br Case report We report on
Case report We report on a 28-year-old male without any past medical history. After a minor work accident (professional mechanic) he noticed significant pain in his left knee. The pain increased over time and a radiograph was taken. It showed minor bone resorption at the neck of the left proximal fibula (Fig. 1). The patient was treated by minor pain medications. Despite 6 months of symptomatic care, pain did not resolve and limping appeared. Another X-ray was taken that showed a concentric shrinkage of almost all proximal fibula, a typical “licked candy stick” appearance. This image led to the radiological presumption of bone tumor. Bone scan showed increased Technetium uptake in the left tibial plateau extending to both the left tibial tuberosity and the left proximal fibula (Fig. 2). Computed-tomography scanner (CT-scan) showed bone resorption in those areas. Around the tibial metaphysis there was an area of massive osteolysis that looked like a pathological fracture. Magnetic resonance imaging (MRI) emphasized involvement of the left fibula and tibia by exuberant disorganized vessels also invading soft tissue of the popliteal space (Fig. 3). Biopsy was taken and histology described a diffuse lymphangioma, showing irregular vascular channels lined by a single epithelial layer, which were embedded in a fibrous stroma also containing residual bone trabeculae (Fig. 4). Endothelial cells did not display any atypia. They expressed podoplanin (D240), which confirmed their lymphatic differentiation. Radiologic imaging combined with histopathology confirmed the diagnosis of Gorham–Stout disease. The patient was first treated by radiotherapy with a total dose of 40Gy given in 2Gy fractions, once a day for 20 days. Thereafter, intravenous zoledronic SAR302503 (Zometa® – 4mg) was administered once every 2 months during 24 months. The patient also received adequate supplementation of vitamin D and calcium. No surgical treatment was considered because of the low aggressive behavior and the necessity for extensive surgery given the location. We monitored the biological responses to zoledronic acid through the measurement of bone alkaline phosphatase (BAP) and C-terminal telopeptide (CTX), a specific marker of bone resorption. Both markers rapidly decreased after initiation of bisphosphonate therapy (Fig. 5). We also closely monitored serum levels of calcium (Ca), creatinine, 25(OH)-vitamin D and parathyroid hormone (PTH). There was no side effect of zoledronic acid therapy and serum levels of creatinine, Ca and PTH remained normal throughout therapy (data not shown). At thirty months after the end of the medical treatment, the patient’s situation improved markedly. Pain disappeared and was only present after longstanding solicitation. MRI showed major reduction of the bone invading lymphangioma (Fig. 6a). On radiographs slight bone regeneration was observed and remaining bone surfaces seemed stable (Fig. 6b, c).
Discussion The invasion of the fibula and part of the tibia is a rare localization of GSD. Generally these lesions are found around the skull and maxillofacial bones, shoulder and pelvic girdle bones but quite rarely around the distal parts of the extremities . In our case report, trauma was considered by the patient as a trigger for the development of GSD, but trauma has never been described as a risk factor for its development [2,3]. Radiation therapy (RT) is suggested by many authors as the most effective treatment of GSD [1,10,25]. Its role is to stop endothelial cell proliferation and therefore avoid progression of bone resorption. Dunbar et al. reported that treatment by radiotherapy (dose ranging from 40 to 45Gy) leads to a good clinical outcome and few long-term complications. However, this study only included 4 patients . A German team reported 10 cases of massive osteolysis treated by radiotherapy. Indications of RT alone were surgically unresectable lesions . Postoperative-RT may also be given as an adjunct to surgery. Patients who were treated with doses over 36Gy had a tendency to disease stabilization and less than 5% showed slight to moderate remineralization . General outcomes were in favor of disease stabilization, allowing to conclude that radiotherapy (doses ranging from 30 to 45Gy) might prevent osteolysis progression in up to 80% of cases . In our patient, despite radiotherapy at efficient doses, bone resorption, estimated by serum CTX levels, was still elevated, arguing for persistent tumor-induced osteolysis. Additional treatment with the bisphosphonate zoledronic acid showed a rapid and persistent suppression of CTX levels and a marked decrease in BAP levels (Fig. 5). Such changes are similar to what is observed after bisphosphonate therapy in patients with metastatic bone disease [26,27]. For such patients, 4mg of zoledronic acid is administered every 4 weeks during at least 2 years . In the absence of guidelines, we chose to administer the classical dose of 4mg of zoledronic acid once every 2 months since the bone lesion was unique. This reduced dosing should also be less likely to induce side effects such as osteonecrosis of the jaw .