Orphanet Journal of Rare Diseases | Pathogenic Mechanisms and Multimodal Therapies for Gorham-Stout Disease with Thoracic Involvement

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This article systematically reviews the pathogenic mechanisms of Gorham-Stout disease, emphasizing respiratory complications caused by thoracic involvement, particularly the high mortality risk associated with chylothorax, and proposes an integrated diagnostic and therapeutic strategy based on anatomical risk stratification.

 

Literature Overview

The article titled 'Gorham-Stout disease with thoracic involvement: pathogenic mechanisms, respiratory complications, and multimodal therapies,' published in the Orphanet Journal of Rare Diseases, reviews and summarizes recent advances in Gorham-Stout disease (GSD), focusing on its pathogenic mechanisms, respiratory complications due to thoracic involvement, particularly the high fatality rate of chylothorax. By systematically analyzing 125 clinical cases, the study proposes a personalized, multidisciplinary diagnostic and treatment framework. It highlights the importance of early recognition of respiratory threats, offering a clinical management pathway for this rare and complex condition.

Background Knowledge

Gorham-Stout disease (GSD), also known as vanishing bone disease, is an extremely rare progressive osteolytic disorder characterized by the replacement of bone tissue with abnormally proliferating vascular and lymphatic structures, leading to the phenomenon of 'bone disappearance.' The etiology of this disease remains unknown, with fewer than 300 cases reported globally and no clear epidemiological data. Its pathological core lies in the dysregulated crosstalk among the immune, vascular, and skeletal systems. Imbalance in key signaling pathways, such as the RANKL/RANK/OPG axis, leads to abnormal osteoclast activation and uncontrolled bone resorption. Simultaneously, pathological lymphangiogenesis driven by the VEGF-C/VEGFR-3 pathway, along with inflammatory cytokines such as TNF-α and IL-6, collectively form the 'triad of mechanisms' in GSD. Thoracic involvement represents the most dangerous clinical phenotype of GSD, potentially leading to chylothorax with a mortality rate as high as 46.8%, making it one of the leading causes of death. Due to the lack of specific biomarkers and standardized diagnostic criteria, GSD is often misdiagnosed as metastatic bone tumors or multiple myeloma, resulting in delayed treatment. Current management primarily relies on multimodal interventions, including sirolimus, bisphosphonates, radiotherapy, and surgery, yet prospective randomized controlled trials are lacking. This study, through a systematic review, integrates molecular mechanisms with clinical phenotypes, providing critical evidence for optimizing the diagnosis and treatment of GSD, especially in patients with respiratory complications.

 

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Research Methods and Experiments

This study employed a systematic literature review approach, searching for case reports on Gorham-Stout disease with thoracic involvement published between January 2010 and June 2025 in databases including PubMed, Embase, Web of Science, and the Cochrane Library. Search terms included 'Gorham-Stout disease,' 'vanishing bone disease,' 'thoracic,' and 'chylothorax.' Inclusion criteria were cases of GSD confirmed clinically, radiologically, and/or histopathologically, with evidence of thoracic bone destruction or thoracic complications. Two researchers independently extracted data, including demographics, lesion sites, clinical manifestations, diagnostic methods, treatment strategies, and outcomes. Due to the heterogeneity of cases, meta-analysis was not performed; instead, a narrative synthesis approach was used to summarize and analyze the data. The study particularly focused on the incidence of respiratory complications, treatment responses, mortality rates, and explored the underlying molecular pathogenic mechanisms.

Key Conclusions and Insights

• Thoracic involvement is the most severe clinical manifestation of Gorham-Stout disease, with over 40% of cases presenting pleural effusion, of which chylothorax accounts for 26.4%, making it the most common single cause of mortality
• The study reveals three core mechanisms driving GSD progression: abnormal lymphangiogenesis, immune dysregulation, and excessive osteoclast activation, with the VEGF-C and RANKL signaling pathways serving as key molecular hubs
• Imaging (CT/MRI/PET) and exclusion diagnosis remain the cornerstones of clinical diagnosis, while serum factors such as IL-6 and VEGF-A/C may serve as potential auxiliary biomarkers for disease activity
• Treatment strategies based on sirolimus, bisphosphonates, radiotherapy, and surgical interventions (e.g., thoracic duct ligation, vertebral stabilization) constitute the current main multimodal therapeutic approaches, with combination therapy outperforming monotherapy
• Early recognition of respiratory threats, development of individualized treatment plans, and coordinated management through multidisciplinary teams are essential to improve patient outcomes

Research Significance and Outlook

By integrating clinical data from 125 cases with the latest molecular mechanism studies, this research provides a comprehensive clinical-pathological framework for Gorham-Stout disease, especially for complex cases with thoracic involvement. It underscores the high mortality risk of chylothorax, urging clinicians to remain highly vigilant in GSD patients presenting with pleural effusion. The proposed multimodal treatment strategy offers clear guidance for clinical practice.

The limitations of this study include its retrospective design and the heterogeneity of case reports, preventing high-level statistical analyses. Future research should prioritize the discovery of reliable biomarkers for early diagnosis and disease activity monitoring. Additionally, there is an urgent need for prospective, multicenter clinical trials to optimize dosing, duration, and combination regimens of drugs such as sirolimus and bisphosphonates, thereby establishing evidence-based medical standards for this rare but devastating disease.

 

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Conclusion

In summary, Gorham-Stout disease is an extremely complex rare bone disorder both clinically and mechanistically, with respiratory complications due to thoracic involvement—particularly chylothorax—posing the primary life-threatening risk. Through a systematic review, this article elucidates the core pathological mechanisms involving RANKL/RANK/OPG axis imbalance, VEGF/TNF-α-driven lymphangiogenesis, and chronic immune microenvironment dysregulation, all contributing to irreversible osteolysis and pathological vascular/lymphatic proliferation. Analysis of 125 cases confirms the high incidence and mortality of chylothorax and systematically outlines current diagnostic and therapeutic strategies. Diagnosis relies on integrated clinical, radiological, and histopathological evaluation, with exclusion of mimicking conditions such as malignancies. Therapeutically, multimodal intervention combining sirolimus and bisphosphonates has become the first-line approach for moderate to severe disease, supplemented by radiotherapy and surgery to manage structural complications. The ultimate significance of this study lies in advocating for early, individualized risk assessment in GSD patients, particularly close monitoring of respiratory function, and emphasizing the central role of multidisciplinary collaboration in improving long-term outcomes. Future research should focus on biomarker discovery and the conduct of prospective therapeutic trials to fill the current gaps in clinical evidence.

 

Naijian Li, Xiang Le, Dawei Xu, Yunxiang Zeng, and Jinlin Wang. Gorham-Stout disease with thoracic involvement: pathogenic mechanisms, respiratory complications, and multimodal therapies. Orphanet Journal of Rare Diseases.