Successful Management of Gorham–Stout Disease in Scapula and Ribs: A Case Report and Literature Review

Abstract

Gorham–Stout disease (GSD) is an extremely rare bone condition of unknown etiology characterized by spontaneous and progressive resorption of bones. GSD can occur at any age and is not related to gender, genetic inheritance, or race. Any part of the skeleton can be affected and the symptoms correlate with the sites involved. The diagnosis of GSD is established based on the combination of clinical, radiologic, and histologic features after excluding other diseases. Because of its rarity, current knowledge is limited to case reports and there is no agreement on the best strategy for treatment. The following case report describes a successfully treated case of GSD in a 26‐year‐old male patient with the left scapula and the 7th–9th left ribs involved. The patient was diagnosed with osteoporosis‐related pleural effusion at a local hospital. In our institution, the patient was diagnosed with GSD and treated with radiotherapy and bisphosphonate. The disease was controlled and there was no evidence of disease progression during follow‐up. Genetic sequencing was performed to investigate the etiology of GSD. In addition, the present study reviews the theories regarding the etiology, the clinical manifestations, the diagnostic approaches, and treatment options for this rare disease.

Introduction

Gorham–Stout disease (GSD), also known as vanishing bone disease, massive osteolysis, and phantom bone disease, is an extremely rare disease characterized by spontaneous, non‐malignant, and progressive resorption of bones1. GSD can affect any part of the skeleton, with shoulders and the pelvis being the most commonly affected regions. It has not been associated with gender, pattern of inheritance, or race2. The clinical manifestations of GSD are variable. Some patients rapidly develop pain, while in other cases, patients experience dull pain and limitation of motion that increases over time, as was the situation for the case reported here. The variation of symptoms mostly depends on the affected sites. If the ribs, the sternum, or the thoracic spine are affected, chylothorax may appear, with consequent respiratory failure, which can have a fatal outcome. When it comes to scapula, humerus, or femur, patients present pain with limitation of movement and progressive loss of muscle strength. Paraplegia may occur when vertebrae are affected. Radiological examinations, such as X‐rays, CT, and MRI, are essential for making the diagnosis. The diagnosis of GSD is essentially one of exclusions and it can be made only after a thorough biochemical screening and exclusion of infective, neoplastic, and traumatic disorders. Heffez et al. suggest the following diagnostic criteria: (i) positive biopsy for angiomatous tissue; (ii) absence of cellular atypia; (iii) minimal or no osteoblastic response and absence of dystrophic calcification; (iv) evidence of local and progressive osseous resorption; (v) nonexpansile, nonulcerative lesion; (vi) absence of visceral involvement; (vii) osteolytic radiographic pattern; and (viii) negative hereditary, metabolic, neoplastic, immunologic, or infectious etiology3. In addition to the exclusion criteria above, other types of idiopathic osteolysis should also be excluded; namely: (i) hereditary multicentric osteolysis with dominant transmission (Type I); (ii) hereditary multicentric osteolysis with recessive transmission (Type II); (iii) nonhereditary multicentric osteolysis with nephropathy (Type III); and (iv) Winchester syndrome (Type IV). Under histological examination it is possible to observe proliferation of the small thin walls of vascular or lymphatic vessels4. The prognosis of GSD depends on the structures involved, and ranges from minimal disability to death. The etiology and molecular mechanism are still unknown and current knowledge of GSD is mostly based on case reports and case series5.

The aim of this article is to explain how the patient was successfully treated with a combination of radiotherapy and bisphosphonate and to review the theories regarding the etiology, the clinical manifestations, the diagnostic approaches, and the treatment options for this rare disease.

Case Presentation

A previously healthy 26‐year‐old man experienced pain in his left shoulder after colliding with others while playing basketball. After 6 months, he presented to a local hospital for treatment because the pain had gradually increased, and he had progressive loss in range of motion. Radiographs revealed osteolysis of the left scapula and the 7th–9th left ribs and pleural effusion on the left side of the chest (Fig. 1). He was diagnosed with osteoporosis‐related pleural effusion and treated with pamidronate and thoracic closed drainage. Aspiration biopsy results revealed no malignant cells in the pleural effusion. After the treatment, the pleural effusion disappeared but the pain in his shoulder persisted, with progressive stiffness and loss of motion. The patient presented to Xijing Hospital for further treatment. Radiographs revealed osteolysis of the left scapula and the 7th–9th left ribs. The bone scan showed deficiency of radioactive tracer in the scapula and ribs (Fig. 2). Biochemical and hematological laboratory test results were normal. In addition, there was no evidence of any pre‐existing bone or systemic disease predisposing the patient to osteolysis. Aspiration biopsy and histopathological examination of the lesion in the left scapula revealed abundant vascularized fibrous tissue with capillary proliferation and bony trabeculae (Fig. 3). We performed exome sequencing of DNA from the lesion (left scapula) and healthy tissue (left ilium) obtained from aspiration biopsy to examine genetic characteristics. Differential diagnosis included giant cell tumor, bone cyst, metastatic tumor of bone, and idiopathic osteolysis. Finally, based on pathological examination, radiographs, and family history, the diagnosis of Gorham–Stout disease was established. In contrast with previous radiographs, the lesion in the ribs had subsided but there was progression in the left scapula. We decided to provide further treatment to control this progression. To preserve the function of the shoulder joint, we chose a more conservative approach instead of surgical treatment. The patient accepted and received radiotherapy on his left shoulder, with a total dose of 40 Gy in 2 Gy fractions, once a day for 20 days, with this treatment being widely described in the literature6. A single dose of intravenous bisphosphonate (zoledronic acid, 4 mg/100 mL) was given by intravenous injection once a month in combination with radiotherapy for 6 months7. The patient also received supplementation with vitamin D and calcium as a part of the treatment. The pain reduced progressively and, finally, the patient recovered.

Figure 1.

Radiographs revealed osteolysis (arrow) of the left scapula (A), the 7th–9th left ribs (B) and pleural effusion (arrow) on the left side of the chest (C).

Figure 2.

X‐ray (A) and 3‐D reconstruction of the CT‐scans (B) at the time of diagnosis revealing the bone destruction (arrows) of the left scapula and the 7th–9th left ribs. The bone scans (C) shows deficiency of radioactive tracer (arrows) in the scapula and ribs.

Figure 3.

Histopathology of the lesion showing abundant vascularized fibrous tissue with capillary proliferation and bony trabeculae.

After treatment, the patient was evaluated every 3 months during a follow‐up period of 34 months. The most recent examination showed no progression or recurrence of GSD. Fig. 4 shows that the bone absorption in the left scapula before treatment was reduced after radiotherapy and bisphosphonate treatment, and bone mineral density (BMD) was improved. This case report demonstrates that radiotherapy in combination with bisphosphonate is a valid treatment option for Gorham–Stout disease. Informed consent was obtained from the patient.

Figure 4.

Latest radiograph showed no progression or recurrence of Gorham–Stout disease (arrows).

To investigate the genomic signature of GSD, we, respectively, sequenced the whole exome of the lesions and healthy tissue after biopsy. Gene sequencing might be help us understand the genomic etiology of GSD. We detected 176 and 277 single nucleotide variants (SNV) in the lesion and healthy tissue, respectively (mutated genes are shown in Fig. 5). We analyzed the functions of the mutated genes to determine the mutations that were related to osteogenesis or osteolysis. The results showed that the mutated genes, TNFRSF11A (c.1070C > T, p. Thr357Ile) and TREM2 (c.110C > T, p.Pro37Leu), are related to osteolytic disease.

Figure 5.

Whole exome DNA sequencing from lesion and healthy tissue.

Discussion

Gorham–Stout disease was first described in 1838 by Jackson, who reported a case of a young man whose humerus disappeared completely over 11 years8. In 1955, Gorham and Stout described the clinical and pathological characteristics of the disease in a study including 24 patients. The etiology of excessive bone resorption in GSD is unclear. Gorham and Stout stated that hyperemia, local alterations of pH, and mechanical forces were responsible for osteolysis9. Similarly, Heyden et al. suggested that sluggish blood flow may lead to hypoxia and lower tissue pH, and favor the activity of acid hydrolases10. More recently, enhanced osteoclast activity has been suggested to contribute to the pathology of GSD. Hirayama et al. isolated osteoclast progenitor cells from a GSD patient and found that they were more sensitive to humoral osteoclastogenic factors RANKL and M‐CSF, which promote osteolysis11. Similarly, Hammer et al. found that interleukin‐6 was elevated in a patient with GSD and returned to a normal level following bisphosphonate treatment7. Wang et al. (2017) demonstrated that lymphatic endothelial cells (LEC) promote osteoclast formation and bone resorption by producing high levels of M‐CSF in vivo in a mouse model established by tibial injection of LEC. Blocking M‐CSF signaling might be a new therapeutic approach for treatment of patients with GSD12. These results suggest that circulating factors could affect osteoclast activity and bone resorption in GSD. Moreover, circulating factors may play an important role in reflecting the progression or remission of GSD.

Advances in DNA‐sequencing technology have facilitated genetic studies of rare diseases. Hopman et al. report a proven germline mutation in PTEN (c.517 C > T, p. Arg173Cys) in a patient with GSD13. The researchers hypothesized that the PTEN mutation was the first of two or more steps in the progression of GSD. However, when this patient was evaluated, next generation sequencing analysis techniques were not yet available. Therefore, they only investigated plausible candidate genes with known functions in vasculogenesis, angiogenesis, and lymphangiogenesis. To determine more comprehensive genetic characteristics of GSD, we sequenced the whole exome of the lesion (left scapula) and healthy tissue (left ilium). We found 176 and 277 SNV in the lesion and healthy tissue, respectively. We focused on the mutated genes that are related to osteolysis, osteogenesis, and angiogenesis (Fig. 5). In our research, we did not find the mutation in PTEN reported by Hopman et al. Instead, we found mutations in other genes, including TNFRSF11A (c.1070C > T, p. Thr357Ile) and TREM2 (c.110C > T, p.Pro37Leu). Mutation in TNFRSF11A is reported to cause familial expansile osteolysis and expansile skeletal hyperphosphatasia14. TREM2 is also a disease‐causing gene related to Nasu–Hakola disease (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy)15. The clinical manifestations and pathologic characteristics of both diseases include osteolysis. Therefore, we hypothesize that mutations in TNFRSF11A and TREM2 correlate with GSD. Unfortunately, there are results from only the 1 patient enrolled in our research. This does not allow confirmation of whether the mutated genes led to Gorham–Stout disease. However, our research could provide a reference for other researchers to replicate the finding of mutated genes from lesions in different patients with GSD. Gene sequencing may lay the foundation for further research into the etiology of the disease.

Due to the low incidence of GSD, the current literature is confined to case reports and case series. There is no standard treatment so far and the therapy depends on patients’ conditions. Therapy might include surgery, radiotherapy, and drugs, with varying degrees of success. Surgery is performed for severe cases and mainly aims to prevent or reduce the formation of fluid in the pleural cavity and to stabilize affected regions of the skeleton. Radiotherapy might stop endothelial cell proliferation and prevent progression of bone resorption1. Heyd et al. reviewed radiation therapy in 44 GSD patients and found that disease remission, arrest, and progression occurred in 27.3%, 50%, and 22.7% of the patients, respectively1. Medicines are used in combination with surgery and radiotherapy. Bisphosphonates might inhibit osteoclast activity and have been widely used to treat osteolytic diseases16. Thalidomide and interferon‐α2b have immunomodulatory and antiangiogenic effects and may have clinical benefits in patients with GSD17. Therapeutic strategies have been used to target the abnormal endothelium in fibrotic tissue and bones. Propranolol, a non‐selective β‐blocker, has also been used as a treatment option for GSD18. Bevacizumab, an anti‐angiogenic drug, has been reported to decrease levels of circulating vascular endothelial growth factor and successfully treated a case of GSD19. GSD is self‐limited and demonstrates spontaneous arrest of osteolysis, but the resorbed bone cannot reform again. Early diagnosis could help prevent the progress of GSD and preserve the function of the joint. However, GSD in the early stages is difficult to diagnose and it is often misdiagnosed as a pathological fracture, osteoporosis, or a neoplasm due to its rarity and non‐typical clinical characteristics. More attention should be paid to osteolytic lesions, with regular follow‐up.

In conclusion, we reported here a successfully treated case of GSD in the left scapula and the 7th–9th left ribs. The disease process was controlled after treatment with a combination of radiotherapy and bisphosphonates. This strategy can provide good results and is suitable for treating other patients with GSD. Moreover, the results of gene sequencing presented here may provide a reference for other researchers to investigate the genetic etiology of the disease and, therefore, to improve treatment options and develop a targeted therapy.