The pathogenesis of LM is incompletely understood due to the lack of proper understanding of lymphatic development.⁷ Very early during embryogenesis, there is no visibly discernible difference between the arterial or venous endothelium and arteries and veins, either in the orbit or elsewhere in the body, and they remain virtually indistinguishable until the dynamics of venous flow starts by the end of the fourth week.¹³ Around this time, endothelial specification into either an arterial or venous fate (arteriovenous specification) is observed, as evidenced by the expression of distinct arterial and venous markers in separate endothelial populations.¹,¹⁴ After the arteriovenous specification is already established, a third endothelial cell type appears later, which is the lymphatic endothelial cell (LEC). There are two competing theories about the embryonic origins of lymphatic vessels and lymphatic development, and these two theories have been debated for over a century.¹⁴,¹⁵ The centrifugal or venous theory maintains that primary lymph sacs bud off from primitive veins from a subset of venous endothelial cells that downregulate genes concerned with venous development and upregulate lymphatic ones.¹⁴,¹⁶ This theory maintains that the lymphatic vessels grow out centrifugally from these sacs by endothelial budding and lymphangiogenesis.¹⁶ In contrast, the centripetal (nonvenous) model maintains that lymphatic vessels and sacs arise from the mesenchyme parallel to the venous circulation which transforms into LEC. These LECs later develop a primitive lymphatic network and subsequently make secondary connections with the venous system.¹⁵,¹⁶

Recently, attempts have been made to reconcile both theories, and a dual venous and nonvenous origin of lymphatic vessels has been suggested.¹⁵ The discovery that the Prox1 gene, one of the most important genes that is involved in lymphatic development, is specifically expressed in a subpopulation of venous endothelial cells supports the centrifugal theory.¹⁵ In contrast, some recent experimental animal studies have demonstrated that while the deep lymphatic vessels are indeed of venous origin, the superficial lymphatic vessels are derived from nonvenous dermatomes.¹⁵

Developmental vascular malformations take place due to a genetic hit to the vascular endothelial cells very early during embryogenesis. This genetic hit usually occurs before endothelial specification into an arterial or venous fate.¹,⁹,¹⁴ Because all vascular components including the lymphatic ones are born from the very same primitive capillary plexus,
conceptually every single tumor or malformation listed in the International Society for the Study of Vascular Anomalies (ISSVA) classification may occur in the orbit as pure (venous, lymphatic, etc.) malformation or in combination (venolymphatic, etc.).¹,¹⁴ It must be stressed that because of the plasticity of the progenitor vascular elements destined to form arterial, venous, or lymphatic vessels, it should come as no surprise that lymphatic vascular malformations may occur in the orbit, a location where the very existence of normal lymphatics is questionable in the first place. This plasticity also helps to explain why the most typical form of LM is a mixed lymphovenous type.¹,⁹

Despite this apparent embryological complexity, one of the two major molecular pathways is deregulated in vascular anomalies, the RAS/MAPK pathway and the PI3K/AKT/mTOR.¹⁷ LM appear to occur due to abnormalities in the PIK3CA catalytic subunit, which is a part of a family of intracellular transducer enzymes called the PI3K (phosphoinositide 3-kinase), which are generally involved in the activation of the mTOR pathway.⁷,¹⁷,¹⁸ The mTOR pathway is a master regulator of cellular growth and development, and its dysregulation results in a variety of diseases besides LM, including cancers, diabetes, obesity, neurological diseases, and genetic disorders.¹⁸ Most cases of LM are sporadic in onset due to somatic or de novo germline mutations, although dominant, recessive, and paradominant (two-hit model) inheritance have been reported.¹⁷

Because LM is a vascular malformation that occurs as a result of a structural defect in vascular morphogenesis, they are usually present at birth, grow in size commensurately with the growth of the individual until the patient reaches adulthood, do not possess a regression or an involutional phase, and have a normal rate of endothelial turnover.¹⁹,²⁰,²¹,²² LM may enlarge with upper respiratory tract infections due to the proliferation of lymphoid aggregates within the tumor.²,²³,²⁴ Other predisposing factors that may cause upregulation in the lymphatic system and cause LM to enlarge include infection, hormonal changes, trauma, or even surgical intervention such as needle aspiration for biopsy or therapeutic purposes which can “ignite” an explosive LM growth.⁹,²¹ Regardless of the predisposing factor, the sudden expansion of the anomalous lymphatic channels can lead to disruptions in the normal capillary network that feeds the malformation, with subsequent bleeding into the dead-end lymphatic channels, which may, in turn, become hemorrhagic cysts.²¹

LM have no sex predilection and the exact prevalence is unknown, although some studies estimate an overall incidence throughout the body to be one in every 2000 to 5000 live births.¹²,²⁵,²⁶,²⁷ Seventy-five percent of LM occur in the head and neck.¹² Within the orbit, it constitutes 4% of all orbital tumors and around 25% of all vascular masses.⁸ Although LM are generally present at birth, it may not become clinically apparent until late in the first or second decades of life, typically following an upper respiratory tract infection or trauma, when bleeding into a previously undetected subclinical LM prompts an ophthalmic evaluation.²,²⁸

Patients with periorbital LM usually present with eyelid swelling or blepharoptosis. Ptosis which may be observed in up to half of the patients with periorbital LM is usually mechanical.²⁷,²⁸ Other less common presentations include pain, proptosis, diplopia, or strabismus which may be more related to orbital LM.²⁸ LM are generally classified into macrocystic (>2 cm²), microcystic (<2 cm²), or mixed lesions, although some authors prefer to bring the cutoff figure for orbital lesions to 1 cm rather than 2.¹ Regardless of the correct cutoff value, from a clinical standpoint, a microcyst should be defined as a cyst which cannot be safely accessed with a needle.²⁷ Of note is that macrocystic LM (previously called cystic hygroma) are more common in the posterior orbit and are often observed with orbital imaging displaying fluid levels, while microcystic LM (previously called lymphangioma circumscriptum) are more common in the anterior orbit, eyelids, and the conjunctiva.²¹,²²

Periorbital LM are rarely pure LM and are more commonly mixed-type malformations that contain venous channels and less commonly arterial or capillary channels.²¹ Based on the predominance of one vascular element, they are sometimes classified as venous-dominant or lymphatic-dominant.²² It should also be pointed out that isolated eyelid LM are exceptionally uncommon, as eyelid lesions are either anterior extensions of orbital LM or eyelid extensions of facial LM.²

Eyelid involvement (either with or without orbital/conjunctival involvement) may present with one of the two different forms. They may present as small superficial cutaneous vesicle-like lesions or cyst-like excrescences which may become hyperkeratotic or verrucous and can be hemorrhagic especially following manipulation.² Fluid levels may be seen within some of the cysts which are typically observed near the eyelid margin. Alternatively, eyelid LM may occur deep to the epidermis as a dark blue solid lesion, which may be soft to firm, fluctuant, and may infiltrate eyelid tissue causing a diffuse or localized thickening of the eyelid (Figure 84.1), and in extreme cases may lead to elephantiasis of the eyelid.²,²¹,²² Both forms of presentation may be observed together.²² LM by definition do not enlarge with the Valsalva maneuver.²¹,²² With a mass in the upper eyelid, significant ptosis can result in obstructing vision (Figure 84.2).