What are Lymphatic Malformations:
Lymphatic Malformations (LM) are rare abnormalities of the lymphatic system, resulting in cyst-like masses, or fluid filled sacs. LMs are formed during embryogenesis, or the time during which the major organs and vessels are being made in a baby, typically during the sixth week of pregnancy. The majority of LMs are sporadic, meaning there is no associated genetic cause however some genetic mutations have been indicated in rare hereditary cases including VEGFR3, FOXC2 mutations. Both mutated genes normally play a role in healthy endothelial growth. While approximately 50% of them are noticed at birth, some can be detected prior to birth (more details below), and some of them do not appear until later in life. Nearly 90% of them however, do appear by the age of two.
The lymph system is similar to the venous system in that it drains fluid from the tissues and is a low-flow rate system, meaning the fluid moves through the lymph vessels slowly. Both systems are also typically under low amounts of pressure but the lymph system is under much lower pressure. These functional differences lead to differences in the types of cells and shape of the vessels that make up the lymph system. Lymphatic malformations are made of the same cells that line the regular lymph system, lymphatic endothelium. Unlike venous endothelial cells, lymphatic endothelial cells do not have a strong structural foundation upon which they lie called a basement membrane, and they are composed mainly of overlapping cells that are not tightly connected to each other. These differences are useful when differentiating between venous malformations and lymphatic malformations on biopsy.
LMs are typically divided into two types, macrocystic and microcystic, depending on their size where macrocystic malformations represent cysts greater than 2cm in size. Another important differentiation is the nature of the malformation, where diffuse malformations affect multiple organs or structures (muscles, bones, etc) and localized are isolated to a smaller location.
Roughly 80% of LMs occur in the head and neck region and complications associated with LMs in this region include:
- Chronic Infection - The lymphatic system plays a role in immunity, and the isolated nature of LMs makes them prone to infection. Infection presents as painful red swelling of the LM.
- Cosmetic Deformity - LMs can be very large and cause significant cosmetic deformity without impact surrounding structures. They may also impact surrounding structures as noted below, leading to further cosmetic deformity.
Compression of Neck Structures:
- Airway Obstruction - Airway obstruction is a common problem in LMs that are present at birth in the neck. LMs which are in the neck region can grow so large that they compress the airway, making it difficult for a newborn child to breath.
- Difficult Swallowing - Similar to airway obstruction, LMs in the neck may also compress the esophagus, and cause dysphagia or difficulty in swallowing food.
- Visual Deficits - LMs occurring in or near the orbit may impact vision.
- Hypertrophy of Facial Bones - LMs that have directly invaded nearby bone may lead to excessive growth of the bone, known as hypertrophy. The most commonly effected bones in the face include the mandible (or jaw bone), and the maxilla (a bone which contributes to the center of the face). Asymmetric hypertrophy of these bones can lead to significant cosmetic deformities.
Similar complications are seen in LMs affecting other regions of the body including overgrowth of associated structures, such as the tongue or infiltrated bones, and infections and swelling impacting other nearby structures.
CLINICAL PRESENTATION and DIAGNOSIS:
LMs present as cyst like formations. Superficial LMs, can be seen as cyst like sacs on the surface of the skin, and deep LMs present as a soft tissue mss that is painless (unless infected) and covered by normal skin. They are typically poorly defined, meaning it is difficult to determine their borders, on palpitation.
Diagnosis is dependent on when the LM is detected:
Diagnosis in utero is challenging and often not definitive, but is done with ultrasound and MRI. Ultrasound reveals asymmetric hypoechoic (or dark fluid filled) cystic malformations typically in the head and neck region, and T2 fat saturated MRI reveals hyperintense fluid filled structures also typically in the head and neck region.
Diangosis after birth can be accomplished with an ultrasound but often requires an MRI. Ultrasound of macrocystic LMs reveals hypoechoic cystic malformations, whereas ultrasound of microcystic LMs may reveal hypoechoic or hyperechoic (debris filled) masses. MRI provides definitive diagnosis, as both macrocystic and microcystic LMs reveal hyperintense (extra bright) cystic structures on T2 Fat-saturated MRI, indicating the presence of fluid in the masses.
Treatment is highly dependent on the surrounding structures and the nature of the LM. LMs which are localized, and easy to excise are treated surgically. Others may be treated with a multi-faceted approach including, surgery, sclerotherapy, various medications, and laser ablation.
Localized malformations are most often excised with surgery. Location of LMs of the head and neck region are carefully considered to avoid injuring nearby nerves in the head and neck. Some complications associated with surgical treatment include cystic rupture and leakage, which could lead to difficult visualization of the LM and resultant incomplete resection or damage to nearby structures.
Sclerotherapy entails injecting a chemical agent into the LM in order to induce damage to the cells and subsequent clotting, fibrosis (replacement of normal tissue with thick fibrous tissue), and scarring in an effort to minimize the size of the lesion. Many different agents can be used for sclerosis of LMs:
- Ethanol- Ethanol is the most effective sclerosing agent, and works by directly damaging the endothelial cells in the LMs. However, ethanol is associated with complications of damage to nearby tissues or nerves, so it is not always the first line of treatment.
- Sodium Tetradecyl Sulfate (STS): STS is a detergent which causes damage by dissolving the endothelial cells. it is considered a more gentle sclerosant than ethanol and is thus often used as the first line of treatment.
- Ethanolamine oleate: Ethanaolamine oleate is a detergent that works similarly to STS, but is used less commonly.
- Bleomycin: Bleomycin is a chemotherapy agent that causes endothelial death by damaging their DNA. It is associated with less inflammation than ethanol so it is sometimes indicated for areas with sensitive nearby structures such as the orbit.
- Doxycycline: Doxycycline is actually an antibiotic that induces endothelial damage and fibrosis. The mechanism of action is not fully elucidated but studies indicate it may play a roll in inhibiting growth factors (or signals that are essential to endothelial cell life).
Mixed results have been achieved in shrinking LMs with the following medications:
- Sildenafil - Sildenafil is a vasodilator, meaning it dilates blood vessels, leading to lower blood pressure. Current theory holds that by decreasing blood pressure, less fluid is sent into the lymphatic malformation allowing for it to shrink. Current studies show sildenafil has mixed effectivity.
- Sirolimus: Sirolimus blocks a powerful cellular activity regular called mTOR. mTOR is responsible for stimulating the release of growth factors (specifically VEGF) for endothelial cells. By suppressing the activity of mTOR, sirolimus prevents the release of growth factors necessary for the lymphatic endothelial cells to live, leading to lymphatic endothelial cell apoptosis. Currently there are several case reports indicating the successful use of sirolimus for LMs however, evidence is not concrete.