Gorham-Stout disease (GSD) is a rare disorder characterized by progressive bone loss and abnormal proliferation of lymphatic and blood vessels. It is also called vanishing bone disease, phantom bone disease, or massive osteolysis.
In 1838, Jackson first reported it as a “boneless arm.” In 1955, Gorham and Stout summarized 24 cases and established the disease concept 5). To date, about 300 cases have been reported worldwide 10).
The prevalence is estimated to be less than 1 in 200,000 people 3). It mainly affects children and young adults, but has a bimodal distribution with cases occurring after age 50. The male-to-female ratio is reported as 1.6:1, but no clear sex or racial differences are recognized.
In the 2018 classification of the International Society for the Study of Vascular Anomalies (ISSVA), it is classified as a lymphatic malformation6). According to the Hardegger classification, it corresponds to type 4 (Gorham’s massive osteolysis) 6).
QHow rare is Gorham-Stout disease?
A
The prevalence is less than 1 in 200,000 people, and only about 300 cases have been reported worldwide, making it an extremely rare disease 3)10). It mainly occurs in children and young adults, but cases have been reported in all age groups.
Progressive osteolysis: Bone resorption and cortical defects progress. Osteoblastic reaction is poor, and normal bone formation does not occur.
Bone tissue replacement: Bone marrow is replaced by fibrovascular tissue and lymphoproliferative tissue.
Chung imaging 4 stages: (1) intramedullary lucent lesions, (2) confluence of lucent lesions, (3) cortical destruction + soft tissue invasion, (4) bone tissue replaced by fibrous tissue9).
Systemic and visceral involvement
Chylothorax: A serious complication due to invasion of the thoracic duct and pleural lymphatics. Mortality with conservative therapy alone is 69%, which decreases to 36% with surgical intervention7).
Ascites and hepatosplenomegaly: Due to invasion of abdominal lymphatics.
Cerebrospinal fluid leak: May occur from epidural lymphatic abnormalities during spinal invasion10).
Orbital mass: Mass formation in the orbital roof and lateral wall. Causes proptosis.
QDoes Gorham-Stout disease affect the eyes?
A
Invasion of the orbital bones (orbital roof, lateral wall, etc.) is rare but has been reported. It can cause acute unilateral proptosis, visual field defects, restricted eye movement (elevation, depression, and abduction deficits), and facial pain. However, even with orbital invasion, ophthalmic examination may sometimes show no abnormalities.
The cause is currently unknown. Inflammation, puberty, and trauma are known to be possible triggers.
The following somatic mutations have been reported:
AKT1/PIK3CA mutations: Involved in activation of the PI3K-AKT-mTOR pathway.
KRAS (p.G12V) mutation: Confirmed in lymphatic endothelial cells. Mouse models have shown reproduction of the GSD phenotype3).
KDR and MYC gene mutations: Reported in some cases3).
NRAS somatic mutation: Reported together with PI3K pathway mutations8).
No familial cases have been reported, and no hereditary pattern has been confirmed3)8). Environmental predispositions have also not been established9).
X-ray: Initially, small radiolucent lesions appear, which enlarge and coalesce with progression, leading to cortical defects. Used for staging based on the Chung classification.
CT: Evaluates localized osteolytic lesions with sclerotic margins and cortical destruction 1).
MRI: Shows low signal on T1, high signal on T2, and heterogeneous enhancement 3). Excellent for assessing the extent of soft tissue invasion and lymphovascular proliferation.
Ultrasound: May show honeycomb-like low-flow vascular lesions and whirlpool-like echogenic aggregates 1).
Single-photon emission computed tomography (SPECT)/CT: Shows high uptake in areas of lymphovascular proliferation and low uptake in areas of bone destruction 3).
When orbital invasion occurs: Depicted as a mass in the orbital roof and lateral wall.
Initial biopsy of soft tissue often does not yield a diagnosis.
Consider the risk of severe bleeding in bone marrow aspiration and percutaneous biopsy.
Characteristic pathological findings: Bone tissue is replaced by fibrous connective tissue and vascular proliferation 5). Malignant features (cellular atypia) are absent 8).
Multiple myeloma / osteolytic metastases: Differentiated by presence of malignant cells.
Eosinophilic granuloma / juvenile Paget disease: Differentiated by pathological findings and clinical course.
Generalized lymphatic anomaly (GLA): GLA is a multifocal lesion confined to the intramedullary space with few clinical symptoms. GSD differs in that it involves progressive osteolysis with cortical destruction and local soft tissue lesions.
This combination is recommended as first-line pharmacotherapy.
IFN-α (interferon alpha): Suppresses VEGF secretion and inhibits proliferation of lymphatic endothelial cells.
Bisphosphonates: Have anti-osteoclastic and anti-angiogenic effects. They induce apoptosis of tumor cells and normalize IL-6. Alendronate (oral) or zoledronic acid (intravenous) are used9).
It is an mTOR (mammalian target of rapamycin) inhibitor. It inhibits VEGF-C-mediated mTOR phosphorylation and suppresses lymphangiogenesis 1).
Efficacy rate in clinical trials: 50–67% 1).
Yip et al. (2023) treated a 14-month-old girl with sirolimus starting at 0.5 mg twice daily, gradually increasing to 1.5 mg twice daily (target trough level 10–15 ng/mL). Near-complete remission was achieved at 12 months, and no recurrence was observed after discontinuation following 3.5 years of treatment 1).
Suzuki et al. (2022) confirmed bone formation after 2 years of combined alendronate and sirolimus therapy 7).
This is a treatment that expects a synergistic effect from dual inhibition of the mTOR pathway 9). Zoledronic acid inhibits the mevalonate pathway and also blocks the mTOR cascade.
Wojciechowska-Durczynska et al. (2022) reported that in a patient unresponsive to alendronate, administration of zoledronic acid plus IFN-α, and ultimately the combination of zoledronic acid and sirolimus, led to resolution of pleural effusion and arrest of osteolysis 9).
Low dose (16–20 Gy): used in early stages of the disease.
Moderate dose (40–45 Gy): more effective, but carries risk of long-term lung and heart complications.
Hyland et al. (2024) administered 40 Gy in 20 fractions to the thoracic spine and left chest wall for chylothorax, and confirmed stability for 5 years postoperatively 4).
Recommended for localized lesions. For extensive lesions, IFN-α is considered more effective.
Resection and reconstruction with bone graft or prosthesis: There is a high risk of resorption after bone grafting; Miao et al. (2024) reported a case of complete resorption of the grafted fibula 2).
Spinal fusion: Performed in combination with scoliosis correction, but the failure rate for long-segment fixation can reach up to 50% 3).
Orbital invasion: Transcranial orbital exploration and craniotomy can reduce proptosis, but there is a risk of decreased visual acuity and color vision postoperatively.
Surgery for chylothorax: Options include video-assisted thoracoscopic surgery (VATS), pleurectomy, talc pleurodesis, and thoracic duct ligation 4). Hyland et al. (2024) achieved 5-year stability with thoracotomy plus rib resection plus pleurectomy plus pleurodesis 4).
QIs there an established treatment for Gorham-Stout disease?
A
No established treatment guidelines currently exist. Multimodal therapy combining pharmacotherapy (IFN-α plus bisphosphonates as first-line), radiotherapy, and surgery is selected on a case-by-case basis. In recent years, the efficacy of sirolimus (an mTOR inhibitor) has been reported, and it is attracting attention as a treatment option, especially in infants and children1).
The pathology of GSD results from a combination of osteolysis promotion by cytokines produced by abnormally proliferating lymphatic and vascular endothelial cells, and impaired bone repair due to suppression of osteoblast function.
VEGF-A: Promotes angiogenesis. Overexpression has been reported in GSD patients7). VEGF-A stimulates bone repair, but in GSD, osteoblasts are degenerated and suppressed, so repair does not occur.
VEGF-C/D: Promote lymphangiogenesis. They activate the PI3K→AKT→mTOR pathway9)1) and drive abnormal proliferation of lymphatic endothelial cells. Propranolol (beta-blocker) targets only VEGF-A, so it is considered insufficient for GSD, where lymphangiogenesis is predominant1).
IL-6: Activates osteoclasts, and elevated levels have been confirmed in GSD patients9).
M-CSF: Lymphatic endothelial cells produce M-CSF, which causes osteoclast proliferation and massive bone resorption8).
RANKL: The sensitivity of osteoclast precursor cells is enhanced9).
TNF-α: Elevated levels have been reported in soft tissue lesions of patients.
PDGF-BB: A growth factor associated with lymphangiogenesis8).
Bone tissue is replaced by fibrovascular tissue, and normal repair bone (woven bone) is not formed7). Bone cell-derived mediators (such as sclerostin) also contribute to osteoblast suppression. This is the essence of the characteristic pathology of “bone disappearance”.
QWhy does bone disappear in Gorham-Stout disease?
A
Cytokines such as VEGF and IL-6 are secreted from abnormally proliferating lymphatic and vascular endothelial cells, activating osteoclasts. At the same time, activation of the PI3K-AKT-mTOR pathway sustains lymphatic proliferation. Osteoblasts are degenerated and suppressed, so bone repair does not occur. As a result, bone tissue is replaced by fibrovascular tissue, and normal bone disappears7)9).
7. Latest Research and Future Perspectives (Research-Stage Reports)
Yip et al. (2023) reported the first case of sirolimus monotherapy in an infant with GSD who was unresponsive to propranolol 1). This demonstrated the importance of targeting the VEGF-C pathway (lymphangiogenesis) rather than VEGF-A. The patient achieved near-complete remission at 12 months and remained recurrence-free after discontinuation following 3.5 years of treatment, suggesting long-term efficacy of sirolimus.
Wojciechowska-Durczynska et al. (2022) reported a strategy of dual mTOR pathway inhibition using a combination of zoledronic acid and sirolimus 9). Zoledronic acid inhibits the mevalonate pathway and also blocks the mTOR cascade, with expected synergistic effects when combined with sirolimus. Serial bone density data from DXA (dual-energy X-ray absorptiometry) were also presented, allowing objective evaluation of treatment efficacy.
Potential for Targeted Therapy Based on Genetic Mutations
Jiao et al. (2024) identified KDR, KRAS, and MYC gene mutations in a case of spinal GSD 3). A mouse model overexpressing KRAS recapitulated the GSD phenotype, and treatment with the MEK inhibitor trametinib showed therapeutic effects. These results suggest the potential for molecular targeted therapy directed at the RAS-MAPK pathway.
Jiao et al. (2024) reported a 14-year-old boy with spinal GSD and scoliosis who underwent corrective surgery (with intraoperative chyle leakage noted) combined with sirolimus, with stable outcomes at 2 years 3).
Epidural Autologous Blood Patch for CSF Leak Management
Xing et al. (2023) reported that an epidural autologous blood patch was performed in a case presenting with GSD-related cerebrospinal fluid (CSF) leakage and Chiari-like cerebellar tonsil herniation, achieving improvement with a minimally invasive approach10).
Miao C, Cao Y, Li C. Mandibular Gorham-Stout Disease With Implanted Fibular Resorption. The Journal of craniofacial surgery. 2024;35(2):e171-e172. doi:10.1097/SCS.0000000000009928. PMID:38252530; PMCID:PMC10880927.
Jiao Y, Sun H, Huang Y, Zhao J, Huang X, Cai H, et al. Surgical treatment of Gorham-Stout disease combined with scoliosis: a case report and literature review. BMC musculoskeletal disorders. 2024;25(1):1068. doi:10.1186/s12891-024-08217-z. PMID:39725952; PMCID:PMC11670467.
Hyland LD, Elsayed A, Hawari M. Successful Management of Chronic Chylothorax Secondary to Gorham-Stout Disease. Annals of thoracic surgery short reports. 2024;2(4):665-668. doi:10.1016/j.atssr.2024.06.020. PMID:39790588; PMCID:PMC11708598.
Saify FY, Gosavi S, Jain S, Sood M. Vanishing bone disease: An enigma. Journal of oral and maxillofacial pathology : JOMFP. 2021;25(Suppl 1):S7-S10. doi:10.4103/jomfp.JOMFP_112_20. PMID:34083962; PMCID:PMC8123260.
Momanu A, Caba L, Gorduza NC, Arhire OE, Popa AD, Ianole V, et al. Gorham-Stout Disease with Multiple Bone Involvement-Challenging Diagnosis of a Rare Disease and Literature Review. Medicina (Kaunas, Lithuania). 2021;57(7). doi:10.3390/medicina57070681. PMID:34356962; PMCID:PMC8304881.
Suzuki N, Cintra FF, Cintra ML, Maciel MG, Amstalden E, Teixeira F, et al. “A case of vanishing bone disease complicated by chylothorax- diagnosis and treatment”. JRSM open. 2022;13(6):20542704221103912. doi:10.1177/20542704221103912. PMID:35774987; PMCID:PMC9237928.
Ahmetgjekaj I, Kola E, Parisapogu A, Hyseni F, Roy P, Hassan A, et al. Gorham-Stout disease, a diagnosis of exclusion. Radiology case reports. 2022;17(9):3243-3246. doi:10.1016/j.radcr.2022.06.016. PMID:35814817; PMCID:PMC9256995.
Wojciechowska-Durczynska K, Zygmunt A, Mikulak M, Ludwisiak M, Lewinski A. Difficult Therapeutic Decisions in Gorham-Stout Disease-Case Report and Review of the Literature. International journal of environmental research and public health. 2022;19(18). doi:10.3390/ijerph191811692. PMID:36141975; PMCID:PMC9517245.
Qian-qian Xing, Meng Miao, Qiao-wei Zhang, Yue Wu, Fei-fang He. Gorham-Stout disease affecting the spine with cerebrospinal fluid leakage and Chiari-like tonsillar herniation: a rare case report and review of literature. BMC Neurol. 2023;23(1). doi:10.1186/s12883-023-03092-y.
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