Major reviewOrbital lymphaticovenous malformations: Current and future treatments
Introduction
Vascular anomalies (malformations) are disorders of vasculogenesis that affect arteries, capillaries, veins, or lymphatics caused by dysfunctional signaling processes that regulate proliferation, differentiation, maturation, apoptosis, and adhesion of vascular cells.186 During the past two decades, advances in genetic and molecular characterization have yielded an evolving understanding of their pathogenesis. This knowledge has informed the development and refinement of the International Society for the Study of Vascular Anomalies classification system that categorizes these anomalies as vascular tumors and vascular malformations (Table 1).35, 102, 117 They are further divided into slow-flow and fast-flow. The third level of division separates lesions based on their vascular components into arterial, capillary, venous, and lymphatic malformations, or combinations of these elements.35, 102, 117
This classification defines the difference between vascular tumors and vascular malformations by evidence of endothelial cell proliferation in the latter (Table 2). Vascular tumors are lesions with endothelial proliferation (with or without dysplasia or anaplasia). Vascular malformations, in contrast, evolve by dysmorphogenesis and exhibit normal endothelial cell turnover.
This system is not perfect, as some anomalies may cross categories. In other words, endothelial mitotic activity is not always diagnostically useful. For instance, infantile hemangiomas, which are categorized as vascular tumors, lose their mitotic activity during the involutional phase. Conversely, some of the vascular malformations may have scattered foci of active capillary or lymphatic proliferation.68, 93, 120, 144
We summarize the current knowledge related to the development of lymphatic vessels and lymphaticovenous malformations and present a brief description of current surgical and nonsurgical therapeutic options for management, with special focus on the development of targeted biologic therapies.
Section snippets
Case presentation
The following case presentation of a lymphaticovenous lesion documents its growth and changing management over a 14-year period. In addition, it demonstrates the development of a clearer understanding of the pathophysiology, assessment techniques, and underlying pathogenesis. The clinical picture, imaging, management, and histopathology outline the various mechanisms of persistence and progression of these lesions including recurrent thrombosis (phleboliths),112 inflammation, mixed lymphatic
Lymphatic system
Lymphatic vessels, part of the lymphatic and immune system, remove fluids and proteins from tissue and return them to the bloodstream. They form a drainage system parallel with veins, collecting lymph from the whole body, which begins with lymphatic capillaries, drains to prenodal and then postnodal lymphatic vessels, and converges into larger vessels carrying lymph to the ductus thoracicus and ductus lymphaticus dexter, finally draining into the confluences of large veins. Their diameters
Development of the lymphatic system
Although the lymphatic system has long been understood, little knowledge concerning its biology has accumulated. Differentiating lymphatic vessels (especially lymphatic capillaries) from small blood vessels is difficult in routine histological examination of bioptic and particularly necrotic human material; however, over the past two decades, with new pathologic techniques and molecular markers,19, 187 our understanding of the lymphatic system, particularly its importance in neoplastic diseases
Molecular aspects of lymphatic development
Most knowledge of the molecular aspects of lymphatic system has come from studies in mouse embryos that follow a general mammalian scheme. One of the landmark findings was the discovery of lymphatic endothelial cell–specific growth factor (VEGF-C), which belongs to the PDGF/VEGF family of growth factors, and its tyrosine kinase receptors, VEGFR-3 (also known as Flt4).73, 77 This was followed by the discovery of podoplanin, a membrane mucoprotein expressed extensively in lymphatic endothelial
Development of lymphaticovenous malformations
There are currently four theories on the development of lymphatic malformations: (1) sequestration of lymph tissue; (2) obstruction of lymph vessels; (3) abnormal budding of lymph vessels; and (4) lack of fusion with the venous system.
Genetics of lymphaticovenous malformations
There is a growing body of literature on genetic abnormalities responsible for vascular abnormalities including capillary and venous malformations, lymphedema, and infantile hemangioma. Capillary and arteriovenous malformation subtypes are associated with a RASA-1 gene mutation with an autosomal dominant inheritance pattern.14, 139, 199, 204 Recently, Shirley et al showed that the Sturge–Weber syndrome and port-wine stains are caused by a somatic activating mutation in GNAQ gene. They
Clinical manifestation
Orbital lymphaticovenous malformations are benign congenital vascular lesions representing 1–3% of all orbital masses in tertiary orbital practices.34, 12, 146 In a 30-year retrospective single-center study including 1,264 orbital lesions, Shields et al reported that orbital lymphangiomas accounted for 25% of orbital vascular lesions and 4% of all orbital lesions.12, 165
These lesions may be evident at birth, but are usually manifest in infancy or childhood. Forthy-three percent of cases are
Conclusion
Orbital lymphaticovenous malformations can cause functional and structural impairments, and their management is challenging. Patients benefit most from a multidisciplinary approach including both nonsurgical and surgical modalities. Because these lesions are typically composed of a spectrum of lymphatic and blood vascular endothelial cells, anti-angiogenic agents targeting both lymphatic and blood vascular endothelial cells may hold some promise; however, further studies of angiogenic activity
Method of literature search
In preparing this review, we conducted a Medline and PubMed search of the medical literature for the period between January 1978 and July 2014 using the following key words in various combinations: vascular anomaly, vascular malformation, orbital lymphangioma, orbital lymphatic malformation, orbital lymphatic-venous malformation, lymphangiogenesis, vascular endothelial growth factor, pathophysiology, genetics, management, hemodynamic assessment. Additional articles and book chapters not
Disclosure
The authors did not receive any financial support from any public or private sources.
The authors have no financial or proprietary interest in a product, method, or material described herein.
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