Elsevier

Survey of Ophthalmology

Volume 60, Issue 5, September–October 2015, Pages 383-405
Survey of Ophthalmology

Major review
Orbital lymphaticovenous malformations: Current and future treatments

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Abstract

Orbital lymphaticovenous malformations consist of abnormal vascular channels lined by endothelial cells with a spectrum from venous to lymphatic characteristics. They may be venous-dominant or lymphatic-dominant. These lesions continue to present management challenges. Total excision or obliteration is not always achievable, recrudescence is common, and interventions carry a risk of damaging normal structures. Patients likely benefit most from a multidisciplinary approach, including both surgical and nonsurgical (e.g., sclerosants and liquid polymers) therapeutic modalities. Targeted biologic therapy would be ideal; nevertheless, this goal is complicated by the heterogeneous venous–lymphatic and stromal characteristics of these lesions. Ideally, antiangiogenic agents targeting both lymphatic and blood vascular endothelial cells will be developed to treat these lesions and reduce their regrowth. Further studies are warranted to enhance our understanding of these orbital lesions with regard to their angiogenic (proliferative) activities and profiles of marker expression, with a goal to produce effective medical therapies.

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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