GORHAM-STOUT DISEASE
Clinical Features
Gorham-Stout disease (GSD) is a rare, sporadically occurring disease characterized by lymphatics in bone and massive bone loss (1). GSD may occur at any age but is most commonly observed in children and young adults (1). The clinical course of GSD is unpredictable. GSD may rapidly progress or spontaneously arrest (1). Symptoms are typically nonspecific, such as weakness, acute pain, and swelling (1). In some cases, the first symptom is bone fracture following minor trauma (1). Although GSD can affect any bone in the body, it frequently affects the shoulder, pelvis, jaw, ribs, and vertebrae (1). Thoracic involvement tends to carry a poor prognosis and can be associated with chylothorax (1-5). This complication can have dire consequences, such as respiratory distress and failure.
The cause of excessive bone resorption in GSD is unclear. Gorham and Stout maintained that osteolysis could be due to hyperemia, changes in pH, or mechanical forces (6). More recently, it has been suggested that osteoclasts contribute to the pathology of GSD. Osteoclasts are bone-degrading cells whose role and presence in GSD have remained controversial. Gorham and Stout failed to identify osteoclasts in the pathological specimens used in their original investigation. Several other reports also document an absence of osteoclasts in GSD (6-10). Conversely, osteoclasts have been noted by others (11-13). This inconsistent observation has been proposed to be due to the evaluation of different phases (active or remission) of the disease (11). Despite the inconsistency in the literature concerning their presence, changes in GSD appear to directly affect osteoclasts and their activity. Osteoclast progenitor cells isolated from a GSD patient were more sensitive to the osteoclastogenic factors RANKL and M-CSF (12). Furthermore, serum from a GSD patient stimulated the formation of osteoclast-like cells better than normal serum, and this activity was blocked by an IL-6 neutralizing antibody (14). These data suggest that circulating factors could influence osteoclast activity and bone resorption in GSD.
Histological Changes
Old case reports on massive osteolysis prompted Gorham and Stout to evaluate the histological changes in 8 prior cases of massive osteolysis (6). In their groundbreaking paper, Gorham and Stout reported that angiomatosis is associated with the complete disappearance of bone(s) (6). In some cases, the abnormal vessels appeared to be blood vessels, whereas in others, the abnormal vessels appeared to be lymphatic vessels. The presence of lymphatic vessels could not be confirmed at the time because there were no immunohistochemical markers of lymphatics. LYVE-1 and podoplanin are two markers of lymphatics. Notably, numerous LYVE-1 and podoplanin-positive lymphatic vessels are present in GSD lesions (2, 15, 16). Together, these observations demonstrate that patients with GSD have lymphatic vessels in their bones.
Biomarkers
There is growing evidence that circulating factors could function as biomarkers of disease activity in GSD. IL-6 is a cytokine involved in bone resorption and is elevated in two patients with GSD and normalizes following bisphosphonate treatment alone (10) or in combination with radiation (14). However, a recent report questions the use of IL-6 as a biomarker of disease activity because the authors found that the levels of IL-6 did not correlate with the state of the disease (2). VEGF-A, a growth factor with hem/lymphangiogenic properties (17, 18), is also a potential biomarker for GSD. VEGF-A was reported to be elevated in 2 patients with active disease, and its levels dropped following disease stabilization (2). Furthermore, VEGF-A was elevated in the plasma of another GSD patient, and its levels decreased following treatment with interferon-alpha 2b (19). More recently, CTX-1 (a fragment of collagen-1 created by osteoclasts) has been found to be elevated in several GSD patients (20). This circulating biomarker could potentially be used to monitor bone disease in patients with GSD. Further exploration of cytokines may lead to the identification of molecules to monitor disease activity in patients with GSD.
Therapies
Several different strategies have been employed to treat GSD. Surgical interventions such as pleurodesis and thoracic duct ligation have been used to manage fluid accumulation in the pleural cavity in GSD patients (21). Pharmacological therapies have also been used to treat GSD. Bisphosphonates inhibit osteoclasts and have been used to treat GSD. Disease stabilization has been noted in cases using bisphosphonates to treat lesions affecting the hand (22), jaw (23), pelvic girdle (24), and ribs (4, 10). However, disease progression has been observed even in the presence of long-term use of bisphosphonates (25). In recent years, Sirolimus has grown in popularity for treating GSD. Several published cases reported positive outcomes in GSD patients treated with Sirolimus (26-31).
Genetics
Somatic activating mutations in KRAS (p.Q61R) were recently identified in two patients with GSD (32, 33). Additionally, an EML4::ALK fusion has been observed in a GSD patient (34).
Animal Models
Transgenic mice that overexpress VEGF-C in bone exhibit a phenotype that resembles GSD. Osx-tTA;TetO-Vegfc mice have lymphatics in their bones, and they have porous cortical bone (35). Osx-tTA;TetO-Vegfc mice also have more osteoclasts than control mice and zoledronic acid can attenuate bone loss in Osx-tTA;TetO-Vegfc mice (35).
Lineage-tracing studies with Osx-tTA;TetO-Vegfc mice revealed that LECs in bone come from preexisting LECs located outside of bone (36). A time course experiment further characterized bone lymphatic development in Osx-tTA;TetO-Vegfc mice. This experiment revealed that bone lymphatics develop in a stepwise manner, where regional lymphatics grow, breach the periosteum, and then gradually invade bone (36). The invading lymphatics were closely associated with osteoclasts, which appeared to create a path through the bone for lymphatic vessels. It was also reported that loss of osteoclasts impaired the development of bone lymphatics in Osx-tTA;TetO-Vegfc mice and that rapamycin can suppress the growth of bone lymphatics in Osx-tTA;TetO-Vegfc mice (36).
KRAS-mutant animal models have also been developed and characterized. Experiments with zebrafish embryos revealed that hyperactive KRAS signaling in LECs causes edema and the enlargement of lymphatic vessels (37). It was recently reported that mouse embryos that express an active form of KRAS (KRASG12D) in their LECs also have edema and enlarged lymphatic vessels (38). Additionally, KRASG12D expression in LECs postnatally stimulates the formation of lymphatics in bone and impairs the formation of lymphatic valves (33). Transcriptional profiling of LECs revealed that KRASG12D decreases the expression of genes that promote lymphatic valve development (38). Importantly, trametinib (an FDA-approved MEK1/2 inhibitor) increases the expression of lymphatic valve genes in KRASG12D LECs and suppresses the loss of lymphatic valves in KRASG12D mice (33, 38). MEK1/2 inhibition also decreases the incidence of edema in zebrafish embryos (37).
GENERALIZED LYMPHATIC ANOMALY
Clinical Features
Generalized lymphatic anomaly (GLA) is a rare disease of the lymphatic system (39). Although GLA can present at any age, it is typically diagnosed in children (39). This condition may affect a single organ but commonly involves multiple organs (39). Thoracic involvement frequently presents with chylous effusions and is associated with a poor prognosis and a high mortality rate, especially in children (39, 40). Symptoms of GLA are nonspecific and include wheezing, cough, dyspnea, and chest pain (41). These nonspecific symptoms cause pulmonary GLA to be misdiagnosed as asthma in many individuals (42). However, imaging (MRI and CT) and histological analysis can assist in the correct diagnosis of GLA. Approximately 40% of patients with GLA have bone involvement (42). These patients exhibit loss of medullary bone but not cortical bone (43). They tend to have more bones affected than GSD patients, and the appendicular skeleton is more frequently involved in GLA than GSD (43).
Histological Changes
The histological features of pulmonary GLA are distinct from other lung diseases. GLA specimens contain numerous anastomosing vessels comprised of flattened endothelial cells that stain positive for D2-40 (44). A biobank of formalin-fixed paraffin-embedded material from 23 GLA/GSD patients has been created (31). Analysis of pulmonary and pleural samples from this biobank revealed that lesions in young patients are more proliferative than in old patients (31). Importantly, this biobank is reported to be open for collaborative ventures on GLA and GSD (31).
Therapies
Sirolimus has been used to treat several cases of GLA (26, 29, 30, 45). In a recent study, 18 patients (13 with GLA and 5 with GSD) were treated with sirolimus (46). Eighty-three percent of patients had improvement in one or more aspects of their disease (46). Bone disease did not progress in patients with bone involvement, and effusions improved in most patients with either a pleural or pericardial effusion (46). Taken together, Sirolimus appears effective at stabilizing or reducing signs/symptoms of disease in patients with GLA or GSD (46).
Genetics
It was recently reported that somatic activating mutations in PIK3CA can cause GLA (47). Mutations in HRAS, KRAS, and BRAF have also been observed in GLA patients (48). An EML4::ALK fusion has also been found in a case of GLA (49).
Animal Models
A PIK3CA-driven mouse model of GLA has been developed cand characterized. Mice that expressed an active form of PIK3CA (Prox1-CreERT2;LSL-PIK3CAH1047R) in their lymphatics developed abnormal lymphatics in their skin and ectopic lymphatics in their bones (47). Importantly, rapamycin inhibited lymphatic hyperplasia and dysfunction in Prox1-CreERT2;LSL-PIK3CAH1047R mice (47).
Transgenic mice have also been created to study lymphatic abnormalities in the lung. CCSP-rtTA;TetO-Vegfc mice develop irregular lymphatic vessels in their lungs and chylothorax (50). Surprisingly, the irregular lymphatics persisted following VEGF-C withdrawal (50). Interestingly, rapamycin partially reversed the lymphatic abnormalities in CCSP-rtTA;TetO-Vegfc mice (51). This work suggests that rapamycin can partially normalize irregular lymphatic vessels.
KAPOSIFORM LYMPHANGIOMATOSIS
Clinical Features
Kaposiform lymphangiomatosis (KLA) is an aggressive lymphatic anomaly. KLA is typically diagnosed in children, and the 5-year survival rate for the disease is 51% (52). Patients with KLA exhibit diffuse lymphatic abnormalities in multiple tissues. The mediastinum, lung, pleura, spleen, and skeleton are frequently affected in patients with KLA (52). Like GLA, bone involvement in KLA is associated with the loss of medullary bone, not cortical bone (42, 52). However, hemorrhagic pleural or pericardial effusions are more common in KLA than in GLA (42). Thrombocytopenia is also more common in KLA than in GLA (52).
Histological Changes
A distinguishing characteristic of KLA is the presence of spindle cells (52). These spindle cells express podoplanin, a marker of lymphatic endothelial cells (52).
Biomarkers
Angiopoietin-2 (Ang-2) is a hem/lymphangiogenic growth factor that can be an agonist or antagonist of Tie-2. Ang-2 serum levels are elevated in KLA patients and can be used to diagnose KLA (53, 54). Interestingly, Ang-2 levels decrease in KLA patients following treatment with sirolimus (53). Therefore, Ang-2 could function as a diagnostic biomarker for KLA and a biomarker to monitor therapy response.
Therapies
Several therapies have been used to treat KLA. The most common treatments include vincristine, trametinib, and sirolimus (30, 42, 52, 55, 56).
Genetics and Animal Models
Lymphatic endothelial cells were recently isolated from a GLA/KLA patient (57). Exome sequencing revealed that the cells harbored an activating mutation in NRAS (p.Q61R) (57). These cells formed lesions when grown in mice, and expression of mutant NRAS in endothelial cells impaired lymphatic development in zebrafish (57). More recently, ten additional patients with KLA were found to have the NRAS p.Q61R variant (58).
The identification of NRAS mutations in KLA patients has facilitated the development of KLA animal models. Mice that express the NRAS (p.Q61R) mutation in lymphatic endothelial cells during embryonic development exhibit dilated lymphatic vessels (59). Interestingly, the expression of NRAS (p.Q61R) in lymphatic endothelial cells during postnatal development does not alter the architecture of the lymphatic network (59). Conversely, when NRAS (p.Q61R) is expressed in blood endothelial cells, it causes vascular defects, splenomegaly, and increases in serum levels of Angpt2(60).
Hot spot PIK3CA mutations have also been identified in patients with KLA (48, 61). It remains unclear whether ANGPT2 is elevated in these patients.
CENTRAL CONDUCTING LYMPHATIC ANOMALY (CCLA)
Central conducting lymphatic anomaly (CCLA) is a complex lymphatic anomaly characterized by the dilatation of lymphatic channels. It was recently discovered that somatic mutations in ARAF can cause CCLA (62). ARAF is a serine/threonine protein kinase that activates MEK. The ARAF mutation (c.640T>C:p.S214P) that was found in two unrelated patients with CCLA is a gain-of-function mutation that promotes MEK/MAPK signaling (62). The MEK inhibitor, trametinib, suppressed MAPK signaling in ARAF-mutant lymphatic endothelial cells, and a different MEK inhibitor normalized lymphatics in ARAF-mutant zebrafish (62). One CCLA patient with an ARAF mutation has been treated with trametinib, and their pulmonary function test markedly improved following 12 months of therapy (62). Somatic mutations in HRAS, KRAS, BRAF, MAP2K1, and PIK3CA have also been identified in CCLA patients (48).
REFERENCES
1. Dellinger MT, et al. Viewpoints on vessels and vanishing bones in Gorham-Stout disease. Bone. 2014;63:47-52.
2. Brodszki N, et al. A novel treatment approach for paediatric Gorham-Stout syndrome with chylothorax. Acta Paediatr. 2011;100(11):1448-53.
3. Deveci M, et al. Gorham-Stout syndrome with chylothorax in a six-year-old boy. Indian J Pediatr. 2011;78(6):737-9.
4. Kuriyama DK, et al. Treatment of Gorham-Stout disease with zoledronic acid and interferon-alpha: a case report and literature review. Journal of pediatric hematology/oncology. 2010;32(8):579-84.
5. Chavanis N, et al. Chylothorax complicating Gorham’s disease. The Annals of thoracic surgery. 2001;72(3):937-9.
6. Gorham LW, and Stout AP. Massive osteolysis (acute spontaneous absorption of bone, phantom bone, disappearing bone); its relation to hemangiomatosis. The Journal of bone and joint surgery American volume. 1955;37-A(5):985-1004.
7. Heyden G, et al. Disappearing bone disease. A clinical and histological study. The Journal of bone and joint surgery American volume. 1977;59(1):57-61.
8. Manisali M, and Ozaksoy D. Gorham disease: correlation of MR findings with histopathologic changes. Eur Radiol. 1998;8(9):1647-50.
9. Hagberg H, et al. Alpha-2b interferon and oral clodronate for Gorham’s disease. Lancet. 1997;350(9094):1822-3.
10. Hammer F, et al. Gorham-Stout disease–stabilization during bisphosphonate treatment. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2005;20(2):350-3.
11. Moller G, et al. The Gorham-Stout syndrome (Gorham’s massive osteolysis). A report of six cases with histopathological findings. The Journal of bone and joint surgery British volume. 1999;81(3):501-6.
12. Hirayama T, et al. Cellular and humoral mechanisms of osteoclast formation and bone resorption in Gorham-Stout disease. J Pathol. 2001;195(5):624-30.
13. Gorham LW, et al. Disappearing bones: a rare form of massive osteolysis; report of two cases, one with autopsy findings. Am J Med. 1954;17(5):674-82.
14. Devlin RD, et al. Interleukin-6: a potential mediator of the massive osteolysis in patients with Gorham-Stout disease. J Clin Endocrinol Metab. 1996;81(5):1893-7.
15. Edwards JR, et al. Lymphatics and bone. Hum Pathol. 2008;39(1):49-55.
16. Hagendoorn J, et al. Platelet-derived growth factor receptor-beta in Gorham’s disease. Nat Clin Pract Oncol. 2006;3(12):693-7.
17. Olsson AK, et al. VEGF receptor signalling – in control of vascular function. Nat Rev Mol Cell Biol. 2006;7(5):359-71.
18. Dellinger MT, and Brekken RA. Phosphorylation of Akt and ERK1/2 Is Required for VEGF-A/VEGFR2-Induced Proliferation and Migration of Lymphatic Endothelium. PloS one. 2011;6(12):e28947.
19. Dupond JL, et al. Plasma VEGF determination in disseminated lymphangiomatosis-Gorham-Stout syndrome: a marker of activity? A case report with a 5-year follow-up. Bone. 2010;46(3):873-6.
20. Liu Y, et al. Gorham-Stout disease: radiological, histological, and clinical features of 12 cases and review of literature. Clinical rheumatology. 2016;35(3):813-23.
21. Patel DV. Gorham’s disease or massive osteolysis. Clin Med Res. 2005;3(2):65-74.
22. Silva S. Gorham-Stout disease affecting both hands: stabilisation during biphosphonate treatment. Hand (N Y). 2011;6(1):85-9.
23. Avelar RL, et al. Use of zoledronic acid in the treatment of Gorham’s disease. Int J Pediatr Otorhinolaryngol. 2010;74(3):319-22.
24. Heyd R, et al. Gorham-Stout syndrome of the pelvic girdle treated by radiation therapy: a case report. Strahlenther Onkol. 2011;187(2):140-3.
25. Lehmann G, et al. Benefit of a 17-year long-term bisphosphonate therapy in a patient with Gorham-Stout syndrome. Arch Orthop Trauma Surg. 2009;129(7):967-72.
26. Adams DM, et al. Efficacy and Safety of Sirolimus in the Treatment of Complicated Vascular Anomalies. Pediatrics. 2016;137(2):1-10.
27. Cramer SL, et al. Gorham-Stout Disease Successfully Treated With Sirolimus and Zoledronic Acid Therapy. Journal of pediatric hematology/oncology. 2016;38(3):e129-32.
28. Garcia V, et al. Sirolimus on Gorham-Stout disease. Case report. Colombia medica. 2016;47(4):213-6.
29. Triana P, et al. Sirolimus in the Treatment of Vascular Anomalies. European journal of pediatric surgery : official journal of Austrian Association of Pediatric Surgery [et al] = Zeitschrift fur Kinderchirurgie. 2017;27(1):86-90.
30. Ozeki M, et al. The impact of sirolimus therapy on lesion size, clinical symptoms, and quality of life of patients with lymphatic anomalies. Orphanet journal of rare diseases. 2019;14(1):141.
31. Mori M, et al. Pulmonary and pleural lymphatic endothelial cells from pediatric, but not adult, patients with Gorham-Stout disease and generalized lymphatic anomaly, show a high proliferation rate. Orphanet journal of rare diseases. 2016;11(1):67.
32. Nozawa A, et al. A somatic activating KRAS variant identified in an affected lesion of a patient with Gorham-Stout disease. J Hum Genet. 2020.
33. Homayun-Sepehr N, et al. KRAS-driven model of Gorham-Stout disease effectively treated with trametinib. JCI Insight. 2021;6(15).
34. Apsel Winger B, et al. Effective Use of ALK Inhibitors in EML4::ALK-Positive Lymphatic Malformations. Pediatric blood & cancer. 2025;72(2):e31441.
35. Hominick D, et al. VEGF-C promotes the development of lymphatics in bone and bone loss. Elife. 2018;7.
36. Monroy M, et al. Lymphatics in bone arise from preexisting lymphatics. Development. 2020.
37. Sheppard SE, et al. Lymphatic disorders caused by mosaic, activating KRAS variants respond to MEK inhibition. JCI Insight. 2023;8(9).
38. Fernandes LM, et al. Hyperactive KRAS/MAPK signaling disrupts normal lymphatic vessel architecture and function. Front Cell Dev Biol. 2023;11:1276333.
39. Faul JL, et al. Thoracic lymphangiomas, lymphangiectasis, lymphangiomatosis, and lymphatic dysplasia syndrome. Am J Respir Crit Care Med. 2000;161(3 Pt 1):1037-46.
40. Alvarez OA, et al. Thoracic lymphangiomatosis in a child. Journal of pediatric hematology/oncology. 2004;26(2):136-41.
41. Satria MN, et al. Pulmonary lymphangiomatosis. Lymphatic research and biology. 2011;9(4):191-3.
42. Ozeki M, et al. Clinical Features and Prognosis of Generalized Lymphatic Anomaly, Kaposiform Lymphangiomatosis, and Gorham-Stout Disease. Pediatric blood & cancer. 2016;63(5):832-8.
43. Lala S, et al. Gorham-Stout disease and generalized lymphatic anomaly-clinical, radiologic, and histologic differentiation. Skeletal radiology. 2013;42:917-24.
44. Du MH, et al. Diffuse pulmonary lymphangiomatosis: a case report with literature review. Chin Med J (Engl). 2011;124(5):797-800.
45. Reinglas J, et al. The successful management of diffuse lymphangiomatosis using sirolimus: a case report. Laryngoscope. 2011;121(9):1851-4.
46. Ricci KW, et al. Efficacy of systemic sirolimus in the treatment of generalized lymphatic anomaly and Gorham-Stout disease. Pediatric blood & cancer. 2019;66(5):e27614.
47. Rodriguez-Laguna L, et al. Somatic activating mutations in PIK3CA cause generalized lymphatic anomaly. The Journal of experimental medicine. 2019;216(2):407-18.
48. Li D, et al. Genomic profiling informs diagnoses and treatment in vascular anomalies. Nature medicine. 2023;29(6):1530-9.
49. Apsel Winger B, et al. EML4::ALK fusions in complex lymphatic malformations. Pediatric blood & cancer. 2023:e30516.
50. Yao LC, et al. Pulmonary lymphangiectasia resulting from vascular endothelial growth factor-C overexpression during a critical period. Circulation research. 2014;114(5):806-22.
51. Baluk P, et al. Rapamycin reversal of VEGF-C-driven lymphatic anomalies in the respiratory tract. JCI Insight. 2017;2(16).
52. Croteau SE, et al. Kaposiform lymphangiomatosis: a distinct aggressive lymphatic anomaly. The Journal of pediatrics. 2014;164(2):383-8.
53. Le Cras TD, et al. Angiopoietins as serum biomarkers for lymphatic anomalies. Angiogenesis. 2017;20(1):163-73.
54. Ozeki M, et al. Potential biomarkers of kaposiform lymphangiomatosis. Pediatric blood & cancer. 2019;66(9):e27878.
55. Wang Z, et al. Successful treatment of kaposiform lymphangiomatosis with sirolimus. Pediatric blood & cancer. 2015;62(7):1291-3.
56. Chowers G, et al. Treatment of severe Kaposiform lymphangiomatosis positive for NRAS mutation by MEK inhibition. Pediatr Res. 2023;94(6):1911-5.
57. Manevitz-Mendelson E, et al. Somatic NRAS mutation in patient with generalized lymphatic anomaly. Angiogenesis. 2018;21(2):287-98.
58. Barclay SF, et al. A somatic activating NRAS variant associated with kaposiform lymphangiomatosis. Genet Med. 2019;21(7):1517-24.
59. Nozawa A, et al. Lymphatic endothelial cell-specific NRAS p.Q61R mutant embryos show abnormal lymphatic vessel morphogenesis. Human molecular genetics. 2024.
60. Pastura P, et al. NRAS(Q61R) mutation drives elevated angiopoietin-2 expression in human endothelial cells and a genetic mouse model. Pediatric blood & cancer. 2024;71(7):e31032.
61. Grenier JM, et al. Pathogenic variants in PIK3CA are associated with clinical phenotypes of kaposiform lymphangiomatosis, generalized lymphatic anomaly, and central conducting lymphatic anomaly. Pediatric blood & cancer. 2023:e30419.
62. Li D, et al. ARAF recurrent mutation causes central conducting lymphatic anomaly treatable with a MEK inhibitor. Nature medicine. 2019;25(7):1116-22.