Introduction 

Have you ever seen or heard of a baby born with a soft, fluid-filled lump under their skin and wondered what it is? These rare growths, called lymphangiomas, can seem worrying at first, but they are not cancerous and usually form in the womb during the early stages of pregnancy.^1,12

In this article, we will guide you through what lymphangiomas are, as well as the genetic factors that play a role in their development.

What is a lymphangioma?

Lymphangiomas are benign (non-cancerous) growths made up of parts of the lymphatic system that were damaged during embryonic development. They typically consist of abnormal lymphatic vessels with fluid inside them,^4,5 but sometimes the lymphangioma can grow into nearby tissues like your muscles.¹

These growths are better described as lymphatic malformations (LMs), since they are caused by how your lymphatic system develops.

Normal structure of the lymphatic system and what can go wrong

Your lymphatic system is made up of:^2,6

• Lymphatic vessels - hollow tubes that carry lymph fluid to neighbouring veins; incoming vessels bring unfiltered fluid towards the lymph nodes, and outgoing vessels carry the filtered fluid away
• Lymph nodes - bean-shaped filters located along vessels which remove infection-causing substances from your lymph fluid
• Lymphoid organs - spleen, tonsils, and mucous membranes serve as battlegrounds where your immune cells fight infection-causing organisms

Your lymphatic system is essentially a big drainage network for your body - it collects extra fluid from your tissues and returns it into your bloodstream. It also carries specific cells to help protect you from infections and keep you healthy.^2,6,8,9 

Lymph fluid is the clear, yellowish fluid that travels through your lymphatic system. When your lymphatic vessels fail to develop properly before birth, it affects their normal function. This can result in fluid-filled masses or cysts appearing under your skin or in deeper tissues (lymphangiomas).⁵

Key characteristics of lymphangioma

• Often present at birth (congenital) or early childhood, but can appear later in life^{1, 5}
• Commonly found in the head and neck area, but can develop anywhere on the skin^3,4,5,8
• Masses tend to be soft^{3 4,5}
• Small lymphangiomas can be surgically removed, larger ones may involve further treatments^1,4
• Symptoms vary based on the location and size

Types

Lymphangiomas are grouped based on their size, depth, and location of the affected lymphatic vessels.

Some of the main types include:^4,5,10,12

• Macrocystic lymphatic malformations - large, fluid-filled cysts with a diameter of > 2 cm 
• Microcystic lymphatic malformations - small cysts with a diameter of < 2 cm 
• Combined lymphangiomas - a mix of large and small cysts in the same area
• Lymphangioma circumscriptum - clusters of purple fluid-filled bumps on the skin

Embryological basis of lymphangioma

Embryological origin

Your lymphatic system develops from the middle layer of the embryo (mesoderm).

Key events during human development:^2,6,7,8

• Weeks 5-6
  • The first structures of your lymphatic system begin to form
  • Cells lining your veins transform into early lymphatic structures called lymph sacs
• Weeks 6-8
  • Many organs, including parts of the lymphatic system, continue to develop and prepare for further growth and maturation
  •  Six main lymphatic sacs develop, ranging from your neck area down to the lower body
  • Lymph sacs eventually spread to create lymphatic vessels throughout your body. At the same time, cells from local tissues move into the sacs to form lymph nodes and support your immune system

Developmental problems leading to lymphangioma

In normal development of the lymphatic system, your lymph sacs change shape and reorganise themselves into a complex, branched network of vessels to help move fluids around your body smoothly.^2,6,8 Think of it like construction work - turning a basic foundation into an intricate drainage system that helps keep you alive every day. 

On some occasions, this does not always go as planned. Instead of creating narrow channels through which the fluid can drain, some vessels stay wide or get blocked^.1 When this happens, lymph fluid cannot drain correctly and starts to build up inside the vessel, making it swell into cyst-like structures.

Similarly, another issue that can occur is when lymphatic vessels fail to connect with neighbouring veins or drainage ducts.^1,5 Without this vital connection, the lymph fluid has nowhere to drain. Because the vessel is cut off from the rest of the lymphatic and venous systems, lymph fluid leaks into surrounding tissues or becomes trapped inside the abnormal vessels. This can cause lymphatic malformations or, in some people, lead to lymphoedema.

Genetic basis of lymphangioma

Some lymphangiomas are caused by genetic factors, but this is not the case for everyone.

Genetic conditions linked to lymphangioma

Some people have conditions affecting their whole chromosomes or specific genes, with lymphatic malformations as a common symptom. These include:¹

• Down syndrome
• Noonan syndrome
• Turner syndrome

Specific gene mutations involved

Your DNA is essentially a set of unique instructions that make all of the proteins and structures needed for your development and survival. Some mutations (changes) in your DNA can disrupt the normal processes that determine how your lymphatic vessels grow and form connections. 

Below are two common gene mutations that negatively affect lymphatic vessels, resulting in the features seen in lymphangiomas:

• The PROX1 gene produces a protein that acts like a switch. It turns on other genes to guide the transformation of certain blood vessel cells into lymphatic endothelial cells (LECs) - the cells lining your lymphatic vessels - during embryonic development.^9,11 A mutated PROX1 gene prevents your lymphatic vessels from connecting to form a functional, branched network
• The PIK3CA gene produces a protein that controls the division and survival of your cells. A change in this gene’s DNA sequence causes your LECs to divide uncontrollably and survive longer than they should, leading to excessive growth or PIK3CA-Related Overgrowth Spectrum (PROS)^10,12,13

Inheritance of lymphangioma 

While some lymphatic malformations are linked to genetic conditions that people are born with, they are simply one of the features that can come with that condition. In other words, lymphangioma is not passed down as a condition of its own. You cannot inherit it from family members who may be affected.

Lymphangiomas are typically caused by errors in the lymphatic system during fetal development, or later in life when something blocks or damages the normal lymphatic drainage, such as surgery or an injury.¹

PIK3CA mosaicism and inheritance

In some cases, lymphangiomas are linked to mosaicism - a genetic phenomenon which helps us understand the pattern and location of lymphangiomas, and why they are not inherited or widespread:^11,13

• PIK3CA mutations are described as “somatic mosaic-like”. This means they develop randomly in some of your body cells, not all of them. It is the reason why lymphangiomas are usually restricted to certain parts of the body
• The severity of a lymphangioma depends on when the PIK3CA mutation occurred during embryonic development. The earlier the mutation, the more cells are impacted, resulting in more severe symptoms. The later the mutation, the fewer cells are impacted, resulting in more localised symptoms
• People with a PIK3CA-related lymphangioma are not at increased risk of passing it down to their child. This is because the mutation was not inherited - it was a random event that occurred after fertilisation and did not involve gametes (egg or sperm cell)

FAQs

How is lymphangioma diagnosed?

Depending on the type and severity of the lymphangioma, a prenatal ultrasound will usually detect any malformations before birth.¹ A healthcare professional will also examine and confirm the condition’s appearance and location through MRI scans and biopsies after birth.⁵

What symptoms might lymphangiomas cause?

Symptoms usually vary between people due to the location where the lymphangioma develops. Common symptoms include:^1,5

• Head and neck region:
  • Visible swelling and facial disfigurement, leading to cosmetic concerns for the person
  • Large lymphangiomas can block the airways, resulting in respiratory problems
• Armpit and groin area - lymphatic malformations can cause a burning sensation and sometimes an infection

In some cases, lymphangiomas can be painless and grow without other symptoms.

Do all lymphangiomas get worse over time?

No, not all lymphangiomas get worse. Some lymphangiomas keep the same size and do not cause problems, while other types often get bigger with age or stay the same size for a while before beginning to grow later on.⁵ Because of this, it is recommended to monitor the condition. If left untreated for too long, the malformations can spread and exert pressure on nearby tissues, leading to further health complications. 

Summary

• Lymphangiomas are benign malformations of the lymphatic system that form when lymphatic vessels do not develop properly.
• They usually appear as fluid-filled cysts and are formed before birth
• Mutations in certain genes, such as PROX1 and PIK3CA, disrupt the normal lymphatic vessel growth and development
• Lymphangiomas are not inherited but can happen due to mosaicism, leading to a localised fluid-filled cyst or mass