Gorham-Stout syndrome in mainland China: a case series of 67 patients and review of the literature#

Gorham-Stout syndrome in mainland China: a case series of 67 patients and review of the literature # # 1 2 first-author †E-mail:hu999po@126.comwang_jian_an@tom.com †E-mail:hu999po@126.comwang_jian_an@tom.com hu999po@126.com 3 1 2 1 corresp ‡Corresponding Author ‡Corresponding Author †E-mail:hu999po@126.comwang_jian_an@tom.com †E-mail:hu999po@126.comwang_jian_an@tom.com hu999po@126.com Cardiovascular Key Lab of Zhejiang Province, Department of Cardiology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China Cardiovascular Key Lab of Zhejiang Province, Department of Cardiology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China Department of Cardiology, Zhejiang Hospital, Hangzhou 310013, China Department of Cardiology, Zhejiang Hospital, Hangzhou 310013, China Department of Internal Medicine, Hangzhou Binjiang Hospital/the Second Affiliated Hospital (Binjiang Branch), School of Medicine, Zhejiang University, Hangzhou 310009, China Department of Internal Medicine, Hangzhou Binjiang Hospital/the Second Affiliated Hospital (Binjiang Branch), School of Medicine, Zhejiang University, Hangzhou 310009, China Objective: 2 Gorham-Stout syndrome (GSS) is a rare disorder of uncertain etiology and unpredictable prognosis. This study aims to present a comprehensive understanding of this rare entity. Methods: 2 A literature search in PubMed and three Chinese databases was performed to screen histologically proven GSS cases among Chinese residents in the mainland. We analyzed the patients’ clinical characteristics, the value of different treatment modalities and their influence on the clinical outcome. Results: 2 Sixty-seven cases were finally enrolled. There were 43 men (64.2%) and 24 women (35.8%). The mean age at diagnosis was 28 years (1.5–71 years). The most common clinical symptoms included pain ( n =40, 59.7%), functional impairment ( n =13, 19.4%), and swelling ( n =12, 17.9%). The radiographic presentation of 37 cases (55.2%) was disappearance of a portion of the bone. The others presented as radiolucent foci in the intramedullary or subcortical regions. A total of 42 cases provided data on therapy, these included surgery ( n =27, 40.3%), radiation therapy ( n =6, 9.0%), surgery combined with radiation therapy ( n =2, 3.0%), and medicine therapy ( n =7, 10.4%). For 30 of these 42 cases, follow-up data were available: 21 cases had the disorder locally controlled and 9 had a symptom progression. Fortunately, the disease is not fatal in the majority of cases. Conclusions: 2 GSS has no specific symptoms and it should be taken into consideration when an unclear massive osteolysis occurs. The efficacies of different treatment modalities are still unpredictable and further research is required to assess the values of different treatments. Gorham-Stout syndrome (GSS) Massive osteolysis Chinese Introduction 1 Gorham-Stout syndrome (GSS) is a very rare disorder characterized by recurrent spontaneous resorption of bones in different regions. This rare entity was initially reported by Jackson ( 1838 1838 ) in a 12-year-old boy. Gorham and Stout ( 1955 1955 ) originally described the disease as a distinct entity. It may affect any part of the skeleton. Involvement of the scapula, ribs, or thoracic vertebra can result in pleural effusions or chylothorax (Tie et al., 1994 1994 ). The diagnosis is established via the combination of clinical, radiologic, and histologic features after excluding neoplastic, endocrinologic, infectious, and inflammatory diseases. The treatment of GSS includes surgery, radiation therapy, and medicine therapy. Generally, the prognosis is considered to be good when only the limbs or the pelvic bones are involved (Kulenkampff et al., 1990 1990 ; Stove and Reichelt, 1995 1995 ; Rauh and Gross, 1997 1997 ; Boyer et al., 2005 2005 ). However, involvement of vital structures may be fatal (Hagberg et al., 1997 1997 ; Ng and Sell, 2003 2003 ; Patel, 2005 2005 ). Since this disease has been first described in Jackson ( 1838 1838 ), so far, no more than 200 cases have been documented in the English literature, and current knowledge of GSS is largely based on sporadic case reports. Herein, to present a comprehensive understanding of this entity, we screened and analyzed all the cases of histologically proven GSS among Chinese residents in the mainland. Materials and methods 1 All cases of GSS were screened from a literature search in PubMed and three Chinese databases (Chinese Biomedicine Literature Database (CBM), VIP Database for Chinese Technical Periodicals, and Wanfang Database). Combinations of the keywords “China” and MeSH (Medical Subject Headings) words “Osteolysis, Essential” or text words like Gorham-Stout syndrome, Gorham syndrome, Gorham disease, Gorham’s massive osteolysis, Morbus Gorham Stout disease, massive osteolysis, vanishing bone disease, disappearing bone disease, disappearing bone, or disappearing bone disease were used for the search. We manually examined references in selected articles and studies. We analyzed the patients’ clinical characteristics, values of different treatment modalities and their influences on the clinical outcome. Inclusion criteria were as follows (Heffez et al., 1983 1983 ): (1) a positive biopsy; (2) the absence of cellular atypia; (3) minimal or no osteoblastic response and absence of dystrophic calcification; (4) evidence of local, progressive osseous resorption; (5) nonexpansile, nonulcerative lesion; (6) absence of visceral involvement; (7) osteolytic radiographic pattern; (8) no known hereditary, metabolic, immunological, or infectious cause; (9) Chinese residents in the mainland. Therapy response was defined as “Controlled” (the radiographic presentation of the affected bone had not changed, and no newly emerging bone destruction) or “Progression” (the progressive resorption of the affected bone and/or newly emerging bone destruction). Results 1 A total of 67 cases (64 in Chinese and 3 in English) of GSS in 54 papers were enrolled for analysis (Table S1 S1 ), of whom 43 patients were male (64.2%), and 24 cases were female (35.8%). The mean age at diagnosis was 28 years (1.5–71 years). No family history of GSS was found in any of the patients. A history of preceding trauma was present in 4 cases (6.0%). Of the 67 cases, the femur ( n =18, 26.9%) was the most common site of involvement. Involvement of more than three sites in the skeletal system occurred in 17 patients (25.4%). Pleural effusion was found in 10 cases, of which 8 had an accompanying chylothorax (11.9%). Only 5 patients had involvement of the bony structures of joints (7.5%). The most common manifestations included pain ( n =40, 59.7%), functional impairment ( n =13, 19.4%), and swelling ( n =12, 17.9%). Eighteen patients (26.9%) were diagnosed after a pathological fracture. Three patients (4.5%) were found with massive osteolysis by coincidence, and 4 patients (6.0%) presented with tooth loss. One case was reported where both the affected bone and the adjacent soft tissue were involved with dilated lymphatic channels. On radiographic evaluations, the disappearance of a portion of the bone was described in 37 cases (55.2%), and the others presented as radiolucent foci in the intramedullary or subcortical regions. In the long bones, the tapering of the residual bone may show “licked candy stick” deformity ( n =14, 20.9%). The most common pathological findings were the presence of numerous thin-walled blood vessels, lymphatic vessels, or fibrous tissue ( n =67, 100%). The osteoclast in areas of bone resorption was found in 5 cases (7.5%), and chronic inflammatory cells in the affected areas were found in 12 cases (17.9%). Results of laboratory analysis were normal, except an elevated erythrocyte sedimentation rate in 2 cases (3.0%) and an increased alkaline phosphatase in 1 case (1.5%). A total of 42 cases had complete data for therapy protocol (Table 1 1 ). For 30 of these 42 cases, follow-up data were available. The mean follow-up time was 20.7 months (2–72 months). Twenty-seven cases underwent surgery (Table 2 2 ), of which 11 cases had the diseases locally controlled (the mean follow-up time was 16.4 months), 5 had a symptom progression (the mean follow-up time was 12.0 months), 1 patient died (the follow-up time was 18.0 months), and the remaining 10 cases were lost to follow up. Six cases underwent radiation therapy, of which 4 cases had the diseases locally controlled (the mean follow-up time was 14.0 months, 1 case at a total dose 50 Gy, and 3 cases lack of details on radiotherapy), and 2 cases had a symptom progression (the mean follow-up time was 66.0 months, 1 case at a total dose 57 Gy, and 1 case lack of details on radiotherapy). Two patients who underwent a combination of surgery and radiation therapy had the disorder locally controlled (the mean follow-up time was 14.0 months, one case at a total dose 30.6 Gy, one case lack of details on radiotherapy). Seven patients only underwent medicine therapies (Table 3 3 ), of which 4 cases had the diseases locally controlled (the mean follow-up time was 22.5 months), 1 had a symptom progression (the follow-up time was 22.0 months), and the remaining 2 cases were lost to follow up. Among the 27 cases who underwent surgery, 13 cases underwent resection of the lesion (3 cases had the diseases locally controlled, 2 had a symptom progression and the remaining 8 cases were lost to follow up), 8 cases underwent reconstruction using prostheses (6 cases had the diseases locally controlled and 2 cases were lost to follow up), 3 cases underwent reconstruction using bone grafts (2 cases had a symptom progression, 1 case died), 1 case underwent thoracic duct ligation combined with chest drainage (the disease was locally controlled), 1 case underwent thoracic duct ligation combined with pleurodesis (the disease was locally controlled), and 1 case underwent pleurodesis combined with chest drainage (had a symptom progression). Controlled: the radiographic presentation of the affected bone had not changed, and no newly emerging bone destruction; Progression: progressive resorption of the affected bone and/or newly emerging bone destruction Treatment modality n Controlled Progression Died Lost to follow up  Surgery 27 11 5 1 10  Radiation 6 4 2 0 0  Medicine therapy 7 4 1 0 2  Surgery+radiation 2 2 0 0 0 In patients with chylothorax Controlled: the radiographic presentation of the affected bone had not changed, and no newly emerging bone destruction; Progression: progressive resorption of the affected bone and/or newly emerging bone destruction Surgery n Controlled Progression Died Lost to follow up  Resection of the lesion 13 3 2 0 8  Reconstruction using prostheses 8 6 0 0 2  Reconstruction using bone grafts 3 0 2 1 0  Thoracic duct ligation+chest drainage * * 1 1 0 0 0  Thoracic duct ligation+pleurodesis * * 1 1 0 0 0  Pleurodesis+chest drainage * * 1 0 1 0 0 Controlled: the radiographic presentation of the affected bone had not changed, and no newly emerging bone destruction; Progression: progressive resorption of the affected bone and/or newly emerging bone destruction Therapy n Controlled Progression Lost to follow up  Interferon 2 1 0 1  Diphosphonate 1 1 0 0  Calcium salts+vitamin D 1 1 0 0  Cyclophosphamide+fluorouracil 2 0 1 1  Calcitonin salmon+alendronate sodium 1 1 0 0 Discussion 1 GSS is a very rare disorder characterized by spontaneous resorption of bones with mono-or poly-ostotic lesions. In most cases, the disease occurs in children or young adults with no clear genetic cause. In the 67 cases, the mean age at diagnosis was 28 years and only 13 patients (19.4%) were older than 40 years. We found that there was a male preference (43 males vs. 24 females, the gender ratio was about 1.8). However, some authors believe that there is no gender preference (Patel, 2005 2005 ; Collins, 2006 2006 ; Tong et al., 2010 2010 ). The clinical complaint of GSS varies depending on the affected site, making the diagnosis of this uncommon entity difficult. The most common clinical symptoms of the 67 cases included pain ( n =40, 59.7%), functional impairment ( n =13, 19.4%), and swelling ( n =12, 17.9%). The pathogenesis of the disorder is poorly understood, and a large variety of possible causes have been reported in the literature. The osteoclast is the only cell capable of bone destruction. However, the role of the osteoclast in this disorder is in dispute. Gorham and Stout ( 1955 1955 ) suggested that “osteoclastosis” was not necessary and Foult et al. ( 1995 1995 ) found that osteolysis was secondary to angiomatosis. In contrast, Spieth et al. ( 1997 1997 ) reported that there was a clear relationship between osteoclasts and this rare syndrome, and Möller et al. ( 1999 1999 ) found a large number of multi-nucleated osteoclasts with hyperactive resorptive function in their patients. In our case series, the osteoclast in areas of bone resorption was found in only five cases (7.5%), which suggested “osteoclastosis” may be not necessary in this entity. Some authors described that interleukin-6 (IL-6) may cause bone resorption because it can stimulate osteoclast activity and increase sensitivity of osteoclast precursors to humoral factors (Möller et al., 1999 1999 ; Hirayama et al., 2001 2001 ; Hammer et al., 2005 2005 ). Devlin et al. ( 1996 1996 ) demonstrated that the blood level of IL-6 was seven times the upper limit of the normal range, and fell to one quarter the pretreatment value after further treatment. In our case series, chronic inflammatory cells in the affected areas were found in 12 cases [IL-6/vascular endothelial growth factor (VEGF) levels are not known for the patients in our case series]. As we know, IL-6 level is closely related to chronic inflammatory cells, so we suggest that IL-6 may play an important role in this entity. Aviv et al. ( 2001 2001 ) suggested that disseminated lymphangiomatosis and GSS might represent two varieties of a single rare disease. Radhakrishnan and Rockson ( 2008 2008 ) suggested that GSS was a disease of disordered lymphangiogenesis. Dupond et al. ( 2010 2010 ) reported that serum VEGF showed a marked elevation at diagnosis, which was normalized after 18 months of interferon treatment. VEGF recruits monocytes/macrophages (Barleon et al., 1996 1996 ) which are reported to secrete the lymphangiogenic growth factors VEGF-C (von Marschall et al., 2003 2003 ). The VEGF-C/VEGF receptor-3 signaling system is the most efficient pathway in regulating lymphangiogenesis (Li et al., 2011 2011 ). In the 67 cases, numerous thin-walled blood vessels, lymphatic vessels, or fibrous tissue are common pathologic findings, which indicated the important role of lymphangiogenesis. Obviously, further research on the relationship between lymphangiogenesis and GSS may help to understand the mechanism of this rare entity. Because of the rarity of the disease, a standardized treatment strategy is not available. The treatment modalities include medicine therapy, radiation therapy, and surgery. Medicine treatments include calcium salts, vitamin D supplements, hormone (calcitonin), interferon, bisphosphonate. One patient in our case series who just underwent calcium salts and vitamin D supplements achieved partial recovery after a follow-up of 5.5 years. However, Vinée et al. ( 1994 1994 ) reported that treatment with hormone combined with calcium salts and vitamins showed no efficacy. Interferon may be useful in disorders with vessel proliferation because of its antiangiogenic properties (Takahashi et al., 2005 2005 ). Interferon α-2b was successfully used to treat one patient at a dosage of (7.5–15) million IU three times a week for five years (Dupond et al., 2010 2010 ). Bisphosphonate is helpful because of its putative antiosteoclastic and anti-angiogenic activity. Lehmann et al. ( 2009 2009 ) reported that a case of GSS was successfully treated with bisphosphonates for more than 17 years. Hammer et al. ( 2005 2005 ) reported that mono-therapy with bisphosphonates (30 mg intravenous every three months) controlled the disorder during two years of follow-up. However, one patient who was treated with interferon α-2b and bisphosphonate died four months after the diagnosis of GSS (Deveci et al., 2011 2011 ). GSS was treated effectively with radiation therapy in several reports (Bruch-Gerharz et al., 2007 2007 ; Johnstun et al., 2010 2010 ; Browne et al., 2011 2011 ; Heyd et al., 2011b 2011b ). Dunbar et al. ( 1993 1993 ) reviewed the 22 published cases of GSS treated with radiation therapy and found that definitive radiation therapy in moderate doses (40–45 Gy at 1.8–2.0 Gy per fraction) was effective. Recently, the German Cooperative Group on Radiotherapy for Benign Diseases conducted a national patterns-of-care study to evaluate the value of radiation therapy in the treatment of GSS. They concluded that radiation therapy may prevent disease progression effectively in GSS in 77% to 80% of cases at a total dose ranging from 30 to 45 Gy (Heyd et al., 2011a 2011a ). However, for young adults and particularly in children, a very critical indication for radiation therapy is required, due to the increased risk of radiotherapy-induced neoplasms and severe late toxicity (McNeil et al., 1996 1996 ; Ricalde et al., 2003 2003 ). Surgical therapy includes resection of the lesion, reconstruction using bone grafts and/or prostheses (Woodward et al., 1981 1981 ; Vinée et al., 1994 1994 ; Wang and Lin, 2004 2004 ; Escande et al., 2008 2008 ), thoracic duct ligation, pleurodesis, and chest drainage. It has been reported that progression of bone graft has led to failure of reconstruction (Woodward et al., 1981 1981 ; Kulenkampff et al., 1990 1990 ; Paley et al., 2005 2005 ); however, reconstruction using prostheses seems to be more effective. In our case series, six patients who underwent reconstruction using prostheses had the disorder controlled and three patients who underwent reconstruction using bone grafts had a symptom progression. However, further clinical studies are needed to evaluate the efficacy of different surgeries. In patients with chylothorax, thoracic duct ligation, pleurodesis, and chest drainage were used. Tie et al. ( 1994 1994 ) reviewed 146 cases of Gorham-Stout syndrome and found that 25 patients (17%) had chylothorax. They reported that some patients underwent successful thoracic duct ligation and survived. However, thoracic duct ligation does not always lead to a lasting resolution of chylothorax (Choma et al., 1987 1987 ; Fujiu et al., 2002 2002 ). In our case series, 2 of the patients who underwent thoracic duct ligation combined with chest drainage or thoracic duct ligation combined with pleurodesis had the disorder controlled, and the patient who underwent pleurodesis combined with chest drainage had a symptom progression. We advise that more research is required to further elucidate the pathogenesis of patients with chylothorax, and further studies are needed to seek effective therapies. Conclusions 1 The characteristics of GSS reported in Mainland China are similar to those reported in Western studies. GSS has no specific symptoms, and it should be taken into consideration when an unclear massive osteolysis occurs in children or adolescents. Due to the rarity of the disorder, no standardized treatment regimen is available. Bone grafts appear to be ineffective and reconstruction using prostheses may be worth considering for cases of pathological fracture and/or massive bone resorption. Assessment of the efficiency of different therapeutic regimen was not allowed because of limited cases in our study, and further clinical studies are needed. References R Aviv , K McHugh , J Hunt . Angiomatosis of bone and soft tissue: a spectrum of disease from diffuse lymphangiomatosis to vanishing bone disease in young patients . Clin Radiol , 2001 . 56 ( 3 ): 184 - 190 . 11247693 DOI: 10.1053/crad.2000.0606 http://doi.org/10.1053/crad.2000.0606 . Angiomatosis of bone and soft tissue: a spectrum of disease from diffuse lymphangiomatosis to vanishing bone disease in young patients B Barleon , S Sozzani , D Zhou , HA Weich , A Mantovani , D Marme . Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1 . Blood , 1996 . 87 ( 8 ): 3336 - 3343 . 8605350 . Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1 P Boyer , P Bourgeois , O Boyer , Y Catonné , G Saillant . Massive Gorham-Stout syndrome of the pelvis . Clin Rheumatol , 2005 . 24 ( 5 ): 551 - 555 . 15827684 DOI: 10.1007/s10067-005-1088-7 http://doi.org/10.1007/s10067-005-1088-7 . Massive Gorham-Stout syndrome of the pelvis JA Browne , TC Shives , RT Trousdale . Thirty-year follow-up of patient with Gorham disease (massive osteolysis) treated with hip arthroplasty . J Arthropl , 2011 . 26 ( 2 ): 339.e7 - 339.e10 . DOI: 10.1016/j.arth.2010.03.003 http://doi.org/10.1016/j.arth.2010.03.003 . Thirty-year follow-up of patient with Gorham disease (massive osteolysis) treated with hip arthroplasty D Bruch-Gerharz , CD Gerharz , H Stege , J Krutmann , M Pohl , R Koester , T Ruzicka . Cutaneous lymphatic malformations in disappearing bone (Gorham-Stout) disease: A novel clue to the pathogenesis of a rare syndrome . J Am Acad Dermatol , 2007 . 56 ( 2 ): S21 - S25 . 17097379 DOI: 10.1016/j.jaad.2006.01.063 http://doi.org/10.1016/j.jaad.2006.01.063 . Cutaneous lymphatic malformations in disappearing bone (Gorham-Stout) disease: A novel clue to the pathogenesis of a rare syndrome ND Choma , CV Biscotti , TW Bauer , AC Mehta , AA Licata . Benign diseases syndrome: a case report and review of the literature . Am J Med , 1987 . 83 ( 6 ): 1151 - 1156 . 3332570 . Benign diseases syndrome: a case report and review of the literature J Collins . Case 92: Gorham syndrome1 . Radiology , 2006 . 238 ( 3 ): 1066 16505400 DOI: 10.1148/radiol.2383032126 http://doi.org/10.1148/radiol.2383032126 . Case 92: Gorham syndrome1 M Deveci , N İnan , F Çorapçıoğlu , G Ekingen . Gorham-Stout syndrome with chylothorax in a six-year-old boy . Ind J Pediatr , 2011 . 78 ( 6 ): 737 - 739 . DOI: 10.1007/s12098-010-0328-2 http://doi.org/10.1007/s12098-010-0328-2 . Gorham-Stout syndrome with chylothorax in a six-year-old boy RD Devlin , 3rd HG Bone , GD Roodman . Interleukin-6: a potential mediator of the massive osteolysis in patients with Gorham-Stout disease . J Clin Endocrinol Metabol , 1996 . 81 ( 5 ): 1893 - 1897 . DOI: 10.1210/jc.81.5.1893 http://doi.org/10.1210/jc.81.5.1893 . Interleukin-6: a potential mediator of the massive osteolysis in patients with Gorham-Stout disease SF Dunbar , A Rosenberg , H Mankin , D Rosenthal , HD Suit . Gorham’s massive osteolysis: the role of radiation therapy and a review of the literature . Int J Rad Oncol Biol Phys , 1993 . 26 ( 3 ): 491 - 497 . DOI: 10.1016/0360-3016(93)90968-2 http://doi.org/10.1016/0360-3016(93)90968-2 . Gorham’s massive osteolysis: the role of radiation therapy and a review of the literature JL Dupond , L Bermont , M Runge , M de Billy . 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 - 876 . 19931435 DOI: 10.1016/j.bone.2009.11.015 http://doi.org/10.1016/j.bone.2009.11.015 . Plasma VEGF determination in disseminated lymphangiomatosis-Gorham-Stout syndrome: a marker of activity? A case report with a 5-year follow-up C Escande , T Schouman , G Fran Oise , J Haroche , P Ménard , JC Piette , JC Bertrand , B Ruhin-Poncet . Histological features and management of a mandibular Gorham disease: a case report and review of maxillofacial cases in the literature . Oral Surg Oral Med Oral Pathol Oral Radiol Endodontol , 2008 . 106 ( 3 ): e30 - e37 . DOI: 10.1016/j.tripleo.2008.02.028 http://doi.org/10.1016/j.tripleo.2008.02.028 . Histological features and management of a mandibular Gorham disease: a case report and review of maxillofacial cases in the literature H Foult , P Goupille , B Aesch , JP Valat , P Burdin , M Jan . Massive osteolysis of the cervical spine: a case report . Spine , 1995 . 20 ( 14 ): 1636 7570181 . Massive osteolysis of the cervical spine: a case report K Fujiu , R Kanno , H Suzuki , N Nakamura , M Gotoh . Chyothorax associated with massive osteolysis (Gorham’s syndrome) . Ann Thoracic Surg , 2002 . 73 ( 6 ): 1956 - 1957 . DOI: 10.1016/S0003-4975(02)03413-6 http://doi.org/10.1016/S0003-4975(02)03413-6 . Chyothorax associated with massive osteolysis (Gorham’s syndrome) LW Gorham , AP Stout . Massive osteolysis (acute spontaneous absorption of bone, phantom bone, disappearing bone). Its relation to hemangiomatosis . J Bone Joint Surg Am , 1955 . 37 ( 5 ): 985 - 1004 . 13263344 . Massive osteolysis (acute spontaneous absorption of bone, phantom bone, disappearing bone). Its relation to hemangiomatosis H Hagberg , K Lamberg , G Astrom . Alpha-2b interferon and oral clodronate for Gorham’s disease . Lancet , 1997 . 350 ( 9094 ): 1822 - 1823 . 9428260 DOI: 10.1016/S0140-6736(05)63639-2 http://doi.org/10.1016/S0140-6736(05)63639-2 . Alpha-2b interferon and oral clodronate for Gorham’s disease F Hammer , W Kenn , U Wesselmann , LC Hofbauer , G Delling , B Allolio , W Arlt . Gorham-Stout disease stabilization during bisphosphonate treatment . J Bone Mineral Res , 2005 . 20 ( 2 ): 350 - 353 . DOI: 10.1359/JBMR.041113 http://doi.org/10.1359/JBMR.041113 . Gorham-Stout disease stabilization during bisphosphonate treatment L Heffez , HC Doku , BL Carter , JE Feeney . Perspectives on massive osteolysis: report of a case and review of the literature . Oral Surg Oral Med Oral Pathol , 1983 . 55 ( 4 ): 331 - 343 . 6574409 . Perspectives on massive osteolysis: report of a case and review of the literature R Heyd , O Micke , C Surholt , B Berger , C Martini , J Füller , T Schimpke , MH Seegenschmiedt . Radiation therapy for Gorham-Stout syndrome: results of a national patterns-of-care study and literature review . Int J Rad Oncol Biol Phys , 2011 . 81 ( 3 ): e179 - e185 . DOI: 10.1016/j.ijrobp.2011.01.006 http://doi.org/10.1016/j.ijrobp.2011.01.006 . Radiation therapy for Gorham-Stout syndrome: results of a national patterns-of-care study and literature review R Heyd , D Rabeneck , O Rnenburg , N Tselis , N Zamboglou . Gorham-Stout syndrome of the pelvic girdle treated by radiation therapy . Strahlenther Onkol , 2011 . 187 ( 2 ): 140 - 143 . 21336714 DOI: 10.1007/s00066-010-2174-6 http://doi.org/10.1007/s00066-010-2174-6 . Gorham-Stout syndrome of the pelvic girdle treated by radiation therapy T Hirayama , A Sabokbar , I Itonaga , S Watt-Smith , NA Athanasou . Cellular and humoral mechanisms of osteoclast formation and bone resorption in Gorham-Stout disease . J Pathol , 2001 . 195 ( 5 ): 624 - 630 . 11745700 DOI: 10.1002/path.989 http://doi.org/10.1002/path.989 . Cellular and humoral mechanisms of osteoclast formation and bone resorption in Gorham-Stout disease J Jackson . A boneless arm . Boston Med Surg J , 1838 . 18 368 - 369 . . A boneless arm J Johnstun , L Brady , R Simstein , N Duker . Chronic recurrent Gorham-Stout syndrome with cutaneous involvement . Rare Tumors , 2010 . 2 ( 3 ): e40 21139956 DOI: 10.4081/rt.2010.e40 http://doi.org/10.4081/rt.2010.e40 . Chronic recurrent Gorham-Stout syndrome with cutaneous involvement HA Kulenkampff , GM Richter , WE Hasse , CP Adler . Massive pelvic osteolysis in the Gorham-Stout syndrome . Int Orthop , 1990 . 14 ( 4 ): 361 - 366 . 2076919 . Massive pelvic osteolysis in the Gorham-Stout syndrome G Lehmann , A Pfeil , J Böttcher , WA Kaiser , J Füller , G Hein , G Wolf . Benefit of a 17-year long-term bisphosphonate therapy in a patient with Gorham-Stout syndrome . Arch Orthop Trauma Surg , 2009 . 129 ( 7 ): 967 - 972 . 18807053 DOI: 10.1007/s00402-008-0742-3 http://doi.org/10.1007/s00402-008-0742-3 . Benefit of a 17-year long-term bisphosphonate therapy in a patient with Gorham-Stout syndrome X Li , B Liu , J Xiao , Y Yuan , J Ma , Y Zhang . Roles of VEGF-C and Smad4 in the lymphangiogenesis, lymphatic metastasis, and prognosis in colon cancer . J Gastrointest Surg , 2011 . 15 ( 11 ): 1 - 10 . 21061184 DOI: 10.1007/s11605-011-1627-2 http://doi.org/10.1007/s11605-011-1627-2 . Roles of VEGF-C and Smad4 in the lymphangiogenesis, lymphatic metastasis, and prognosis in colon cancer KD McNeil , K Fong , Q Walker , P Jessup , P Zimmerman . Gorham’s syndrome: a usually fatal cause of pleural effusion treated successfully with radiotherapy . Thorax , 1996 . 51 ( 12 ): 1275 - 1276 . 8994530 . Gorham’s syndrome: a usually fatal cause of pleural effusion treated successfully with radiotherapy G Möller , M Priemel , M Amling , M Werner , A Kuhlmey , G Delling . The Gorham-Stout syndrome (Gorham’s massive osteolysis). A report of six cases with histopathological findings . J Bone Joint Surg , 1999 . 81 ( 3 ): 501 - 506 . . The Gorham-Stout syndrome (Gorham’s massive osteolysis). A report of six cases with histopathological findings CL Ng , P Sell . Gorham disease of the cervical spine—a case report and review of the literature . Spine , 2003 . 28 ( 18 ): E355 - E358 . 14501935 DOI: 10.1097/01.BRS.0000084557.38858.85 http://doi.org/10.1097/01.BRS.0000084557.38858.85 . Gorham disease of the cervical spine—a case report and review of the literature M Paley , C Lloyd , C Penfold . Total mandibular reconstruction for massive osteolysis of the mandible (Gorham-Stout syndrome) . Br J Oral Maxillofac Surg , 2005 . 43 ( 2 ): 166 - 168 . 15749219 DOI: 10.1016/j.bjoms.2004.09.008 http://doi.org/10.1016/j.bjoms.2004.09.008 . Total mandibular reconstruction for massive osteolysis of the mandible (Gorham-Stout syndrome) DV Patel . Gorham’s disease or massive osteolysis . Clin Med Res , 2005 . 3 ( 2 ): 65 - 74 . 16012123 . Gorham’s disease or massive osteolysis K Radhakrishnan , SG Rockson . Gorham’s disease: An osseous disease of lymphangiogenesis? . Ann N Y Acad Sci , 2008 . 1131 203 - 205 . 18519972 DOI: 10.1196/annals.1413.022 http://doi.org/10.1196/annals.1413.022 . Gorham’s disease: An osseous disease of lymphangiogenesis? G Rauh , M Gross . Disappearing bone disease (Gorham-Stout disease): report of a case with a follow-up of 48 years . Eur J Med Res , 1997 . 2 ( 10 ): 425 - 427 . 9348269 . Disappearing bone disease (Gorham-Stout disease): report of a case with a follow-up of 48 years P Ricalde , R Ord , CCJ Sun . Vanishing bone disease in a five year old: report of a case and review of the literature . Int J Oral Maxillofac Surg , 2003 . 32 ( 2 ): 222 - 226 . 12729788 DOI: 10.1054/ijom.2002.0306 http://doi.org/10.1054/ijom.2002.0306 . Vanishing bone disease in a five year old: report of a case and review of the literature M Spieth , A Greenspan , DM Forrester , AN Ansari , RL Kimura , I Gleason-Jordan . Gorham’s disease of the radius: radiographic, scintigraphic, and MRI findings with pathologic correlation . Skel Radiol , 1997 . 26 ( 11 ): 659 - 663 . . Gorham’s disease of the radius: radiographic, scintigraphic, and MRI findings with pathologic correlation J Stove , A Reichelt . Massive osteolysis of the pelvis, femur and sacral bone with a Gorham-Stout syndrome . Arch Orthop Trauma Surg , 1995 . 114 ( 4 ): 207 - 210 . 7662475 . Massive osteolysis of the pelvis, femur and sacral bone with a Gorham-Stout syndrome A Takahashi , C Ogawa , T Kanazawa , H Watanabe , M Suzuki , N Suzuki , Y Tsuchida , A Morikawa , H Kuwano . Remission induced by interferon α in a patient with massive osteolysis and extension of lymph-hemangiomatosis: a severe case of Gorham-Stout syndrome . J Pediatr Surg , 2005 . 40 ( 3 ): E47 - E50 . 15793714 DOI: 10.1016/j.jpedsurg.2004.11.015 http://doi.org/10.1016/j.jpedsurg.2004.11.015 . Remission induced by interferon α in a patient with massive osteolysis and extension of lymph-hemangiomatosis: a severe case of Gorham-Stout syndrome ML Tie , GA Poland , 3rd EC Rosenow . Chylothorax in Gorham’s syndrome. A common complication of a rare disease . Chest , 1994 . 105 ( 1 ): 208 - 213 . 8275732 . Chylothorax in Gorham’s syndrome. A common complication of a rare disease ACK Tong , TM Leung , PT Cheung . Management of massive osteolysis of the mandible: a case report . Oral Surg Oral Med Oral Pathol Oral Radiol Endodontol , 2010 . 109 ( 2 ): 238 - 241 . DOI: 10.1016/j.tripleo.2009.08.044 http://doi.org/10.1016/j.tripleo.2009.08.044 . Management of massive osteolysis of the mandible: a case report P Vinée , M Tanyü , K Hauenstein , G Sigmund , B St Ver , C Adler . CT and MRI of Gorham syndrome . J Comput Assist Tomogr , 1994 . 18 ( 3 ): 985 - 989 . 7962815 . CT and MRI of Gorham syndrome Z von Marschall , A Scholz , T Cramer , G Schäfer , M Schirner , K Öberg , B Wiedenmann , M Höcker , S Rosewicz . Effects of interferon α on vascular endothelial growth factor gene transcription and tumor angiogenesis . J Nat Cancer Inst , 2003 . 95 ( 6 ): 437 - 438 . 12644537 . Effects of interferon α on vascular endothelial growth factor gene transcription and tumor angiogenesis HC Wang , GT Lin . Close-wedge osteotomy for bony locking stiffness of the elbow in Gorham disease patients: a case report . Kaohsiung J Med Sci , 2004 . 20 ( 5 ): 250 - 255 . 15233238 DOI: 10.1016/S1607-551X(09)70115-9 http://doi.org/10.1016/S1607-551X(09)70115-9 . Close-wedge osteotomy for bony locking stiffness of the elbow in Gorham disease patients: a case report HR Woodward , DPK Chan , J Lee . Massive osteolysis of the cervical spine a case report of bone graft failure . Spine , 1981 . 6 ( 6 ): 545 - 549 . 7038906 . Massive osteolysis of the cervical spine a case report of bone graft failure Compliance with ethics guidelines Po HU, Xiang-gui YUAN, Xin-yang HU, Fa-rong SHEN, and Jian-an WANG declare that they have no conflict of interest. This article does not contain any studies with human or animal subjects performed by any of the authors. 10.1631/jzus.B1200308 , 2012-11-09 2013-07-19 2013-03-05 2022-01-05 Copyright © Zhejiang University and Springer-Verlag Berlin Heidelberg 2013 2013 Journal of Zhejiang University-SCIENCE B (Biomedicine and Biotechnology) 08 14