First report of effective and feasible treatment of multifocal lymphangiomatosis (Gorham–Stout) with bevacizumab in a child

Abstract

Vascular tumours comprise a broad spectrum of benign as well as highly malignant tumours and are occasionally enigmatic diseases. Multifocal lymphangiomatosis, also designated Gorham–Stout disease (GSD), idiopathic osteolysis or vanishing bone disease, is a rare angiomatosis of unknown aetiology mainly affecting the paediatric population. GSD predominantly originates in shoulder or pelvic regions and typically begins with progressive osteolysis followed by intraosseous and extraosseous proliferation of lymphatic vessels. Routine laboratory parameters are usually within normal range [1.Gorham L.W. Wright A.W. Shultz H.H. Maxon Jr., F.C. Disappearing bones: a rare form of massive osteolysis; report of two cases, one with autopsy findings.Am J Med. 1954; 17: 674-682Abstract Full Text PDF PubMed Scopus (183) Google Scholar, 2.Ozeki M. Funato M. Kanda K. et al.Clinical improvement of diffuse lymphangiomatosis with pegylated interferon alfa-2b therapy: case report and review of the literature.Pediatr Hematol Oncol. 2007; 24: 513-524Crossref PubMed Scopus (39) Google Scholar]. Recent evidence suggests that GSD, like Hodgkin’s disease and Kaposi’s sarcoma, might be triggered and maintained by occult neoplastic cells, which can be cultured ex vivo and which share characteristics of immature macrophages and osteoclasts. These tumour cells produce large amounts of interleukin-6 and vascular endothelial growth factor (VEGF), which in turn might boost reactive, rather than neoplastic, osteolysis and outgrowth of leaky lymphatic vessels [3.Colucci S. Taraboletti G. Primo L. et al.Gorham-Stout syndrome: a monocyte-mediated cytokine propelled disease.J Bone Miner Res. 2006; 21: 207-218Crossref PubMed Scopus (56) Google Scholar]. Consequently, GSD is often lethally complicated by pathological fractures, chyleous pleural effusions and ascites [2.Ozeki M. Funato M. Kanda K. et al.Clinical improvement of diffuse lymphangiomatosis with pegylated interferon alfa-2b therapy: case report and review of the literature.Pediatr Hematol Oncol. 2007; 24: 513-524Crossref PubMed Scopus (39) Google Scholar]. To date, there is no standardised therapy regimen. In single cases, however, stable disease and/or remission was achieved through treatment with bisphosphonates, tyrosine kinase inhibitors, Pegylated (PEG)–interferons and glucocorticoids [2.Ozeki M. Funato M. Kanda K. et al.Clinical improvement of diffuse lymphangiomatosis with pegylated interferon alfa-2b therapy: case report and review of the literature.Pediatr Hematol Oncol. 2007; 24: 513-524Crossref PubMed Scopus (39) Google Scholar]. Taking into account the high levels of circulating VEGF seen in patients with GSD [4.Dupond J.L. 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: 873-876Crossref PubMed Scopus (33) Google Scholar], antiangiogenic drugs like bevacizumab (Avastin®; Genentech/Roche, South San Francisco, CA), a humanised monoclonal anti-VEGF antibody, might represent promising novel treatment options. Here, we present, to the best of our knowledge, the first report of effective and feasible treatment of GSD with bevacizumab in a child. At the age of 2.5 years, our male patient suffered an atraumatic fracture of the left clavicle. A computed tomography scan revealed multiple osteolyses of the sternum, the left clavicle and several left-sided ribs (Figure 1A and B). An initial biopsy showed unspecific signs of inflammation. During a short treatment trial with steroids, the patient was tachydyspnoeic due to a painful chylous pleural effusion (Figure 1C), which had to be drained. On abdominal ultrasound examination, a mild hepatosplenomegaly was observed. Subsequent secondary biopsy now clearly documented the histology of cystic lymphangiomatosis (Gorham–Stout) (Figure 1D). Thus, therapy with PEG-interferon-alpha-2b, bisphosphonates and the BCR-ABL tyrosine kinase inhibitor imatinib (Glivec®; Novartis) was initiated and administered for a 6-month period. Unfortunately, osteolyses were progressive and expanded onto the spinal column (Figure 1E) and pelvis (not shown). Furthermore, the patient frequently suffered massive pleural effusions. Facing this dramatic clinical course and considering new data about the VEGF-driven pathology of GSD and the safety of antiangiogenic drugs in children with oncologic diseases [3.Colucci S. Taraboletti G. Primo L. et al.Gorham-Stout syndrome: a monocyte-mediated cytokine propelled disease.J Bone Miner Res. 2006; 21: 207-218Crossref PubMed Scopus (56) Google Scholar, 5.Glade Bender J.L. Adamson P.C. Reid J.M. et al.Phase I trial and pharmacokinetic study of bevacizumab in pediatric patients with refractory solid tumors: a Children’s Oncology Group Study.J Clin Oncol. 2008; 26: 399-405Crossref PubMed Scopus (210) Google Scholar], bevacizumab was added to the therapy regimen (Avastin®, 10 mg/kg once/month i.v.), which ultimately halted the progression of osteolysis. Moreover, the patient suffered no further pleural effusions under treatment with bevacizumab. The patient is now still on bevacizumab and multiple follow-up whole-body magnetic resonance images could entirely confirm stable disease for >27 months without any clinically apparent side-effect including growth delay. Thus, we conclude that bevacizumab should be considered as a feasible and effective primary therapy for adult and paediatric patients with GSD since mortality and morbidity strongly correlate with the extent of osteolytic disease. None of the authors declare conflicts of interest.