Gorham-Stout disease of the mandible, manubrium and cervical spine presenting as bilateral chylothorax

Abstract

Gorham-Stout disease (GSD) is an extremely rare musculoskeletal disease of unknown aetiology characterised by non-neoplastic proliferation of vascular and lymphatic channels causing massive osteolysis, typically affecting younger individuals. Chylothorax is a known complication of GSD which is postulated to occur from thoracic spine involvement leading to pleural or thoracic duct invasion. In our case, bilateral chylothorax developed in a 60-year-old woman without any thoracic spine involvement of her disease, challenging the proposed mechanism. Despite bilateral pleural drainage and escalating doses of sirolimus, she ultimately developed respiratory failure and shock and succumbed to her illness. Overall survival of GSD is unknown, but when complicated by chylothorax, prognosis is typically poor. GSD represents a diagnostic and management challenge due to the paucity of knowledge surrounding its aetiology and management. These patients require multidisciplinary coordinated care. It is also important to note its high mortality when associated with chylothorax in particular.

Background

Gorham-Stout disease (GSD) is a rare disease of unclear aetiology characterised by aggressive and progressive non-neoplastic proliferation of vascular and lymphatic channels, resulting in massive osteolysis and bone resorption.^1–3 These pathological changes remain undetected until clinical symptoms emerge such as pathologic bone fracture, subcutaneous swelling and effusions, of which chylothorax is a serious complication and often fatal.¹ Some cases stabilise spontaneously, others improve with proposed medical therapies, while others experience uncontrolled osteolysis and ultimately succumb to complications despite aggressive medical care.⁴ GSD typically involves the maxilla, skull, shoulder, pelvis and vertebrae.^{2 4} The proposed mechanism behind the development of chylothorax is the direct extension and invasion of lymphangiogenesis into the pleural cavity or thoracic duct due to involvement of adjacent thoracic spine or scapular belt.^{2 3 5} It typically affects children and young adults with the reported mean age of 18 years.³ The aim of this case report is to introduce an unusual presentation of a very rare case of GSD in an elderly patient that presented with bilateral chylothorax without thoracic spine or shoulder involvement, which argues against the theorised mechanism of chylothorax in this disease process.

Case presentation

A 60-year-old woman with a history of diabetes, hypertension and sleep apnoea presented as a transfer to our hospital with acute onset shortness of breath. Her initial presentation began 6 months prior when she developed tooth decay and underwent multiple tooth extractions by her dentist that were complicated by poor wound healing. Unusually, the dentist noted drainage from the site of extraction which was initially presumed to be pus, but when further analysed, it was found to be lymphatic drainage. Initial pathology was interpreted as fibromyxoid connective tissue with vascular and myofibroblastic proliferation and the possibility of GSD was raised. Immunohistochemical staining was positive for CD31 and CD34. Vimentin and smooth muscle actin stains were positive, with S-100 negative. Additionally, D2-40 staining was negative throughout. The diagnosis was inconclusive at that time. Due to progressive pain and inability to chew on the left side, she was referred to oral surgery at our institution. Her original pathology was sent to our pathology lab for second opinion and a diagnosis of fibromyxoid proliferation with cystic epithelium was made. GSD was raised again as a possibility, but due to the absence of prominent angiomatous proliferation, the pathologist could not confirm the diagnosis. A repeat biopsy of her mandible was performed by our oral surgeons showing fibromyxoid connective tissue with myofibroblastic and intraosseous vascular proliferative tissue staining positive for CD31 and D2-40 and massive osteolysis. She presented to her surgeon again with jaw pain, and on discovery of pathologic fracture of her left mandible causing jaw instability, mandibular resection with reconstruction was performed by oral and plastic surgery. Six weeks later, she presented with dyspnoea to her local hospital. A thoracic CT scan showed large bilateral pleural effusions (figures 1 and 2), and bilateral pigtail catheters were placed with return of chylous fluid based on chemistry and appearance. At that time, cultures and cytology from the pleural fluid were negative. She then developed an examination suggestive of unilateral cervical myelopathy. A cervical spine CT scan demonstrated extensive erosion of the clivus and C1 vertebrae causing dislocation and basilar displacement of the medulla. She was then transferred to our institution for higher level of medical and surgical care. She underwent a bone scan showing additional uptake in the manubrium and left lateral skull. There was notable absence of thoracic spine or scapular involvement. Multiple medicine and surgical subspecialties including thoracic and orthopaedic surgery, pulmonary, endocrinology, rheumatology, haematology, oncology and interventional radiology worked together to formulate a treatment plan. Once her cervical spine was emergently stabilised, she was initiated on sirolimus with an initial goal of 7–10 ng/mL which was increased to a goal of 10–15 ng/mL due to disease progression. Despite escalating doses of sirolimus, she continued to have high output from her chest tubes. She ultimately developed multiple episodes of septic and hypovolaemic shock accompanied by respiratory failure requiring intubation and repeated stays in the intensive care unit. Her clinical status continued to deteriorate despite aggressive care. The patient was eventually transitioned to hospice care and expired after 3 months of hospitalisation.

Figure 1.

Axial view of a CT thorax demonstrating large bilateral (left>right) pleural effusions causing compressive atelectasis and near-complete collapse of left lung.

Figure 2.

Coronal view of a CT thorax demonstrating large bilateral (left>right) pleural effusions causing compressive atelectasis and near-complete collapse of left lung.

Discussion

Chylothorax is a severe complication noted in 17%–42% of reported cases of GSD leading to progressive respiratory failure with a mortality rate exceeding 50%.^{2 6 7} Due to the limited amounts of cases reported in the literature, overall survival is unknown, but when complicated by chylothorax, prognosis is poor.^{2 3} Currently, there is no standardised therapy for GSD. There are several proposed medical treatments including interferon therapy, mammalian target of rapamycin (mTOR) inhibitors, bisphosphonates and radiotherapy, which are typically used in combination. There are case reports and case series reporting promising results regarding the efficacy of sirolimus due to its inhibitory effect on lymphangiogenesis; however, due to the low incidence of GSD, randomised clinical trials are lacking.1 2 8 9 In the majority of cases treated with sirolimus, remission was achieved in patients with an age range of 1–43 years.⁸ In patients who did not respond to sirolimus, two-thirds had pleural effusions.⁸ We propose that our patient’s poor outcome was not only due to advanced age at presentation but also significant involvement of the pleural space. Unfortunately, there was a delay in diagnosis of GSD due to the lack of clarity in her pathologic examination, as well as the fact that her care was undertaken at multiple institutions. Advanced cases of GSD typically respond poorly to proposed therapies, and by the time the diagnosis of GSD had been made in our patient, she had significant disease progression.¹ Bisphosphonate therapy was also considered in our patient. However, endocrinology had concerns about initiating bisphosphonate therapy in the setting of low vitamin D and calcium levels as well as her jaw involvement of GSD due to heightened risk of osteonecrosis of jaw. Due to our patient’s clinical instability, she was also unable to undergo surgery safely and thus was only managed with chest tubes, in addition to sirolimus. Our case is unusual in which she developed bilateral chylothorax despite no thoracic spine or shoulder involvement, conflicting with the proposed mechanism of extension from the thoracic spine. She was found to have involvement of the manubrium on bone scan, which, in this case, may have ultimately led to chylothorax by direct extension to the pleural cavity, given the close proximity.

GSD is an extremely uncommon musculoskeletal disease that should be considered when chylothorax presents as a first sign. Due to its rarity and provider unfamiliarity, it can often be misdiagnosed as a neoplasm, tuberculosis, haemangiomas, angiosarcomas or chronic osteomyelitis.^{5 7} GSD represents a diagnostic and management challenge due to the paucity of knowledge surrounding its aetiology and management. It is important for physicians managing these patients to understand that their care requires multidisciplinary coordination and input. It is also important to note its high mortality when associated with chylothorax particularly, as it may lead to earlier discussion of goals of care enabling the patient to avoid unnecessary and burdensome healthcare.

Learning points.

• Gorham-Stout disease (GSD) is serious and rare disease of abnormal lymphatics that is progressive and causes devastating complications and sometimes death, and often requires a multimodal approach to management.

• GSD should be considered as a rare diagnosis if a patient presents with chylothorax of unknown aetiology.

• The mortality rate is high when GSD is complicated by chylothorax.

• The mechanism of chylothorax in GSD appears to be direct pleural or thoracic duct extension of lymphatic invasion via the thoracic spine, however there may be additional mechanisms.