Lymphatic Vascular Malformations

Frequency

Lymphatic VMs are the most common bases for macrocheilia, macroglossia, macrotia, and macromelia.[5] Combined lymphaticovenous malformation (LVM) occurs particularly in the craniofacial region.[6]

The vascular system is built by 2 processes, vasculogenesis and angiogenesis. In vasculogenesis, a primitive vascular plexus is established from endothelial precursors.[7] The vascular plexus is connected to the developing heart tube, and after onset of the heartbeat, the vascular channels are perfused with blood and the primary circulation is established by the end of the third week of development. In angiogenesis, new vessels arise from these preexisting vessels by migration and proliferation of endothelial cells.[7]

In general, the endothelial cell's fate is determined by the combined effects of a large number of positive and negative signals simultaneously transduced by numerous receptors.

Many molecules have been defined that regulate vessel growth in vivo and in vitro.[7] In general, the formation and remodeling of blood vessels are controlled by paracrine signals; many are protein ligands that bind and modulate transmembrane receptor tyrosine kinases.[7] Known negative regulators are angiostatin, endostatin, and thrombospondin. Positive regulators are vascular endothelial growth factor (VEGF), fibronectin, 5-integrin, vascular endothelial cadherin, and transforming growth factor-1 or TGF-1.[7]

Cha and Srinivasan suggested that Wnt/β-catenin signaling is essential to lymphatic vascular formation, acting as a mechanotransducer that regulates such development in association with fluid force.[8]

The lymphatic system begins to develop at the end of the fifth week.[7, 9] Lymphatic vessels develop as endothelial outgrowths from the venous system. First, 6 lymphatic sacs are formed.[7] These lymph sacs sprout from large central veins. The exact modulator that causes lymphatic VM is not known yet; however, genetic studies provide insight into the effect of positive and negative signals on the formation of those lesions. By analyzing a 2-generation family, an autosomal dominant type of congenital hereditary lymphedema has been mapped to chromosome 5.[7]

The candidate region contains a gene that encodes VEGF receptor 3 (VEGFR-3). Cervicofacial lymphatic VM further occurs in trisomy 13, 18, and 21 and in Turner syndrome.[7] Some have suggested that sporadic cases of lymphatic VM are caused by de novo dominant somatic mutations and that germline mutations are lethal.[7] Mapping of the human genome will help clarify the exact regulators that are involved in the formation of lymphatic VMs.

A study by Yan et al found a significant increase in VEGF-C and neuropilin 2 in patients with recurrent lymphatic VM microcystic lesions, compared with individuals with nonrecurrent lesions.[10]

See Etiology section above.

The diagnosis of a vascular lesion is based on medical history, physical examination, and imaging tests. The type of lesion usually can be determined easily based on the first 2 items. Imaging studies are mostly useful for confirming the clinical diagnosis, estimating the extent of the lesion, and determining the feasibility of surgical resection.

Medical history

When obtaining the medical history, ask the following 4 questions:

1. Was the lesion present at birth?

2. Did proportional or disproportional growth of the lesion occur after birth?

3. Did an involution phase occur?

4. Did an episodic enlargement occur?

Clinical diagnosis of hemangiomas and venous, lymphatic, and arterial lesions can be made in a straightforward fashion based on the answers to the above questions (see chart below).

A common feature of lymphatic VM is episodic enlargement associated with systemic or localized infection. The image below shows a 5-year-old child with a right leg lymphatic VM. The right lower picture shows acute infection of the lesion with typical redness, swelling, local warmth, and high systemic fever.

Physical examination

The physical examination of a patient with a vascular lesion includes inspection, palpation, and transillumination. The diagnosis of hemangiomas and venous, lymphatic, and arterial lesions can be made simply based on the above questions (see chart below).

Lymphatic VM can have a small and localized or an extensive presentation. Lesions that are limited to the superficial layer of the skin are called lymphangioma circumscriptum (see images below).

In the head and neck area, the lesions can involve the orbit and eyelids, cheek, tongue, and neck (see images below).

In the extremities, lymphatic VM can present as a localized or extensive extremity lesion associated with lymphedema and dysfunction (see images below).

Skeletal distortion and hypertrophy are also common features of limb and facial lymphatic malformations. The image below shows the effect of a cheek lymphatic malformation on the mandible.

Assessment of asymmetry and deformity of the facial and limb skeleton should be part of the physical examination of patients with lymphatic VMs.

Differential diagnosis

Lymphatic VMs may be confused with deep hemangiomas or venous VMs. The presence of the lesion at birth supports the diagnosis of a VM, although congenital hemangiomas can be observed at birth. MRI can help distinguish between a VM and a hemangioma. The differential diagnosis also includes gliomas, benign tumors, and malignant tumors. The image below shows the differential diagnosis of orbital lymphatic VMs.

Lymphatic VMs never involute. They expand or contract depending on the ebb and flow of lymphatic fluid and the occurrence of inflammation and intralesional bleeding.[5] Several indications for treatment exist. The size and location of the lesion, recurrent infection, and pain are the most frequent indications for treatment.[4]

Vision

An intraorbital lesion usually presents as proptosis. It may expand rapidly and cause optic nerve compression, disk swelling, and decreased vision. Cysts filled with blood ("chocolate" cysts) or lymph fluid may be aspirated under ultrasonographic guidance. Currently, no well-tested pharmacologic treatments for lymphatic VMs are available. Preliminary studies demonstrate that OK-432 may be useful for intralesional injection.[11] Surgery may be indicated for superficial eyelid lesions and in selected patients with intraorbital lesions. Sufficient surgical excision of orbital tumors without injury to intervening structures is difficult.

The first image below shows a 14-year-old boy with a right upper eyelid lymphatic lesion that had caused ptosis of the right upper eyelid (images on left). The second image shows an MRI of the lesion. Improvement in his visual field was achieved after excision of the lesion.

Breathing

Sublaryngeal lesions may compress the soft tracheal rings of infants. Intralesional injection with alcohol may be successful in macrocystic lesions but also may be followed by acute swelling and airway obstruction.[12] Tracheostomy may be required in selected patients.

A nationwide Japanese survey by Ueno et al of children with head and neck lymphatic malformation (in whom the mediastinum was not involved), found that in over 70% of patients who underwent tracheostomy, the associated lesion was in contact with the airway. However, such contact occurred in only 12% of children who were not treated with tracheostomy.[13]

Limb function

Localized limb lesions (see images below) are mostly of aesthetic concern.

Large lesions (see images below) may be associated with functional handicap. Treatment may be indicated in such individuals.

Recurrent infections

Infections as part of a systemic disease or as a localized problem are frequently observed in patients with lymphatic VMs. The image below (lower right) shows acute infection of a lower limb lesion. Long-term antibiotic treatment and compression stockings may decrease the incidence of infections.

Hygiene

Lymphatic lesions with a superficial component are associated with chronic shedding of small cysts, lymph leak, staining, and an unpleasant odor. The image below shows a 12-year-old boy with a lymphatic lesion involving the entire right leg. Good hygiene was very difficult to maintain at the toe area.

Aesthetic concerns

Lesions that involve the head and neck area may be associated with significant aesthetic deformity. The images below show some common head and neck lesions with aesthetic deformities. Parental concerns and the psychosocial effect of the deformity on the growing child should be taken into consideration and may be indications for early treatment.[12]

Normal lymphatic capillaries consist of single-layer endothelial cells without surrounding pericytes and without valves. These lymphatic capillaries merge into collecting lymphatic vessels,[7] which consist of a thin endothelial lining, surrounded by an incomplete layer of smooth muscle cells, with valves. Finally, either the thoracic or the right lymphatic duct delivers lymph to the venous system. Their walls contain a tunica intima, media, and adventitia, with the media containing bundles of smooth muscle cells.[7]

Lymphatic VMs are composed of dilated lymphatic channels.[7] They are filled with a proteinaceous fluid and do not have connections to the normal lymphatic system. Lesions can be primarily macrocystic or microcystic. Thoracic lesions are usually macrocystic and cervicofacial lesions are usually microcystic.[7] Lesions are located at the skin and subcutaneous tissue but may invade the floor of the mouth, cheek muscles, and other anatomic structures. The images below show an MRI of a 9-year-old child with a right facial lesion that extended into the floor of the mouth and cheek.

Sclerotherapy may be contraindicated in the following situations:

• Patient is allergic to the sclerosant or contrast media.

• Patient has a cardiac condition.

• Bleeding cannot be controlled.

• Systemic leak of the sclerosant cannot be avoided.

• Significant skin or mucosal injury is expected.

• Postinjection swelling puts another organ at risk (eg, injury to the optic nerve).

• Postinjection airway swelling cannot be managed by a tracheal tube or tracheostomy.

Surgery may be contraindicated in the following situations:

• Intraoperative and postoperative bleeding cannot be controlled.

• Surgery puts another organ at risk (eg, injury to the eye or facial nerve).

See the list below:

• The most important imaging tool is contrast-enhanced MRI.[3] This diagnostic test, which requires sedation or general anesthesia for children younger than 6 years, demonstrates the extent of the lesion and helps to differentiate between hemangiomas and venous, lymphatic, and arterial lesions. It also may help to differentiate between a vascular lesion and a nonvascular lesion, such as those found in neurofibromatosis.

  • MRI scans have 3 basic images: T1-weighted spin-echo image, T2-weighted spin-echo image, and contrast-enhanced (gadolinium) T1-weighted spin-echo image. T refers to the time necessary for the protons to discontinue spinning (see the first image below). T1 refers to a value around 600 milliseconds, and T2 refers to a value around 4000 milliseconds. The typical findings in the 3 modes are presented in the second image below.

    MRI - MRI T1, T2.
    Diagnosis – MRI.

  • Lymphatic VMs have a typical solid appearance with low intensity on T1-weighted spin-echo image, which is equal to that of venous VMs and less intense than that of hemangiomas.[3] Contrast-enhanced T1-weighted images show a very low central intensity with a typical rim enhancement of the lymphatic lesion. The first image below shows a patient with cystic hygroma. The second image below (image on left) shows a moderate intensity at T2-weighted spin-echo image and very low central intensity with typical rim enhancement of the lymphatic lesion on contrast-enhanced T1-weighted image (image on right).

    Cystic hygroma.
    MRI of cystic hygroma.

• Ultrasonography helps differentiate a low-flow from a high-flow lesion. Prenatal ultrasonography can detect relatively large lesions as early as the second trimester.[14]

• CT can detect calcifications, which are present in low-flow combined venous lymphatic lesions.

Lymphatic malformations are composed of dysplastic vesicles or pouches filled with lymphatic fluid. They can be described as either microcystic, macrocystic, or combined forms. Lymphatic VMs have walls of variable thickness, composed of both striated and smooth muscle, with nodular collections of lymphocytes in the connective tissue stroma.[5]

Local pressure

Elastic support stockings may help to decrease the swelling and the functional handicap associated with lymphatic VMs of the extremities (see image below).

Antibiotics

Viral or bacterial infection can cause acute infection of a lymphatic VM. Infection may be associated with acute enlargement, pain, local warmth, redness, and elevated systemic fever. Intravenous (IV) antibiotics and nonsteroidal anti-inflammatory drugs (NSAIDs) are indicated during such episodes.

Sclerotherapy

Transcutaneous injection of a sclerosant such as alcohol or sodium tetradecyl sulphate (STS) may help to decrease a lymphatic VM.[4] It is mostly useful for macrocystic malformations and for combined venous-lymphatic lesions. The procedure is painful; therefore, it is performed by an invasive radiologist under general anesthesia.

Initially, 5 mL of contrast fluid is injected through a venous catheter to delineate the anatomy of the lesion and to detect escape of contrast to the systemic circulation (see the upper left portion of the image below). The upper middle portion of the image below shows injection of contrast into a facial venous-lymphatic malformation. The catheter was relocated when escape of contrast to the facial vein was detected (upper right). When a lumen filled with lymphatic fluid is detected, the lymph is aspirated. Alcohol (100%) mixed with a small amount of contrast fluid (alcohol-to-contrast ratio of 20:5) is then injected through the same venous catheter.

The total amount of alcohol injected into a lesion of a full-sized male is approximately 50 mL. Exceeding a dose of 1 mL/kg is not advised. The catheter is left in place following alcohol injection in case some of the alcohol needs to be withdrawn. Injection is discontinued when skin changes such as peau d'orange, erythema, and bruising are observed. The upper left portion of the image above shows bruising and peau d'orange changes following injection with alcohol of a chest venous-lymphatic VM.

Additionally, doxycycline percutaneous image-guided sclerotherapy of macrocystic intra-abdominal lymphatic malformations has been shown to be safe and effective.[15]

To decrease the swelling, 4 mg of dexamethasone (PO/IV) is administered 3 times every day for 3 days after the procedure. NSAIDs are administered for pain control. The patient usually stays in the hospital overnight for pain control and for monitoring of possible vascular or neurologic limb compromise. Systemic leakage of alcohol may cause myocardial depression. Injection of alcohol close to the skin or mucosa may cause skin slough or skin necrosis. The lower right and left portions of the image above) shows necrosis of skin and mucosa following injection of alcohol to the forearm and tongue, respectively. It was found that more complications were seen with the use of alcohol, prompting a change of practice to favour STS as the primary agent, especially for head and neck lesions.[16]

Sclerotherapy with intralesional bleomycin and OK-432 have been reported to have dramatic results.[14, 17] For example, a retrospective study by Mohan et al indicated that sclerotherapy with serial intralesional bleomycin injections can effectively treat slow-flow VMs, including the lymphatic kind. The study involved 32 children, including 27 with mixed venous-capillary malformations and five with lymphatic malformations, with 29 patients (91%) responding to the treatment and 28% achieving complete resolution of the malformations (mean follow-up period, 38 mo).[18]

Another study, by Paramasivam et al, found image-guided bleomycin sclerotherapy to be effective in treating orbital lymphatic VMs. The study involved 14 patients, all of whom experienced improvement in exophthalmos and either stable or improved vision.[19]

Surgery is the only way to "cure" a lymphatic malformation. It should be considered in the following situations:

• When intraoperative and postoperative bleeding can be controlled

• When surgery does not put another organ at risk (eg, injury to the eye or facial nerve)

The surgery must be well planned. Most lesions cannot be resected completely; therefore, the extent of the resection needs to be defined before the procedure. In certain situations, such as eyelid surgery, performing the surgery under local anesthesia is better. This facilitates intraoperative navigation. The image below shows an upper right eyelid lesion before and after resection under local anesthesia.

Lymphangioma circumscriptum is a superficial lymphatic malformation of the skin. This often can be resected completely and the defect reconstructed with a skin graft (see image below). Administration of hemostatic agents such as recombinant factor VIIa (rVIIa) may decrease bleeding and improve surgical efficiency.[20]

A study by Bonilla-Velez et al indicated that surgery can serve as a safe and effective first-line treatment for selected macrocystic lymphatic malformations of the head and neck. Most of the patients in the report had unilateral infrahyoid, unilateral suprahyoid, or unilateral infrahyoid and suprahyoid lesions, affecting the neck. Patients experienced such surgical complications as seroma/hematoma (9.5%), transient nerve weakness (facial nerve, sympathetic chain, or phrenic nerve; 6.3%), and infection (1.6%). At median 12-month follow-up, 90.5% of patients had experienced a complete response with a single surgery. In addition, over an observation period of up to 15 years, 86% of patients achieved recurrence-free survival.[21]

Vision

Obstruction of vision during the first 6 months of life by a periorbital, cheek, forehead, or nasal VM may cause long-term visual damage. Early treatment with transcutaneous sclerosis and/or surgery is indicated in such patients.

Breathing

Lymphatic VM, which invades the neck, may compress the soft tracheal rings of infants and present as stridor. Direct excision of the lesions is impossible in most patients because of the close proximity of the lesion to vital structures. Consider tracheostomy in patients in whom pharmacologic treatment has failed.[12]

Psychosocial complications

The presence of a VM psychosocially affects both the patient and his or her parents. Parents may be subjected to comments, questions, and unsolicited advice from friends, family, and complete strangers. Early psychosocial support by primary caregivers with the help of a dedicated vascular birthmark clinic team is mandatory.[22] Early surgery may be indicated in patients with visible facial VMs.

Lymphatic lesions gradually enlarge and worsen with time.[5] Surgery is the only complete cure for this problem. However, this is not always possible, and the goal of treatment in many patients is improvement rather than cure.

A significant contribution to the understanding of vascular lesions is the introduction of a classification method by Mulliken and associates.[1] This made diagnosis and treatment more accurate and predictable. However, confusing and occasionally misleading terms used by different subspecialties are still found.

Improvement in patient monitoring and anesthesia during and after surgery made early excisions and transcutaneous sclerosis safer and more acceptable.

A major controversy is the timing of operative procedures. No clear-cut answer exists to this question. The authors believe that decisions should be made according to the individual patient. The psychosocial consequences of growing up with a facial deformity always should be taken into consideration.

Future research of specific genes and their angiogenic growth factor products will contribute to the understanding of the mechanism underlying the formation of lymphatic VMs and may provide new modalities of treatment at the gene level.[7]