Where does epithelioid hemangioendothelioma develop?
Epithelioid hemangioendothelioma can arise in almost any organ, but it most commonly involves the liver, lungs, and soft tissues.
Skin and superficial soft tissue tumours are usually single lesions, while tumours in internal organs or bone are often multifocal, meaning multiple lesions are present at diagnosis. In some patients, lesions in different organs represent spread from a single original tumour rather than separate independent tumours.
What are the symptoms of epithelioid hemangioendothelioma?
The symptoms of epithelioid hemangioendothelioma depend on where the tumour develops.
When the tumour arises in soft tissue, it often presents as a painful mass. Tumours arising from or near large blood vessels can cause symptoms related to blood flow blockage, such as swelling or inflammation of nearby veins.
Symptoms related to liver involvement can vary and may include abdominal discomfort, weight loss, or fluid accumulation in the abdomen. Because this tumour can grow slowly, some patients have few symptoms at first.
Who gets epithelioid hemangioendothelioma?
This tumour can occur at almost any age, but most often affects adults. It is rare in children. Tumours involving internal organs show a slight female predominance. A subset of tumours with a specific genetic change (described below) tends to occur in younger patients.
What causes epithelioid hemangioendothelioma?
Most epithelioid hemangioendotheliomas are caused by an acquired genetic fusion, in which two genes abnormally join together. A genetic fusion changes how cells behave by altering the proteins they produce.
In more than 90% of cases, the tumour cells contain a WWTR1–CAMTA1 gene fusion. This fusion disrupts a normal cell-control system called the Hippo pathway, keeping growth-promoting signals active when they should be turned off.
A smaller group of tumours has a different fusion, YAP1–TFE3, which leads to similar growth-promoting effects but is associated with somewhat different microscopic features and may behave more aggressively.
These genetic changes are considered sporadic, meaning they occur by chance and are not inherited.
How is the diagnosis made?
The diagnosis is made by examining tumour tissue under the microscope and confirming the findings with immunohistochemistry and, in selected cases, molecular testing.
Imaging
Imaging studies, such as CT or MRI, help identify the location and extent of disease. Tumours in deep soft tissue or internal organs are often larger than superficial lesions and may involve blood vessels.
Microscopic (pathologic) features
Under the microscope, epithelioid hemangioendothelioma exhibits a distinctive pattern reflecting its blood vessel origin. The tumour often grows in and around blood vessels, expanding and sometimes blocking the vessel wall before spreading into nearby tissue.
The tumour cells are typically epithelioid, meaning they are rounded with moderate amounts of pink (eosinophilic) cytoplasm. The nuclei are round with fine chromatin and small or inconspicuous nucleoli. Many cells contain small internal vacuoles, which may represent early blood vessel formation and sometimes contain red blood cells.
The cells grow in cords or small nests within a characteristic myxohyaline or fibrous stroma, which has a glassy or scar-like appearance. In some cases, this stroma can be so dense that it partially hides the tumour cells. Areas of haemorrhage, cystic change, sclerosis, or even bone formation may be seen.
Most tumours show minimal atypia and very few dividing cells. However, a small subset of cases exhibits more aggressive features, including increased nuclear irregularity, higher mitotic activity, solid sheet-like growth, and areas of tumour necrosis (cell death). These tumours may resemble angiosarcoma, but the presence of classic epithelioid hemangioendothelioma areas or specific genetic markers supports the correct diagnosis. Tumours with these atypical features are more often associated with aggressive behaviour.
Tumours with a YAP1–TFE3 fusion often look different. They are more likely to form well-developed vascular spaces and have tumour cells with brighter pink cytoplasm and more solid growth, features that are not typical of the classic form.
Immunohistochemistry
Immunohistochemistry uses special stains to identify proteins made by tumour cells.
Epithelioid hemangioendothelioma cells typically express endothelial markers, including CD31, CD34, FLI1, ERG, and D2-40 (podoplanin).
Many tumours show strong nuclear staining for CAMTA1, which supports the presence of a WWTR1–CAMTA1 fusion. Tumours with YAP1–TFE3 fusion show nuclear TFE3 expression, although TFE3 staining can occasionally be seen in other cases as well.
Some tumours show low-level keratin expression, which can lead to confusion with carcinoma, but EMA staining is usually absent or weak.
Molecular testing
Molecular testing can identify the WWTR1–CAMTA1 or YAP1–TFE3 gene fusions. These tests are especially helpful in difficult cases or when the tumour shows atypical features. Identifying one of these fusions helps distinguish epithelioid hemangioendothelioma from other vascular tumours.
How is epithelioid hemangioendothelioma staged?
There is no single TNM staging system that applies to all cases.
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Tumours arising in soft tissue of the trunk or extremities are staged using standard soft tissue sarcoma staging systems.
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For tumours in the abdomen or chest, formal TNM staging is not applicable. Instead, doctors record the size of the largest lesion and assess the number of organs involved.
What is the prognosis for a person with epithelioid hemangioendothelioma?
The prognosis for a patient diagnosed with epithelioid hemangioendothelioma varies depending on the tumour location, size, and growth rate.
Soft tissue tumours can behave in an indolent way, but about 20% may spread, and approximately 15–20% of patients die of the disease. Larger tumours and those with higher mitotic activity have a worse prognosis.
Tumours with a YAP1–TFE3 fusion may have a higher risk of spread, although data are limited. Tumours arising in the lung or bone tend to have a worse prognosis than those in soft tissue, while tumours limited to the skin have an excellent outcome.
Importantly, even tumours that look bland under the microscope can sometimes spread, so long-term follow-up is essential.
Questions to ask your doctor
- Where did my tumour start, and which organs are involved?
- Does my tumour have a WWTR1–CAMTA1 or YAP1–TFE3 fusion?
- Does my tumour show any features linked to aggressive behaviour?
- What treatment options are recommended for my case?
- How often will I need follow-up imaging or testing?
