (each 8.3%) (Fig. 1 ). Treatment and efficacy The treatment for the cohort is illustrated in a flow diagram in Fig. 2 . Three patients underwent surgical removal of a single subcutaneous soft tissue lesion, and one of them also received lymph nodes radiotherapy after the operation. Other patients all received chemotherapy as initial treatment. Six patients received cytarabine based regimens, in which two received cytarabine monotherapy, two were combined with idarubicin, one was combined with methotrexate (MTX) and one with cladribine. Four patients received CHOP based treatment, including one patient with lesion expressing CD30 received CHOP in combination with brentuximab vedotin and cladribine. In this cohort of 13 patients, first-line therapy achieved an objective response rate (ORR) of 53.8%, comprising four CR and three PR. Among all the relapsed or refractory patients, three eventually received targeted therapies. Three patients received targeted therapy: two with MEK inhibitor trametinib (one with CBL mutation, the other with CBL and PTPN11 mutations), and one with PARP inhibitor niraparib (harboring BRCA2 mutation). All of them achieved PR, demonstrating promising efficacy. Prognosis The median follow-up duration of the 13 patients was 18.2 months (range, 2.6–93.1 months). One patient died and the estimated 2-year OS rate was 92.3%. Totally 8 patients experienced disease progression during the follow-up process, with six progressing following first-line therapy and two relapsing after achieving CR to initial treatment. The estimated 2-year PFS rate was 32.9% (Fig. 3 ). Compared with patients who received other regimens for first-line treatment, patients who received CHOP based regimens for first-line treatment had a worse PFS. Median PFS was 7.7 months and 17.2 months for patients who received CHOP based regimens as first-line treatment and those who did not, respectively (p = 0.014, 95% CI 0.007–0.573). Among patients with single lesions, the 2-year OS and PFS rates were 100% and 50%, respectively; for those with multiple lesions, the rates were 87.5% and 18.8%. No significant difference in OS (p = 0.657) or PFS (p = 0.341) was observed between the groups. Discussion In the WHO and International Consensus Classification, MH encompasses histiocytic sarcoma, LCS, and interdigitating dendritic cell sarcoma. Patients with LCS may present with multi-organ involvement including skin, lymph nodes, bone, lung, bone marrow, and brain, and previous report showed that lymph nodes and skin were the most common organs involved 10 . Similarly, the most commonly affected organs were the subcutaneous soft tissue and lymph nodes in our research. Notably, LCS exhibits a distinct molecular landscape characterized by recurrent somatic mutations and genomic instability, contrasting with the predominantly BRAF V600E driven pathogenesis of LCH 11 . A genomic study of ten LCS patients revealed recurrent alterations in CDKN2A (50%), TP53 (40%), KRAS (40%), PTEN (30%), BCL2 (20%), BRAF V600E (10%), and CSF1R (10%) 12 .In our research, 92.3% (12/13) of the patients underwent genetic testing, which is the cohort with the largest number of genetic tests conducted on LCS patients to date. CBL mutations were detected in 33.3% patients, followed by TP53 and PTPN11 each in 25.0%. The mutation lineages of LCH and LCS were different, which underscored the necessity for comprehensive molecular profiling in suspected LCS cases to confirm diagnosis and guide therapeutic decisions. Owing to its rarity, standard treatment for LCS has not been established to date. Of the 52 LCS patients from NCDB, 20 received chemotherapy as first-line therapy, 24 received surgery, and 15 received radiotherapy. Patients who were managed with radiotherapy had a better OS compared to those who received no radiotherapy 2 . Another study reviewed 46 case series including 66 subjects with LCS, chemotherapy was used alone or in combination in 47 cases (71%) followed by surgery in 31 cases (47%) 5 . Bendamustine 13 , EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) and pegylated interferon-α2b 14 regimens have also been used in patients with LCS 15 . BRAF V600E mutated LCS patients can get temporary remission under treatment with BRAF inhibitor dabrafenib 16 . In our study, most patients are treated with cytarabine based regimen, and the vast majority of patients treated with this regimen in the first and second line can achieve disease remission. However, patients receiving the CHOP based regimen all progressed. The salvage therapies of trametinib and niraparib obtained promising therapeutic effect. Given its high-risk nature, management of LCS warrants aggressive therapeutic strategies, especially molecularly targeted agents. Early integration of next-generation sequencing combined with RNA sequencing and exploration of novel targeted therapies are strongly recommended to improve survival outcomes in this rare malignancy. In our cohort, two LCS patients harbored EZH2 mutations. Although EZH2 inhibitors are not currently approved for clinical use, preclinical evaluation of their therapeutic potential in LCS is warranted. National database studies from the United States have reported a median OS of 19 months for LCS, and the 1-year OS rate was 62% 2 . The prognosis of patients in our cohort is better than previously reported, with estimated 2-year OS rate 92.3%, which may be related to genetic testing of patients whenever possible and the use of targeted therapies after first-line protocols have failed, but due to the small sample size, there was no statistical difference. Previous studies have shown that in MH, whether the lesion is single or multiple varies significantly in prognosis 4 . Another systematic review of LCS also concluded that localized lesions are curable with surgery 5 . However, in this cohort of LCS, no significant difference in OS or PFS was observed between the groups. This study advances our understanding of LCS by delineating its distinct clinical and molecular landscape, therapeutic vulnerabilities, and dismal prognosis. The poor overall survival observed in LCS underscores the critical importance of comprehensive molecular profiling, including both DNA-based NGS and RNA sequencing, to identify actionable targets for precision therapy. Notably, the relatively favorable outcomes in our cohort may reflect the early adoption of molecularly guided interventions, as patients failing first-line therapies frequently received targeted agents tailored to their mutational profiles. However, further validation in larger, multicenter studies is required. Future research should focus on optimizing molecularly targeted therapies and individualized treatment strategies to improve survival rates and quality of life for LCS patients. Conclusion This study showed that LCS is extremely rare. Genetic sequencing and the use of targeted therapies may offer a survival advantage for patients with LCS. Abbreviations LCS Langerhans cell sarcoma WHO World Health Organization LCH Langerhans cell histiocytosis MH malignant histiocytosis CHOP cyclophosphamide, doxorubicin, vincristine, and prednisone CT computed tomography FDG-PET fluorodeoxyglucose positron emission tomography CR complete response PR partial response SD stable disease PD progressive disease PFS progression-free survival OS overall survival MTX methotrexate ORR objective response rate EPOCH etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin Declarations Data availability statement: The data analyzed during the current study is available from the corresponding author upon reasonable request. Funding sources: This study was supported by Beijing Natural Science Haidian Frontier Foundation (L222081 for XX Cao), National Key Research and Development Program of China (2022YFC2304605 for XX Cao). Conflict of interest disclosure: The authors declare no competing interests. Ethics approval statement: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Patient consent statement: Written informed consent was obtained from the patients included in the study. Permission to reproduce material from other sources: n/a Clinical trial registration: n/a Author contributions: ML contributed to data analysis and manuscript writing; XJZ and LC contributed essential data and figures; DBZ and WZ contributed to conceptualization and supervision; XXC contributed to supervision and manuscript revising; and all authors revised the paper and approved the submitted version. Acknowledgements: The authors thank the patients and their families for their trust, respect and support. They also acknowledge all clinicians for their help in accomplishing this work. References Emile J-F, et al. Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood. 2016;127:2672–81. Tella SH, Kommalapati A, Rech KL, Go RS, Goyal G, Incidence. Clinical Features, and Outcomes of Langerhans Cell Sarcoma in the United States. Clin Lymphoma Myeloma Leuk. 2019;19:441–6. Pileri SA, et al. Tumours of histiocytes and accessory dendritic cells: an immunohistochemical approach to classification from the International Lymphoma Study Group based on 61 cases. Histopathology. 2002;41:1–29. Ruan GJ, et al. Clinical characteristics, molecular aberrations, treatments, and outcomes of malignant histiocytosis. Am J Hematol. 2024;99:871–9. Howard JEF, Dwivedi RC, Masterson L, Jani P. Langerhans cell sarcoma: a systematic review. Cancer Treat Rev. 2015;41:320–31. Khoury JD, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia. 2022;36:1703–19. Chen J, et al. Diverse kinase alterations and myeloid-associated mutations in adult histiocytosis. Leukemia. 2022;36:573–6. O JH, Lodge MA, Wahl RL, Practical PERCIST. A Simplified Guide to PET Response Criteria in Solid Tumors 1.0. Radiology. 2016;280:576–84. Schwartz LH, et al. RECIST 1.1-Update and clarification: From the RECIST committee. Eur J Cancer Oxf Engl 1990. 2016;62:132–7. Campo E, et al. The International Consensus Classification of Mature Lymphoid Neoplasms: a report from the Clinical Advisory Committee. Blood. 2022;140:1229–53. Lang M, et al. BRAF Deletion in Adult Patients with Langerhans Cell Histiocytosis Correlates with Multisystem Disease and Poor Outcomes. Clin Cancer Res Off J Am Assoc Cancer Res. 2025;31:197–204. Massoth LR, et al. Histiocytic and Dendritic Cell Sarcomas of Hematopoietic Origin Share Targetable Genomic Alterations Distinct from Follicular Dendritic Cell Sarcoma. Oncologist. 2021;26:e1263–72. Miyazawa Y, et al. [Clinical experience of bendamustine for adult Langerhans cell sarcoma]. Rinsho Ketsueki. 2014;55:563–9. Ishitsuka Y, et al. Pegylated interferon-α2b for local control of Langerhans cell sarcoma. Eur J Dermatol EJD. 2018;28:835–6. Matsukawa T, et al. Successful treatment of an elderly Langerhans cell sarcoma patient by EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) chemotherapy. J Clin Exp Hematop JCEH. 2018;58:184–7. Mourah S, et al. Dramatic transient improvement of metastatic BRAF(V600E)-mutated Langerhans cell sarcoma under treatment with dabrafenib. Blood. 2015;126:2649–52. Supplementary Files LCSSupplementaryTable.docx Cite Share Download PDF Status: Published Journal Publication published 20 Jan, 2026 Read the published version in Orphanet Journal of Rare Diseases → Version 1 posted Editorial decision: Major revision 27 Oct, 2025 Reviewers agreed at journal 16 Sep, 2025 Reviewers invited by journal 16 Sep, 2025 Editor invited by journal 15 Sep, 2025 Editor assigned by journal 25 Aug, 2025 First submitted to journal 24 Aug, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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07:05:57","extension":"png","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":11344,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineFigure1.png","url":"https://assets-eu.researchsquare.com/files/rs-7445461/v1/d8dbfc9c86b99d5de1f6f19c.png"},{"id":92233563,"identity":"30c1baa3-0463-428e-9f19-2e067d96f093","added_by":"auto","created_at":"2025-09-26 06:57:57","extension":"png","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":31004,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineFigure2.png","url":"https://assets-eu.researchsquare.com/files/rs-7445461/v1/d90d94ab38f3c6ae6ea470bb.png"},{"id":92233571,"identity":"89b6072c-2c0c-4a39-a1d6-a2e6c5fed467","added_by":"auto","created_at":"2025-09-26 06:57:57","extension":"png","order_by":15,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":257254,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineFigure3.png","url":"https://assets-eu.researchsquare.com/files/rs-7445461/v1/8f4de67c50a1501d53f27dd9.png"},{"id":92233573,"identity":"5f955c98-6765-433a-837b-42b6529a0f88","added_by":"auto","created_at":"2025-09-26 06:57:57","extension":"xml","order_by":16,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":67860,"visible":true,"origin":"","legend":"","description":"","filename":"OJRDD25012650structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7445461/v1/9808a2b1c9cfbb34d761eaa6.xml"},{"id":92233574,"identity":"a40d1f6c-fb4f-44f2-83a4-0dabfd49bb29","added_by":"auto","created_at":"2025-09-26 06:57:57","extension":"html","order_by":17,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":75656,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7445461/v1/c119f6ef723c3aba0217d5f7.html"},{"id":92233558,"identity":"b9138105-5cc7-415f-bbfb-b00e5785ded6","added_by":"auto","created_at":"2025-09-26 06:57:57","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":109963,"visible":true,"origin":"","legend":"\u003cp\u003eGenomic profiling of lesion tissues of LCS patients\u003c/p\u003e","description":"","filename":"Figure1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7445461/v1/884c847150f567631bf1abac.jpeg"},{"id":92233562,"identity":"9fb973e9-8254-4c19-9fa3-36ec97b14e85","added_by":"auto","created_at":"2025-09-26 06:57:57","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":87465,"visible":true,"origin":"","legend":"\u003cp\u003eTreatment for the LCS patients. LCS: Langerhans cell sarcoma; CHOP: cyclophosphamide, doxorubicin, vincristine, and prednisone; CR: complete response; PR: partial response; PD: progressive disease.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7445461/v1/30e9f1724c748afdcda1da8a.jpg"},{"id":92233560,"identity":"f9e277a3-028d-44b2-9d77-57f439446012","added_by":"auto","created_at":"2025-09-26 06:57:57","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":2008083,"visible":true,"origin":"","legend":"\u003cp\u003eOS and PFS of the LCS patients\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7445461/v1/49b30e7509df6046d6a342f2.jpg"},{"id":101153340,"identity":"092541dc-af25-4a99-bd9a-9c4a4c427ecc","added_by":"auto","created_at":"2026-01-26 16:14:45","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2914265,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7445461/v1/29a3de35-18dd-42a2-bce5-60aabee28657.pdf"},{"id":92233567,"identity":"556d1b39-327e-4858-8ada-e98ba912b7a2","added_by":"auto","created_at":"2025-09-26 06:57:57","extension":"docx","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":32840,"visible":true,"origin":"","legend":"","description":"","filename":"LCSSupplementaryTable.docx","url":"https://assets-eu.researchsquare.com/files/rs-7445461/v1/f10e5801aee9717f7cf7fb11.docx"}],"financialInterests":"","formattedTitle":"Clinical characteristics, genomic profiling, treatments, and outcomes of Langerhans Cell Sarcoma","fulltext":[{"header":"Introduction","content":"\u003cp\u003eLangerhans cell sarcoma (LCS) is a rare malignant histiocytosis characterized by multi-organ involvement and an aggressive clinical course, which belongs to the M group in the 2016 World Health Organization (WHO) classification of histiocytic disorders\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. The overall incidence of the disease was 0.2 per 10,000,000 and did not differ by race or sex\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Histopathologically, LCS is identified by the presence of cytologically malignant histiocytoid cells with longitudinally grooved nuclei, prominent nucleoli, and a Langerhans cell phenotype by immunohistochemistry with expression of CD68, CD1a, and CD207 (Langerin). While LCS and Langerhans cell histiocytosis (LCH) share overlapping immunohistochemical profiles, diagnostic differentiation requires assessment of elevated Ki-67 proliferation index and cytologic atypia in LCS\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eDue to lack of pathologically confirmed cases in the literature, there is a paucity of data in LCS. Little is known about the molecular data in people with LCS. One study of malignant histiocytosis (MH) included eight patients with LCS and identified genetic mutations, such as \u003cem\u003eKRAS\u003c/em\u003e, \u003cem\u003eTP53\u003c/em\u003e, \u003cem\u003eNRAS\u003c/em\u003e, \u003cem\u003eBRAF\u003c/em\u003e, \u003cem\u003eMAP2K1\u003c/em\u003e, and \u003cem\u003ePTPN11\u003c/em\u003e\u003csup\u003e4\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eSince the existing treatment-specific information are derived from case reports and registry-based studies, the standard of treatment has not been established. There is currently no consensus on treatment options for LCS, surgery has a role in localized disease, treatments such as conventional lymphoma therapy protocols using the cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen and soft tissue sarcoma regimen (doxorubicin, ifosfamide, and dacarbazine) have been used, while further research is required to obtain a consensus on chemotherapeutic regimen. Targeted therapies, such as MEK inhibitors, have shown promising results in patients with specific genetic mutations\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eAbove all, to fill the knowledge gap of LCS, this study integrated clinical evaluation, molecular landscape profiling, and longitudinal outcome analysis in a LCS cohort of 13 patients.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003ePatients\u003c/h2\u003e\u003cp\u003eThis retrospective study included patients diagnosed with LCS from October 2015 to April 2025. We included patients\u0026thinsp;\u0026ge;\u0026thinsp;18 years old with biopsy proven LCS by two specialized pathologists in this analysis. The histological findings were consistent with LCS on the basis of the WHO classification of hematopoietic neoplasms\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. The study was conducted in accordance with the ethical standards of the 1964 Declaration of Helsinki and its subsequent amendments. Ethical approval and waivers of informed consent were obtained from the Peking Union Medical College Hospital Ethics Committee and National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eData collection\u003c/h3\u003e\n\u003cp\u003eIn this study, patient demographics, disease characteristics and treatments were collected through electronic medical records. Baseline characteristics included the gender of the patient, age at diagnosis, disease onset location and clinical manifestations. Laboratory examination including complete blood count, liver and renal function. Radiological data, including thoracic and abdominal computed tomography (CT) and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), were collected. Patients with available samples, tissues from the lesions underwent capture-based RNA sequencing for fusion gene and single nucleotide variant detection (Supplementary Table\u0026nbsp;1) or DNA target gene sequencing of 183 genes as previously described\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e (Supplementary Table\u0026nbsp;2).\u003c/p\u003e\n\u003ch3\u003eTreatment and outcomes\u003c/h3\u003e\n\u003cp\u003eThe treatment regimens included chemotherapy, targeted therapy and surgical interventions. Therapeutic effect evaluation using the PET Response Criteria in Solid Tumors (PERCIST 1.0) \u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e or the Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1)\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e, with outcomes classified as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD).\u003c/p\u003e\u003cp\u003ePatient outcomes were collected by clinical follow-up and telephone follow-up, and the last follow-up was on May 1, 2025. If the patient was not contacted at the last follow-up, we analyzed the patients' conditions between diagnosis and the last follow-up record. Progression-free survival (PFS) was defined as the duration from diagnosis of LCS to the date of disease progression or death from any cause or last follow-up for patients with no recorded date of progression or death. Overall survival (OS) was defined as the duration from the diagnosis of LCS to the date of death from any cause or last follow-up.\u003c/p\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eDescriptive statistics were used to summarize the demographic profile and disease characteristics of the patients. Categorical variables were compared using Fisher\u0026rsquo;s exact test, while continuous variables were compared with the Mann-Whitney U test. PFS and OS were estimated using the Kaplan-Meier method, with log-rank tests to compare differences between groups. Univariate and multivariate Cox regression models were used to compare variables of interest. \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. Statistical analyses were performed using R software (version 3.6.3) and the R package ComplexHeatmap (RRID:SCR_017270), and SPSS 25.0 (SPSS Inc., Chicago, Illinois, USA, RRID:SCR_002865).\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eDemographics and disease characteristics\u003c/h2\u003e\u003cp\u003eThe study included 13 patients, including 5 males and 8 females. The median age at diagnosis was 59 years (33\u0026ndash;71), and the median duration from symptom onset to diagnosis was 16.9 months (1.0-152.9). All the patients underwent full body CT scans at diagnosis, and the proportion of patients underwent FDG-PET was 84.6% (n\u0026thinsp;=\u0026thinsp;11). Clinical manifestations leading to diagnosis were dominated by mass causing symptoms (10 cases), with additional symptoms such as pain, itching, rash, loosening of tooth and diabetes insipidus presented in one patient each. The most commonly affected organs were the subcutaneous soft tissue (61.5%), followed by lymph nodes (53.8%), skin (30.8%), bone (23.1%), pituitary gland, spleen, oral mucosa and gum in one patient each. Five patients had a single lesion, with three cases affecting subcutaneous soft tissue, one case affecting the skin, and one affecting the gum; the remaining eight patients had multiple lesions. The Ki-67 index of the lesion tissues in all patients was \u0026ge;\u0026thinsp;60%. The clinical and pathological characteristics of each patient are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"12\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eID\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSex\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAge (years)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eTime to diagnosis (months)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSite of lesion\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eKi-67 index\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eGenomic profiling\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eFirst-line treatment\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eResponse evaluation\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003ePFS (months)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c11\"\u003e\u003cp\u003eSurvival state\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c12\"\u003e\u003cp\u003eOS (months)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLCS-01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eBone, subcutaneous soft tissue, lymph nodes, spleen\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e60%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eKRAS、IGHD、KMT2D、TNFAIP3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCHOP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003ePD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e2.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eDeath\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e2.6\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLCS-02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e61\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e22.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSkin, lymph nodes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e80%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCBL、PTPN11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCHOP、brentuximab vedotin、cladribine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003ePD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e12.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eSurvive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e14.6\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLCS-03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e24.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSubcutaneous soft tissue\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e60%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNegative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eSurgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eCR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e79.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eSurvive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e79.3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLCS-04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e70\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e36.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSubcutaneous soft tissue, lymph nodes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e80%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCBL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eSurgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003ePD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e76.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eSurvive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e93.1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLCS-05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e16.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eGum\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e80%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNegative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCytarabine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003ePD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e11.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eSurvive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e33.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLCS-06\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e64\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e86.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSubcutaneous soft tissue, lymph nodes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e80%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNegative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCytarabine、cladribine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003ePR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e6.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eSurvive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e7.3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLCS-07\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e41\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e5.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSubcutaneous soft tissue\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e80%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCBL、TP53\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCytarabine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003ePR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e10.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eSurvive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e10.1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLCS-08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e33\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e16.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eBone, skin, subcutaneous soft tissue, lymph nodes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e60%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eSCN1A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCytarabine、idarubicin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003ePR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e11.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eSurvive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e11.7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLCS-09\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e43\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e19.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSkin, lymph nodes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e60%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eEZH2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCHOP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003ePD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e4.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eSurvive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e6.9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLCS-10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e61\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e13.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eBone, pituitary gland, oral mucosa\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e80%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eUntested\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCytarabine、MTX\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eCR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e20.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eSurvive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e86.8\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLCS-11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e37\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSubcutaneous soft tissue\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e70%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eKRAS、PTPN11、MAP2K1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCytarabine、idarubicin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eCR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e42.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eSurvive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e43.9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLCS-12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e61\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e152.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSkin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e70%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eTP53、ABL2、ARID2、BRCA2、CREBBP、DNMT3A、EZH2、FCGR2B、ATM::WNK2 fusion\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCHOP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003ePD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e10.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eSurvive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e25.0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLCS-13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e56\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSubcutaneous soft tissue, lymph nodes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e60%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCBL、TP53、PTPN11、NTRK3、CDH1、SPOP、TTF1、CHEK2、TSC1 deletion\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eSurgery, radiotherapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eCR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e17.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eSurvive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e18.2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"12\"\u003eClinical characteristics of LCS patients. LCS:Langerhans cell sarcoma; OS:overall survival; PFS:progression-free survival; CHOP:cyclophosphamide, doxorubicin, vincristine, and prednisone; MTX:methotrexate; CR:complete response; PR:partial response; PD:progressive disease\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eGenomic profiling\u003c/h3\u003e\n\u003cp\u003eAmong 13 patients with LCS, targeted DNA sequencing of lesion tissues was successfully performed in 12 cases, supplemented by RNA sequencing in one case. Three patients (25.0%) showed no detectable alterations. The alterations were categorized into three groups: \u003cem\u003eMAPK/PI3K\u003c/em\u003e pathway alterations (6/12, 50%), comprising recurrent \u003cem\u003eCBL\u003c/em\u003e mutations (n\u0026thinsp;=\u0026thinsp;4, 33.3%), \u003cem\u003ePTPN11\u003c/em\u003e mutations (n\u0026thinsp;=\u0026thinsp;3, 25.0%), \u003cem\u003eKRAS\u003c/em\u003e mutations (n\u0026thinsp;=\u0026thinsp;2, 16.7%), and single instances of \u003cem\u003eMAP2K1\u003c/em\u003e mutation and \u003cem\u003eTSC1\u003c/em\u003e deletion (each 8.3%); epigenetic regulator alterations, including \u003cem\u003eEZH2\u003c/em\u003e mutations (n\u0026thinsp;=\u0026thinsp;2, 16.7%) and single alterations in \u003cem\u003eKMT2D\u003c/em\u003e, \u003cem\u003eARID2\u003c/em\u003e, \u003cem\u003eCREBBP\u003c/em\u003e and \u003cem\u003eDNMT3A\u003c/em\u003e (each 8.3%); and other alterations such as \u003cem\u003eTP53\u003c/em\u003e mutations (n\u0026thinsp;=\u0026thinsp;3, 25.0%) along with single cases of \u003cem\u003eIGHD\u003c/em\u003e, \u003cem\u003eTNFAIP3\u003c/em\u003e, \u003cem\u003eSCN1A\u003c/em\u003e, \u003cem\u003eABL2\u003c/em\u003e, \u003cem\u003eBRCA2\u003c/em\u003e, \u003cem\u003eFCGR2B\u003c/em\u003e, \u003cem\u003eNTRK3\u003c/em\u003e, \u003cem\u003eCDH1\u003c/em\u003e, \u003cem\u003eTTF1\u003c/em\u003e, \u003cem\u003eSPOP\u003c/em\u003e and \u003cem\u003eCHEK2\u003c/em\u003e mutations, plus one \u003cem\u003eATM::WNK2\u003c/em\u003e fusion (each 8.3%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\n\u003ch3\u003eTreatment and efficacy\u003c/h3\u003e\n\u003cp\u003eThe treatment for the cohort is illustrated in a flow diagram in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Three patients underwent surgical removal of a single subcutaneous soft tissue lesion, and one of them also received lymph nodes radiotherapy after the operation. Other patients all received chemotherapy as initial treatment. Six patients received cytarabine based regimens, in which two received cytarabine monotherapy, two were combined with idarubicin, one was combined with methotrexate (MTX) and one with cladribine. Four patients received CHOP based treatment, including one patient with lesion expressing CD30 received CHOP in combination with brentuximab vedotin and cladribine.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eIn this cohort of 13 patients, first-line therapy achieved an objective response rate (ORR) of 53.8%, comprising four CR and three PR. Among all the relapsed or refractory patients, three eventually received targeted therapies. Three patients received targeted therapy: two with MEK inhibitor trametinib (one with \u003cem\u003eCBL\u003c/em\u003e mutation, the other with \u003cem\u003eCBL\u003c/em\u003e and \u003cem\u003ePTPN11\u003c/em\u003e mutations), and one with PARP inhibitor niraparib (harboring \u003cem\u003eBRCA2\u003c/em\u003e mutation). All of them achieved PR, demonstrating promising efficacy.\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003ePrognosis\u003c/h2\u003e\u003cp\u003eThe median follow-up duration of the 13 patients was 18.2 months (range, 2.6\u0026ndash;93.1 months). One patient died and the estimated 2-year OS rate was 92.3%. Totally 8 patients experienced disease progression during the follow-up process, with six progressing following first-line therapy and two relapsing after achieving CR to initial treatment. The estimated 2-year PFS rate was 32.9% (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Compared with patients who received other regimens for first-line treatment, patients who received CHOP based regimens for first-line treatment had a worse PFS. Median PFS was 7.7 months and 17.2 months for patients who received CHOP based regimens as first-line treatment and those who did not, respectively (p\u0026thinsp;=\u0026thinsp;0.014, 95% CI 0.007\u0026ndash;0.573). Among patients with single lesions, the 2-year OS and PFS rates were 100% and 50%, respectively; for those with multiple lesions, the rates were 87.5% and 18.8%. No significant difference in OS (p\u0026thinsp;=\u0026thinsp;0.657) or PFS (p\u0026thinsp;=\u0026thinsp;0.341) was observed between the groups.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn the WHO and International Consensus Classification, MH encompasses histiocytic sarcoma, LCS, and interdigitating dendritic cell sarcoma. Patients with LCS may present with multi-organ involvement including skin, lymph nodes, bone, lung, bone marrow, and brain, and previous report showed that lymph nodes and skin were the most common organs involved\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Similarly, the most commonly affected organs were the subcutaneous soft tissue and lymph nodes in our research.\u003c/p\u003e\u003cp\u003eNotably, LCS exhibits a distinct molecular landscape characterized by recurrent somatic mutations and genomic instability, contrasting with the predominantly \u003cem\u003eBRAF\u003c/em\u003e\u003csup\u003e\u003cem\u003eV600E\u003c/em\u003e\u003c/sup\u003e driven pathogenesis of LCH\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. A genomic study of ten LCS patients revealed recurrent alterations in \u003cem\u003eCDKN2A\u003c/em\u003e (50%), \u003cem\u003eTP53\u003c/em\u003e (40%), \u003cem\u003eKRAS\u003c/em\u003e (40%), \u003cem\u003ePTEN\u003c/em\u003e (30%), \u003cem\u003eBCL2\u003c/em\u003e (20%), \u003cem\u003eBRAF\u003c/em\u003e\u003csup\u003e\u003cem\u003eV600E\u003c/em\u003e\u003c/sup\u003e (10%), and \u003cem\u003eCSF1R\u003c/em\u003e (10%)\u003csup\u003e12\u003c/sup\u003e.In our research, 92.3% (12/13) of the patients underwent genetic testing, which is the cohort with the largest number of genetic tests conducted on LCS patients to date. \u003cem\u003eCBL\u003c/em\u003e mutations were detected in 33.3% patients, followed by \u003cem\u003eTP53\u003c/em\u003e and \u003cem\u003ePTPN11\u003c/em\u003e each in 25.0%. The mutation lineages of LCH and LCS were different, which underscored the necessity for comprehensive molecular profiling in suspected LCS cases to confirm diagnosis and guide therapeutic decisions.\u003c/p\u003e\u003cp\u003eOwing to its rarity, standard treatment for LCS has not been established to date. Of the 52 LCS patients from NCDB, 20 received chemotherapy as first-line therapy, 24 received surgery, and 15 received radiotherapy. Patients who were managed with radiotherapy had a better OS compared to those who received no radiotherapy\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Another study reviewed 46 case series including 66 subjects with LCS, chemotherapy was used alone or in combination in 47 cases (71%) followed by surgery in 31 cases (47%)\u003csup\u003e5\u003c/sup\u003e. Bendamustine\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e, EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) and pegylated interferon-α2b\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e regimens have also been used in patients with LCS\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. \u003cem\u003eBRAF\u003c/em\u003e\u003csup\u003e\u003cem\u003eV600E\u003c/em\u003e\u003c/sup\u003e mutated LCS patients can get temporary remission under treatment with BRAF inhibitor dabrafenib\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. In our study, most patients are treated with cytarabine based regimen, and the vast majority of patients treated with this regimen in the first and second line can achieve disease remission. However, patients receiving the CHOP based regimen all progressed. The salvage therapies of trametinib and niraparib obtained promising therapeutic effect. Given its high-risk nature, management of LCS warrants aggressive therapeutic strategies, especially molecularly targeted agents. Early integration of next-generation sequencing combined with RNA sequencing and exploration of novel targeted therapies are strongly recommended to improve survival outcomes in this rare malignancy. In our cohort, two LCS patients harbored \u003cem\u003eEZH2\u003c/em\u003e mutations. Although \u003cem\u003eEZH2\u003c/em\u003e inhibitors are not currently approved for clinical use, preclinical evaluation of their therapeutic potential in LCS is warranted.\u003c/p\u003e\u003cp\u003eNational database studies from the United States have reported a median OS of 19 months for LCS, and the 1-year OS rate was 62%\u003csup\u003e2\u003c/sup\u003e. The prognosis of patients in our cohort is better than previously reported, with estimated 2-year OS rate 92.3%, which may be related to genetic testing of patients whenever possible and the use of targeted therapies after first-line protocols have failed, but due to the small sample size, there was no statistical difference. Previous studies have shown that in MH, whether the lesion is single or multiple varies significantly in prognosis\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Another systematic review of LCS also concluded that localized lesions are curable with surgery\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. However, in this cohort of LCS, no significant difference in OS or PFS was observed between the groups.\u003c/p\u003e\u003cp\u003eThis study advances our understanding of LCS by delineating its distinct clinical and molecular landscape, therapeutic vulnerabilities, and dismal prognosis. The poor overall survival observed in LCS underscores the critical importance of comprehensive molecular profiling, including both DNA-based NGS and RNA sequencing, to identify actionable targets for precision therapy. Notably, the relatively favorable outcomes in our cohort may reflect the early adoption of molecularly guided interventions, as patients failing first-line therapies frequently received targeted agents tailored to their mutational profiles. However, further validation in larger, multicenter studies is required. Future research should focus on optimizing molecularly targeted therapies and individualized treatment strategies to improve survival rates and quality of life for LCS patients.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study showed that LCS is extremely rare. Genetic sequencing and the use of targeted therapies may offer a survival advantage for patients with LCS.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eLCS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eLangerhans cell sarcoma\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eWHO\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eWorld Health Organization\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eLCH\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eLangerhans cell histiocytosis\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMH\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003emalignant histiocytosis\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCHOP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ecyclophosphamide, doxorubicin, vincristine, and prednisone\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ecomputed tomography\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eFDG-PET\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003efluorodeoxyglucose positron emission tomography\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ecomplete response\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003epartial response\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003estable disease\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eprogressive disease\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePFS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eprogression-free survival\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eOS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eoverall survival\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMTX\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003emethotrexate\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eORR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eobjective response rate\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eEPOCH\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eetoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData availability statement:\u0026nbsp;\u003c/strong\u003eThe data analyzed during the current study is available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding sources:\u003c/strong\u003e This study was supported by Beijing Natural Science Haidian Frontier Foundation (L222081 for XX Cao), National Key Research and Development Program of China (2022YFC2304605 for XX Cao).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest disclosure:\u003c/strong\u003e The authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval statement:\u003c/strong\u003e All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatient consent statement:\u003c/strong\u003e Written informed consent was obtained from the patients included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePermission to reproduce material from other sources:\u0026nbsp;\u003c/strong\u003en/a\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial registration:\u0026nbsp;\u003c/strong\u003en/a\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u003c/strong\u003e ML contributed to data analysis and manuscript writing; XJZ and LC contributed essential data and figures; DBZ and WZ contributed to conceptualization and supervision; XXC contributed to supervision and manuscript revising; and all authors revised the paper and approved the submitted version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e The authors thank the patients and their families for their trust, respect and support. They also acknowledge all clinicians for their help in accomplishing this work.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eEmile J-F, et al. Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood. 2016;127:2672\u0026ndash;81.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTella SH, Kommalapati A, Rech KL, Go RS, Goyal G, Incidence. Clinical Features, and Outcomes of Langerhans Cell Sarcoma in the United States. Clin Lymphoma Myeloma Leuk. 2019;19:441\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePileri SA, et al. Tumours of histiocytes and accessory dendritic cells: an immunohistochemical approach to classification from the International Lymphoma Study Group based on 61 cases. Histopathology. 2002;41:1\u0026ndash;29.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRuan GJ, et al. Clinical characteristics, molecular aberrations, treatments, and outcomes of malignant histiocytosis. Am J Hematol. 2024;99:871\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHoward JEF, Dwivedi RC, Masterson L, Jani P. Langerhans cell sarcoma: a systematic review. Cancer Treat Rev. 2015;41:320\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKhoury JD, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia. 2022;36:1703\u0026ndash;19.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChen J, et al. Diverse kinase alterations and myeloid-associated mutations in adult histiocytosis. Leukemia. 2022;36:573\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eO JH, Lodge MA, Wahl RL, Practical PERCIST. A Simplified Guide to PET Response Criteria in Solid Tumors 1.0. Radiology. 2016;280:576\u0026ndash;84.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSchwartz LH, et al. RECIST 1.1-Update and clarification: From the RECIST committee. Eur J Cancer Oxf Engl 1990. 2016;62:132\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCampo E, et al. The International Consensus Classification of Mature Lymphoid Neoplasms: a report from the Clinical Advisory Committee. Blood. 2022;140:1229\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLang M, et al. BRAF Deletion in Adult Patients with Langerhans Cell Histiocytosis Correlates with Multisystem Disease and Poor Outcomes. Clin Cancer Res Off J Am Assoc Cancer Res. 2025;31:197\u0026ndash;204.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMassoth LR, et al. Histiocytic and Dendritic Cell Sarcomas of Hematopoietic Origin Share Targetable Genomic Alterations Distinct from Follicular Dendritic Cell Sarcoma. Oncologist. 2021;26:e1263\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMiyazawa Y, et al. [Clinical experience of bendamustine for adult Langerhans cell sarcoma]. Rinsho Ketsueki. 2014;55:563\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eIshitsuka Y, et al. Pegylated interferon-α2b for local control of Langerhans cell sarcoma. Eur J Dermatol EJD. 2018;28:835\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMatsukawa T, et al. Successful treatment of an elderly Langerhans cell sarcoma patient by EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) chemotherapy. J Clin Exp Hematop JCEH. 2018;58:184\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMourah S, et al. Dramatic transient improvement of metastatic BRAF(V600E)-mutated Langerhans cell sarcoma under treatment with dabrafenib. Blood. 2015;126:2649\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Langerhans cell sarcoma, target therapy, prognosis","lastPublishedDoi":"10.21203/rs.3.rs-7445461/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7445461/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Langerhans cell sarcoma (LCS), an exceptionally rare and aggressive neoplasm, remains poorly characterized due to its scarcity. To address this knowledge gap, we conducted a retrospective analysis of 13 LCS patients. This retrospective study included patients ≥18 years old with biopsy proven LCS from October 2015 to April 2025.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eThe median age at diagnosis was 59 years (range: 33-71). The mostcommonly affected organs were the subcutaneous soft tissue (61.5%), followed by lymph nodes (53.8%), skin (30.8%), and bone (23.1%). \u003cem\u003eCBL\u003c/em\u003e was the most common mutation, detected in four patients (33.3%). Notably, first-line treatment options included surgery and chemotherapy, with an overall response rate of 53.8%. Among all the relapsed or refractory patients, three eventually received targeted therapies (two trametinib and one niraparib), demonstrating promising efficacy with all patients achieved partial remission. With a median follow-up of 18.2 months (range: 2.6-93.1), the estimated 2-year overall survival rate was 92.3%, while the estimated 2-year progression-free survival rate stood at 32.9%.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e In our cohort of LCS, we found that prognosis of LCS was poor. Genetic sequencing and the use of targeted therapies may offer a survival advantage for patients with LCS.\u003c/p\u003e","manuscriptTitle":"Clinical characteristics, genomic profiling, treatments, and outcomes of Langerhans Cell Sarcoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-26 06:57:52","doi":"10.21203/rs.3.rs-7445461/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2025-10-27T20:10:04+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-09-16T21:56:55+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-16T21:45:20+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"Orphanet Journal of Rare Diseases","date":"2025-09-15T06:05:17+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-25T13:52:57+00:00","index":"","fulltext":""},{"type":"submitted","content":"Orphanet Journal of Rare Diseases","date":"2025-08-24T06:04:01+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"69ea575e-ba21-424f-8aeb-63650a257ecb","owner":[],"postedDate":"September 26th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-01-26T16:13:24+00:00","versionOfRecord":{"articleIdentity":"rs-7445461","link":"https://doi.org/10.1186/s13023-026-04199-4","journal":{"identity":"orphanet-journal-of-rare-diseases","isVorOnly":false,"title":"Orphanet Journal of Rare Diseases"},"publishedOn":"2026-01-20 15:57:22","publishedOnDateReadable":"January 20th, 2026"},"versionCreatedAt":"2025-09-26 06:57:52","video":"","vorDoi":"10.1186/s13023-026-04199-4","vorDoiUrl":"https://doi.org/10.1186/s13023-026-04199-4","workflowStages":[]},"version":"v1","identity":"rs-7445461","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7445461","identity":"rs-7445461","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}