Orphanet Journal of Rare Diseases | Clinical Characteristics, Genomic Profiling, Treatments, and Outcomes of Langerhans Cell Sarcoma

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This study conducted a retrospective analysis of 13 patients with Langerhans cell sarcoma, revealing its unique molecular features and the potential advantages of targeted therapy, providing new evidence for precision treatment of this rare disease.

 

Literature Overview

The article 'Clinical characteristics, genomic profiling, treatments, and outcomes of Langerhans cell sarcoma,' published in the journal Orphanet Journal of Rare Diseases, retrospectively summarizes clinical data, genomic profiles, treatment strategies, and outcomes of 13 adult patients with Langerhans cell sarcoma (LCS). The study reveals that LCS exhibits a highly heterogeneous molecular landscape, with CBL mutations being the most common genetic alteration. Targeted therapy also demonstrates promising efficacy in relapsed or refractory cases. This study highlights the critical value of molecular testing in the diagnosis and management of LCS, providing a foundation for future individualized treatment strategies.

Background Knowledge

Langerhans cell sarcoma (LCS) is an extremely rare and highly aggressive histiocytic tumor, classified under malignant histiocytoses (MH), characterized by multi-organ involvement and an aggressive clinical course. Although LCS shares similar immunophenotypic features with Langerhans cell histiocytosis (LCH), such as CD1a and CD207/Langerin positivity, it displays a higher Ki-67 proliferation index and marked cellular atypia, indicating more aggressive biological behavior. Due to its rarity, the incidence of LCS is extremely low (approximately 0.2 per 10 million), and standardized treatment protocols are lacking. Clinical management primarily relies on case reports and small-scale retrospective studies. Currently, surgery, chemotherapy (e.g., CHOP regimen), and radiotherapy are used for localized or systemic disease, but with limited efficacy. In recent years, with the advancement of high-throughput sequencing technologies, multiple gene mutations in LCS—such as BRAF, NRAS, TP53, and MAP2K1—have been identified, suggesting that the MAPK/PI3K signaling pathway may be involved in its pathogenesis, offering potential therapeutic targets. However, the genomic landscape of LCS remains incompletely understood, and the clinical significance of mutations such as CBL and PTPN11 requires further validation. Additionally, translating molecular findings into effective treatment strategies remains a major challenge. This study integrates clinical, genomic, and treatment data to systematically characterize the molecular profile of LCS and evaluate the efficacy of targeted therapies, offering critical insights to address these challenges.

 

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Study Methods and Experiments

This multicenter, retrospective study included 13 pathologically confirmed LCS patients (aged ≥18 years) diagnosed between October 2015 and April 2025. All cases were independently reviewed and confirmed by two expert pathologists according to WHO classification criteria for hematopoietic tumors. Clinical data—including demographics, disease manifestations, laboratory tests, imaging findings (CT and FDG-PET), and treatment regimens—were collected. Targeted DNA sequencing (183-gene panel) or hybrid-capture-based RNA sequencing was performed on available tumor samples to detect single nucleotide variants and fusion genes. Treatment responses were evaluated using PERCIST 1.0 or RECIST 1.1 criteria and categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Kaplan-Meier methods were used to estimate progression-free survival (PFS) and overall survival (OS), and univariate and multivariate Cox regression analyses were performed. Statistical analyses were conducted using R and SPSS software.

Key Findings and Insights

• The median age at diagnosis was 59 years. The most commonly involved organs were subcutaneous soft tissue (61.5%) and lymph nodes (53.8%). All patients exhibited a Ki-67 index ≥60% in tumor tissues, indicating high proliferative activity
• Genomic analysis revealed that 50% of patients harbored alterations in the MAPK/PI3K pathway. CBL mutations were most frequent (33.3%), followed by TP53 and PTPN11 mutations (each 25.0%), and the ATM::WNK2 fusion event was reported for the first time
• First-line treatment was primarily chemotherapy. The objective response rate (ORR) with cytarabine-containing regimens was 53.8% (4 CR, 3 PR), whereas all patients receiving CHOP-based therapy experienced disease progression
• In relapsed or refractory patients, targeted therapies with MEK inhibitors (trametinib) or PARP inhibitors (niraparib) achieved partial responses, demonstrating favorable efficacy
• With a median follow-up of 18.2 months, the 2-year overall survival rate was as high as 92.3%, but the 2-year progression-free survival rate was only 32.9%, indicating a high risk of relapse
• Univariate analysis showed that first-line use of CHOP regimen was significantly associated with shorter PFS (p = 0.014), while no significant survival difference was observed between single and multiple lesions

Research Significance and Future Perspectives

This study represents the largest cohort of LCS patients with comprehensive molecular profiling to date, systematically mapping the genomic landscape of LCS. It identifies the high frequency of CBL mutations and reports the novel ATM::WNK2 fusion, expanding our understanding of the molecular mechanisms underlying LCS. The study confirms that targeted therapies can yield significant clinical benefits in patients with corresponding mutations, supporting routine molecular testing in clinical practice to guide personalized treatment.

Although limited by small sample size, this study suggests that the conventional CHOP regimen may be suboptimal for LCS patients, while cytarabine-containing regimens may be more effective. Larger, multicenter studies are needed to validate these findings and explore the potential of additional targeted agents (e.g., EZH2 inhibitors). Furthermore, developing LCS-specific risk stratification models and conducting prospective clinical trials will be essential to optimize treatment strategies and improve long-term survival.

 

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Conclusion

This study systematically analyzes 13 patients with Langerhans cell sarcoma, revealing the disease’s distinct clinical and molecular characteristics. CBL mutation is identified as the most common genetic event in LCS, and MAPK/PI3K pathway alterations are present in half of the patients, underscoring the pathway’s critical role in disease pathogenesis. Despite a high overall survival rate, the progression-free survival rate is only 32.9%, indicating a high risk of relapse and the inability of current therapies to sustain long-term remission. Notably, targeted therapies—particularly MEK and PARP inhibitors—demonstrate promising efficacy in relapsed or refractory patients, achieving partial responses and highlighting the pivotal role of molecular profiling in guiding precision medicine. Additionally, the use of CHOP regimen as first-line therapy is associated with inferior PFS, suggesting it should be avoided as a standard approach. This study emphasizes the importance of early and comprehensive genomic analysis in LCS patients to identify targetable driver alterations and inform individualized treatment. Future validation in larger cohorts and the initiation of clinical trials evaluating targeted therapies are essential to improve long-term outcomes for this rare and aggressive malignancy.

 

Min Lang, Xiao-juan Zheng, Long Chang, Wei Zhang, and Xin-xin Cao. Clinical characteristics, genomic profiling, treatments, and outcomes of Langerhans cell sarcoma. Orphanet Journal of Rare Diseases.