Gorham-Stout Disease
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Disease Entity
Disease
Gorham-Stout disease (GSD) is a rare, progressive angiomatous disorder characterized by osteolysis and vascular anomalies [1]. GSD, also known as “vanishing bone disease,” frequently involves a bone of the axial skeleton [2]. The disorder is characterized by resorption, cortical loss, and progressive osteolysis of bone with an angiomatosis of blood vessels and sometimes of lymphatic vessels [2].
Epidemiology
GSD, first characterized in the 1950s, has both congenital and acquired forms [1]. Although GSD primarily affects children and young adults, there is a bimodal distribution pattern and some patients present after the age of 50 years [1][3]. GSD shows no predilection for gender or race [3].
Etiology
The etiology of GSD is unknown. Slow endothelial turnover and cutaneous lymphatic malformations have suggested a developmental, lymphatic origin [2][4] but dysfunction in endothelial cells, lymphangiogenesis, osteoclasts, and osteoblasts have also been proposed in the pathogenesis of GSD [5].
Inflammation, puberty, and trauma may induce GSD [6]. Genetic mutations, such as somatic activating mutations in AKT1 and PIK3CA, may lead to some of osteolytic bone lesions as well [5][6].
Pathophysiology
The pathophysiology of GSD is not entirely known [1]. Angiogenic and osteoclastogenic cytokine production, including vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6), are hypothesized to drive the disease processes [7][8][9]. VEGF and VEGF-C are overexpressed in GSD patients, indicating their implications in the pathologic endothelial cell proliferation [1]. Furthermore, VEGF and VEGF-C are also involved in disease activity and response to interferon-α (IFN-α) therapy in some patients [9][10]. Amounts of IL-6, VEGF-A, and tumor necrosis factor-α (TNF-α) are elevated in ex vivo cells from a patient’s soft-tissue lesion [8].
Angiomatous proliferation in GSD can invade local soft tissue and bones [1][2]. The ribs are most commonly affected, followed by the cranium, clavicle, and cervical spine [2]. Also, GSD often involves the visceral organs, especially the lungs, liver, and spleen [11]. If the lesion is in the orbit, the pathology may demonstrate an intraosseous cavernous angioma [1]. Pathologic examination of the resected bone and soft-tissue specimen can support the diagnosis of GSD by revealing an intraosseous angioma and infiltrated fat by angiomatous tissue, respectively [1].
Ocular Manifestations
Ocular manifestations of GSD are rare. When they occur, patients may present with facial pain and acute unilateral proptosis with visual field defects and superficial keratopathy [1]. If GSD involves the wall of the orbit, the side with the orbital lesion may show limited eye movements, such as impaired elevation, depression, and abduction of the affected eye [1]. However, ophthalmic and fundoscopic examinations may be unremarkable [1].
Diagnosis
Clinical findings vary as the disease manifests different clinical courses depending on the affected site and extent of involvement [1]. GSD may be a likely diagnosis if a patient presents an early asymptomatic clinical course, positive biopsy of angiomatous tissue, progressive osteolysis of a bone in the axial skeleton, and osteolytic radiographic pattern with negative hereditary, metabolic, immunologic, infectious, or neoplastic etiology [12].
Signs/Symptoms
Localized pain is the most common symptom, while other symptoms include weakness, swelling, and functional impairment of affected limbs [5]. GSD patients may be asymptomatic until they experience a minor trauma or a fracture [5]. Patients may present with respiratory or neurological complications depending on whether GSD involves the skull, temporal bone, or vertebral column [12].
Biopsy
An initial biopsy of the soft tissue may be non-diagnostic [1]. If GSD involves the orbit, multiple biopsy specimens of the orbital lesion may reveal an intraosseous cavernous angioma infiltrated by orbital fat from angiomatous tissue [1]. Bone marrow aspiration and transcutaneous biopsy can be complicated by severe bleeding [1].
Imaging
Disseminated bony involvement of the axial skeleton may suggest the diagnosis of GSD [1]. Osteolytic lesions may appear as small radiolucent foci that enlarge and coalesce over time [13]. If GSD affects the orbit, neuroimaging would demonstrate a mass involving the roof and lateral wall of the orbit [1]. Brain computed tomography (CT) can further assess intraosseous lesions and the extent of bony mass around the orbital soft tissue [1].
MRIs can be used to analyze the lesion; high T2 signal intensity and intense enhancement after administration of contrast material can further reveal soft-tissue infiltration and lymphovascular proliferation [1][2][14].
Differential diagnosis
Although other osteolytic disorders, such as multiple myeloma, osteolytic metastases, eosinophilic granuloma, and juvenile Paget disease may reveal similar imaging findings, GSD may be a potential differential if a patient presents asymptomatic clinical course, distinct vascular or lymphatic proliferation, or the transformation to fibrous tissue [12].
Also, it is important to differentiate GSD from generalized lymphatic anomaly (GLA). GLA would typically show numerous lytic lesions of the axial skeleton confined to the medullary cavity, while GSD shows a localized soft-tissue lesion with osteolysis of a bone, such as the sphenoid bone [2]. Both GSD and GLA frequently involve visceral organs, including the lungs, liver, and spleen [11]. On CTs, GSD shows progressive osteolysis with cortical loss and involvement of mirroring clinical presentations, GLA typically reveals multifocal involvement lacking clinical symptoms [2][6].
Although Kato et al suggested the lack of a large mass as a distinguishing feature of GSD from malignant tumors [6], Inna et al presented a GSD imaging that demonstrated growth over several months and rapidly progressive soft-tissue lesion [1].
Management
There is no established guideline for treatments for GSD due to the lack of sufficient cases [11]. However, there are treatment options, including medication, surgery, and radiation [15].
Medical therapy
The efficacy and success of medications differ due to various clinical courses. Treatments for GSD include interferon, bevacizumab, bisphosphonates, sirolimus, calcium, and vitamin D [1].
Bisphosphonates, with its antiosteoclastic and potentially antiangiogenic properties, has shown success in treating GSD with interferon-α (IFN-α) or radiation [16]. Bisphosphonates can prevent local osteolysis by inducing apoptosis of tumor cells and normalizing serum levels of IL-6 [17]. IFN’s mechanism is proposed to downregulate the secretion of VEGF and inhibit the proliferation of lymphatic endothelial cells [17][18]. Considering the number of published cases treated with IFN-α2b and bisphosphonates, a combination of bisphosphonates and IFN-α2b is suggested as the first-line medical therapy [11]. As IFN-α2b helps with the stabilization of disease, it has been used as adjuvant therapy after surgeries as well [11].
Sirolimus and bevacizumab have also been used as antiangiogenic agents to treat GSD by inhibiting the proliferation of vascular endothelial cells in osteolytic lesions [1][19]. Sirolimus, an inhibitor of the mTOR pathway, is shown to treat GSD by possibly downregulating the production of VEGF [18][20]. Bevacizumab has shown variable successes in patients with GSD [12][21].
Radiation Therapy
When medical therapy fails to halt the disease progression, radiation therapy could be considered [11]. Lower range of effective doses (16 - 20 Gy) can be beneficial for patients with early disease [11]. Moderate doses (40 - 45 Gy) are effective yet may have long-term complications due to significant thoracic involvement and the prohibitive normal tissue tolerances of the lung and heart [11]. Radiation therapy is recommended in localized lesions, while interferon may work effectively for extensive lesions [17].
Surgery
After surgery and re-grafting, the disease mostly remains stable with new bone formation and decreased neuropathy [17]. Resection through craniotomy with transcranial orbital exploration at the orbital roof and/or wall can be beneficial for the patient who presents with proptosis due to GSD [1]. Surgery can reduce proptosis, but visual acuity and color vision may decrease postoperatively [1]. A soft-tissue mass may fill the orbit and induce afferent pupillary defect and optic nerve compression [1].
Prognosis
The prognosis of GSD is considered good if its involvement is limited to the limbs or pelvic bones [12]. However, GSD may lead to neurological symptoms, paralysis, or even death due to its involvement of vertebrae [5]. Cortical bone loss can further lead to severe disability or deformation [22]. Visceral organ damage can present as hepatosplenomegaly, ascites, and chylothorax [21]. If these visceral involvements severely worsen, the disease can be fatal. However, the disease can spontaneously stabilize [5].
Summary
GSD is a rare disorder characterized by progressive osteolysis and angiomatosis of blood vessels and lymphatic vessels. Although ocular manifestations of GSD are rare, the ophthalmologist can play an important role in the diagnosis of GSD if a patient presents with proptosis with cortical resorption, massive osteolysis, and angiogenic malformations. Medication, surgery, and radiation are available treatment options, but appropriate management on a case-by-case basis would lead to favorable results in GSD patients.
References
- ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 1.21 1.22 1.23 1.24 Stroh IG, Ediriwickrema LS, Miller NR. Gorham-Stout disease presenting as acute unilateral proptosis. Journal of Neuro-Ophthalmol. 2018;37:70-74.
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 Lala S, Mulliken JB, Alomari AI, Fishman SJ, Kozakewich HP, Chaudry G. Gorham-Stout disease and generalized lymphatic anomaly–clinical, radiologic, and histologic differentiation. Skeletal Radiol. 2013;42:917–924.
- ↑ 3.0 3.1 Gorham LW, Wright AW, Shultz HH, Maxon FC Jr. Disappearing bones: a rare form of massive osteolysis; report of two cases, one with autopsy findings. Am J Med. 1954;17:674–682.
- ↑ Bruch-Gerharz D, Gerharz CD, Stege H, et al. 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:S21–5.
- ↑ 5.0 5.1 5.2 5.3 5.4 5.5 Dellinger MT, Garg N, Olsen BR. Viewpoints on vessels and vanishing bones in Gorham-Stout disease. Bone. 2014;63:47–52.
- ↑ 6.0 6.1 6.2 6.3 Kato H, Ozeki M, Fukao T, Matsuo M. Craniofacial CT findings of Gorham-Stout disease and generalized lymphatic anomaly. Neuroradiology. 2016;58:801–806.
- ↑ Hagendoorn J, Yock TI, Borel Rinkes IH, Padera TP, Ebb DH. Novel molecular pathways in Gorham disease: implications for treatment. Pediatr Blood Cancer. 2014;61:401–406.
- ↑ 8.0 8.1 Colucci S, Taraboletti G, Primo L, Viale A, Roca C, Valdembri D, Geuna M, Pagano M, Grano M, Pogrel AM, Harris AL, Athanasou NN, Mantovani A, Zallone A, Bussolino F. Gorham-Stout syndrome: a monocyte-mediated cytokine propelled disease. J Bone Miner Res. 2006;21:207–218.
- ↑ 9.0 9.1 Brodszki N, Lansberg JK, Dictor M, Gyllstedt E, Ewers SB, Larsson MK, Eklund EA. A novel treatment approach for paediatric Gorham-Stout syndrome with chylothorax. Acta Paediatr. 2011;100:1448–1453.
- ↑ Dupond JL, Bermont L, Runge M, de Billy M. Plasma VEGF determination in disseminated lymphangiomatosis-Gorham-Stout syndrome: a marker of activity? A case report with a 5- year follow-up. Bone. 2010;46:873–876.
- ↑ 11.0 11.1 11.2 11.3 11.4 11.5 11.6 11.7 Hagendoorn J, Yock TI, Borel Rinkes IH, Padera TP, Ebb DH. Novel molecular pathways in Gorham disease: implications for treatment. Pediatr Blood Cancer. 2014;61:401–406.
- ↑ 12.0 12.1 12.2 12.3 12.4 Ohla V, Bayoumi AB, Hefty M, Anderson M, Kasper EM. Complex single step skull reconstruction in Gorham’s disease - a technical report and review of the literature. BMC Surgery. 2015;15:24.
- ↑ Johnson PM, Mc CJ. Observations on massive osteolysis; a review of the literature and report of a case. Radiology 1958;71:28–42.
- ↑ Morimoto N, Ogiwara H, Miyazaki O, Kitamuara M, Nishina S, Nakazawa A, Maekawa T, Morota N. Gorham-Stout syndrome affecting the temporal bone with cerebrospinal fluid leakage. Int J of Ped Otorhinolaryngology. 2013;77:1596-1600.
- ↑ Nikolaou VS, Chytas D, Korres D, Efstathopoulos N. Vanishing bone disease (Gorham-Stout syndrome): a review of a rare entity. World J Orthop. 2014;5:694–698.
- ↑ Marcucci G, Masi L, Carossino AM, Franchi A, Capanna R, Sinigaglia L, Brandi ML. Cystic bone angiomatosis: a case report treated with aminobisphosphonates and review of the literature. Calcif Tissue Int. 2013;93:462–471.
- ↑ 17.0 17.1 17.2 17.3 Maillot C, Cloche T, Le Huec JC. Thoracic osteotomy for Gorham-Stout disease of the spine: a case report and literature review. Eur Spine J. 2018;27:2285-2290.
- ↑ 18.0 18.1 Raig ET, Jones NB, Varker KA, Benniger K, Go MR, Biber JL, Lesinski GB, Carson WE III. VEGF secretion is inhibited by interferon-alpha in several melanoma cell lines. J Interferon Cytokine Res. 2008;28:553–561.
- ↑ Nozawa A, Ozeki M, Kuze B, Asano T, Matsuoka K, Fukao T. Gorham-stout disease of the skull base with hearing loss: dramatic recovery and antiangiogenic therapy. Pediatr Blood Cancer. 2016;63:931–934.
- ↑ Shirazi F, Cohen C, Fried L, Arbiser JL. Mammalian target of rapamycin (mTOR) is activated in cutaneous vascular malformations in vivo. Lymphat Res Biol. 2007;5:233–236.
- ↑ 21.0 21.1 Grunewald TG, Damke L, Maschan M, Petrova U, Surianinova O, Esipenko A, Konovalov D, Behrends U, Schiessl J, Wortler K, Burdach S, von LuettichauI. First report of effective and feasible treatment of multifocal lymphangiomatosis (Gorham-Stout) with bevacizumab in a child. Ann Oncol. 2010;21:1733–1734.
- ↑ Najm A, Soltner-Neel E, Le Goff B, Guillot P, Maugars Y, Berthelot JM. Cystic angiomatosis, a heterogeneous condition: four new cases and a literature review. Medicine (Baltimore). 2016;95:e5213.
