Lymphatic Malformation

The lymphatic system is a normal part of the human body.  As the blood circulates from the heart through the arteries and capillaries and back through the veins there is a constant slight leak of fluid into the tissues.  Lymphatic vessels which are found throughout the body collect this fluid and return it to the circulation.  The ‘collecting lymphatics’ join together into larger channels and the fluid passes through the ‘lymph nodes’ which are found mostly at the base of each limb and in the neck, and which act as filters and part of the immune system.  Lymphatic vessels all join together to form the ‘thoracic duct’ which deposits fluid back into the circulation via a large vein on the left side of the neck.  If there is a deficiency of lymphatics in one part of the body then the fluid is not collected and this results in swelling which is known as ‘lymphoedema’ (spelt ‘lymphedema’ in the U.S.). In a Lymphatic Malformation there is the opposite problem. An excess of lymphatic vessels has grown in one location, which are not connected to the lymphatic system. Those vessels continue to collect fluid as normal lymphatics do, but with nowhere for the fluid accumulates to form fluid filled sacs or ‘cysts’ which can become very large.

The main sign of a lymphatic malformation is swelling. This can vary from a subtle bulge to a very large swelling which can be very obvious. Sometimes the swelling is quite localized, at other times it can be quite diffuse and spread across a large area. Lymphatic malformations can become larger over time, by containing more fluid, but they tend not to increase the part of the body which is involved, in other words they do not ‘grow’, except that as a child grows the area involved will increase in proportion to the growth of the child.

About half of lymphatic malformations are identified at birth, and more than 90% have become evident by the age of ten. 

Only very rarely do they make their first appearance in adulthood.  Once present they tend to grow in proportion with the child without invading into adjacent tissues, continuing to occupy just the same part of the body as when they first presented.  All this suggests that most, and possibly all lymphatic malformations are present at birth, but those deeper in may only make their presence felt when some event occurs, such as a bleed into a cyst. There is no way to know whether this is true for sure, but most experts in the field think that whether they are obvious or not, lymphatic malformations are present from birth.

The most common complication in lymphatic malformation is bleeding into one of the cysts.  Small, fragile blood vessels are present in the wall of the cyst and these can rupture and bleed.  This is similar to a bruise occurring in normal tissue, but the space in the cyst allows bleeding to continue and the lymphatic malformation can enlarge quickly and very alarmingly: the malformation may appear to ‘grow’ over a few hours to be two or three times its normal size. Most often bleeds seem to happen spontaneously, there has been no bump or fall in the hours leading up to it.  Unless the swelling is pressing on some vital structure like the eye or the airway, no specific treatment is required apart from pain relief.  Pain typically gradually settles over a few days.  Straight after the bleed the blood forms a clot which gradually dissolves and the fluid is resorbed and the swelling gradually goes down, typically over about three or four months.  Often the swelling goes back down to where it was before the bleed, but sometimes it never goes back down completely.  When the bleed has just happened, the blood will already have formed a clot so there is no possibility of draining the fluid through a needle and hence no place for sclerotherapy until the selling has resolved.  Having a bleed is a common way in which lymphatic malformations not evident a birth first announce their presence. 

A less common complication is infection.  Although true infection in a lymphatic malformation is rare, the consequences can be significant.  The body’s immune system has difficulty penetrating into the cystic spaces and infection can be prolonged.  Treatment with antibiotics usually settles an infection fairly quickly, but it is common for the infection to flair up again weeks or months later and some patients have recurrent episodes of infection over several years.  This may require continuous treatment with long-term antibiotics.   In our institution we try to treat the first episode of infection aggressively with a very long course of antibiotics (around three months) which in most patients prevents this recurrent cycle from establishing. 

When a child presents with an acute swelling in their lymphatic malformation it can be difficult to tell whether this is a bleed or an infection.  Since the pain and swelling of a bleed tends to resolve over a few days, the fact that symptoms settle on antibiotics does not indicate one way or the other.  A blood test called a CRP can be very useful in distinguishing between bleed and infection.

It used to be said that lymphatic malformations were due to errors in theformation of the lymphatic system in the embryo, but we now recognise that the event that leads to the malformation is a ‘somatic’ genetic mutation in a specific gene.  We inherit genes from both our parents, soinherited genetic conditions are caused by an error in one or both parental contributions.  This is not what happens with a lymphatic malformation.  As the embryo grows the inherited genetic material is copied every time a cell divides, and errors occur in copying the genetic code from one cell to the next.  These are called ‘somatic mutations’.   While such errors are rare, it takes so many cell divisions to make a human body that the errors accumulate.  If by chance such an error occurs at exactly the right place, in exactly the right gene (PIK3CA) and in just the right cell it causes a lymphatic malformation.  The somatic genetic mutation is therefore only present in the cells in the lymphatic malformation, it is not found elsewhere in the body. 

Nothing that a mother has done or not done during pregnancy has ever been shown to increase the chances of developing a lymphatic malformation.

Much of the swelling in lymphatic malformations is caused by the fluid in the cysts.  If a needle is placed into the cyst and the fluid extracted then the swelling goes down, but if nothing else is done cyst will continue to draw in fluid as it normally does will return to its previous size.  In sclerotherapy, the fluid is sucked out through a needle, and an agent is injected into the cyst through the same needle, which kills the lining cells of the cyst and effectively sticks the sides together so that there is no space for the fluid to return (or for a future bleed).  Several different agents are used in sclerotherapy, some are more effective but cause more swelling and tissue damage, others are milder but not as effective.  Interventional radiologists who perform the procedure choose the agent that they feel gives the best balance of effectiveness and risk.

Yes, a lymphatic malformation can be surgically removed, but the margins of a lymphatic malformation are usually not well defined.  They extend into spaces and wrap around vital structures like nerves and blood vessels, so in surgery some part of the lymphatic malformation is always left behind.  When surgeons operate on cancer they aim to ensure that every part is removed, which is achieved by removing a ‘margin’ of normal tissue all around the tumour, including nerves, vessels and any other structure which is close to the tumour.  This would not be appropriate for a benign condition like lymphatic malformation.  The aim of surgery istherefore to remove as much of the lymphatic malformation as possible without damaging the important adjacent structures. The small amount of malformation left behind may need to be addressed at some stage in the future, but more likely it will never reach sufficient size to cause an issue.  Since both surgery and sclerotherapy leave some part of the malformation untreated, parents and the treating doctor should always have a clear conception of what the treatment is aiming to achieve.  For instance, does it aim to improve the appearance, improve function or prevent some complication like bleeding or infection? 

 The somatic mutation which causes lymphatic malformation is nearly always in a gene called PIK3CA.  This gene codes for part of a ‘switch’ mechanism within the cell which turns on a signalling pathway thatcontrols a number of cell functions including growth.  Normally this switch is turned on only when it is required, but the error in the gene code which causes lymphatic malformation puts this switch permanently in the ‘on’ position so the pathway is always activated.  Sirolimus or rapamycin is a drug which inhibits the signalling further down the pathway.  It has been used for decades for other purposes, but when it emerged that lymphatic malformations are caused by PIK3CA somatic mutations it was tested in lymphatic malformations and found to be effective.  

Sirolimus is a generally well-tolerated drug but it does have some side effects, including mouth ulcers.  It also increases cholesterol.  It has been used for many years as part of a regimen for preventing organ transplant rejection, so it has some inhibitory effect on the immune system which some people find concerning.  On the other hand, animals given rapamycin are found to live longer and there is interest in the ‘wellness’ community about long term use of rapamycin, including to ‘boost’ the immune system.  The effects of rapamycin are clearly complex, and like every other treatment the use is a balance between benefits and risks.  Your doctor will take this into account when recommending the drug.  Opinions vary as to whether sirolimus can reduce the size of established lymphatic malformations (this is surprisingly hard to quantify because they go up and down in size depending on how much fluid is in them) but it can be very effective in clearing up blebs on the skin or on the tongue.  It is sometimes very effective in reducing pain in the few cases where this is present.

 The lymphatic system is part of the immune system so it is common for lymphatic malformations to temporarily increase in size when there is an infection nearby.  When a lymphatic malformation suddenly gets bigger it is most often due to a bleed, and less often to infection (see question 4 above).

 At the moment, genetic testing doesn’t make a great deal of difference to treatment.  It is a requirement for many clinical trials, so getting genetic testing done may make someone eligible for a trial, but it is not used in routine care.  Having said that, as new medical treatments come through it is likely that they will increasingly be guided by the results of genetic testing so there may well be advantage in the future in knowing what particular variant is the cause of the lymphatic malformation.

Some people find it reassuring to know the results of genetic testing, they feel that it gives them some control to understand how the lymphatic malformation has come about.

 When doctors talk about ‘genetic testing’ they most often mean what is called ‘germline genetic testing’.  This involves taking a sample of blood or saliva and looking for a genetic variant which has usually been inherited and so is found in cells throughout the body.  This type of testing has little or no role in lymphatic malformation.  Genetic testing for lymphatic malformation needs to be performed on a piece of tissue from the malformation, or sometimes on fluid aspirated from one of the cysts (a ‘liquid biopsy’).  If surgery is performed, then some of the tissue can be separated from the specimen and sent for genetic testing.  If someone has had surgery in the past, and tissue from the lymphatic malformation was sent for pathology testing, usually this tissue will be stored somewhere, and it may be possible to test that tissue for genetic variants, even if the surgery was several years ago.

This refers to the size of the cysts in the malformation, and is really about whether the cysts are large enough to make conventional sclerotherapy worthwhile (see Q6 above). Microcystic lymphatic malformations are not generally suitable for sclerotherapy, although injection of the drug bleomycin into the malformation may cause a moderate improvement in size of the lesion and symptoms.  There is no agreed cut-off for how big a cyst needs to be to be a macrocyst, and many lymphatic malformations have a combination of macro and microcysts.

Since lymphatic malformations only grow with the body, and changes in size are usually due to the amount of fluid in the lymphatic malformation, there is no need to perform routine imaging to ‘monitor’it.  It is more important to check on the symptoms, so a yearly or two yearly review by a doctor who knows about lymphatic malformations is more useful than imaging.  An MRI scan is usually performed prior to any treatment, but this is to help plan the treatment.  Since changes are often slow, an MRI performed some time ago, even years ago may be adequate, especially if there has been no other treatment performed in the interim. 

No. Some other types of vascular malformation can have a tendency to be inherited, but this has not been described for lymphatic malformations.  

‘Complex Lymphatic Anomalies’ (or CLAs) are a very rare group of conditions which are classified by ISSVA as types of lymphatic malformations, but they tend to have very different behaviour from the usual type of lymphatic malformation, and it is extremely unlikely that someone with an established diagnosis of lymphatic malformation will subsequently be diagnosed as having a complex lymphatic anomaly. 

There are currently three main types of CLA:

Gorham Stout Disease (also known as ‘Vanishing bone disease’).

Generalized Lymphatic Anomaly  (GLA)

Kaposiform Lymphatic Anomaly (KLA)

‘Central Conducting Lymphatic Anomaly’ or CCLA which involves obstruction of the thoracic duct in the chest is often considered to be a fourth type, but it can also describe a complication occurring in the other types of CLA. There is significant overlap in the symptoms of these conditions and they must be treated in a centre which specializes in vascular anomalies.  Unlike lymphatic malformations they can affect multiple areas of the body. The chest and the lungs are the most frequently affected sites.