Gorham-Stout disease

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 by Bayan Al Othman, MD on June 30, 2020.


Gorham-Stout disease


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

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