Encapsulated angioinvasive follicular thyroid carcinoma

by Jason Wasserman MD PhD FRCPC
July 3, 2025

Encapsulated angioinvasive follicular thyroid carcinoma is a type of thyroid cancer that starts from the follicular cells of the thyroid gland. These are the same cells that produce thyroid hormones. This tumour is considered a well-differentiated carcinoma, meaning the cancer cells still look similar to normal thyroid cells under the microscope.

The word encapsulated means the tumour is surrounded by a clear, fibrous capsule. Angioinvasive means that cancer cells have invaded into one or more nearby blood vessels, either within or beyond the capsule. This type of invasion is important because it increases the risk of the cancer spreading to other parts of the body, such as the lungs or bones, through the bloodstream.

Encapsulated angioinvasive follicular thyroid carcinoma is more aggressive than minimally invasive follicular carcinoma (which only invades the capsule), but it usually has a better prognosis than widely invasive carcinoma, especially when blood vessel invasion is limited.

What are the symptoms of encapsulated angioinvasive follicular thyroid carcinoma?

Most people with this type of cancer notice a painless lump in the front of the neck. It may be found during a routine check-up or imaging test. In many cases, there are no symptoms, and the tumour is found incidentally.

In larger tumours, symptoms may include:

• A feeling of pressure or tightness in the neck.

• Difficulty swallowing (dysphagia).

• Hoarseness or voice changes.

This cancer typically does not spread to lymph nodes in the neck, but in some cases, it may spread to other parts of the body, especially the lungs and bones.

What causes encapsulated angioinvasive follicular thyroid carcinoma?

Most cases develop sporadically, meaning there is no known inherited cause. However, certain risk factors have been associated with the development of this tumour:

• Iodine deficiency: Common in areas where iodine is lacking in the diet.

• Radiation exposure, especially in childhood.

• Genetic syndromes such as PTEN hamartoma tumour syndrome (Cowden syndrome), DICER1 syndrome, Werner syndrome, and Carney complex.

If multiple thyroid nodules or cancers are found, or if you are diagnosed at a young age, your doctor may consider testing for a hereditary syndrome.

How is encapsulated angioinvasive follicular thyroid carcinoma diagnosed?

The diagnosis is usually made after surgery, when the tumour is removed and examined under a microscope. A fine-needle aspiration biopsy (FNAB), often done before surgery, can suggest a diagnosis of follicular neoplasm, but cannot distinguish between benign and malignant tumours or identify blood vessel invasion.

The diagnosis of encapsulated angioinvasive follicular thyroid carcinoma requires proof that cancer cells have entered blood vessels. This is something the pathologist looks for by examining the entire capsule and nearby vessels on many tissue sections under the microscope.

What does encapsulated angioinvasive follicular thyroid carcinoma look like under the microscope?

When examined under the microscope, this type of tumour shows:

• A fibrous capsule that surrounds the tumour.

• Invasion into blood vessels, usually veins, either inside or just outside the capsule.

• Follicular cells that look similar to normal thyroid cells, arranged in small round follicles, solid areas, or trabecular (cord-like) patterns.

• No nuclear features of papillary thyroid carcinoma (such as nuclear grooves or pseudoinclusions).

• Low mitotic activity (few dividing cells).

• No tumour necrosis (dead tumour tissue).

The number of blood vessels invaded by tumour cells is important:

• Fewer than 4 foci of invasion is called limited angioinvasion.

• 4 or more foci is called extensive angioinvasion.

Extensive angioinvasion is associated with a higher risk of spread and a worse prognosis.

Immunohistochemistry

Immunohistochemistry is a special test that pathologists use to help diagnose and classify tumours. It works by using antibodies to detect specific proteins made by the tumour cells. These proteins can help confirm that the tumour started in the thyroid and may also provide clues about how the tumour is likely to behave.

For encapsulated angioinvasive follicular thyroid carcinoma, immunohistochemistry typically shows the following:

• Thyroglobulin: This protein is made by normal thyroid cells and is usually found in the cytoplasm (the inside of the cell). Most follicular thyroid carcinomas are positive for thyroglobulin, which confirms that the tumour came from thyroid follicular cells.

• Thyroid transcription factor 1 (TTF-1) and PAX8: These are nuclear proteins that are also commonly found in thyroid cells. Most follicular thyroid carcinomas show strong nuclear staining for both.

• Cytokeratins (CAM5.2, CK7): These proteins help support the structure of cells and are usually present in follicular thyroid carcinoma. They help distinguish thyroid tumours from other types of cancer.

• Calcitonin and CK20: These markers are negative in follicular thyroid carcinoma, which helps rule out other types of thyroid cancer (such as medullary thyroid carcinoma or metastatic cancers).

• Ki-67: This protein helps measure how quickly the tumour cells are dividing. Most follicular thyroid carcinomas have a low Ki-67 index (less than 5%), indicating that the tumour cells are not dividing rapidly. A higher Ki-67 index may suggest a more aggressive tumour or raise concern for a different type of cancer, such as poorly differentiated thyroid carcinoma.

These tests help pathologists confirm that the tumour started in the thyroid and rule out other possibilities. However, they do not reliably distinguish between follicular adenoma (a benign tumour) and encapsulated angioinvasive follicular thyroid carcinoma because both may show similar staining. The final diagnosis still depends on whether the tumour has invaded surrounding tissue or blood vessels, which must be seen under the microscope.

Molecular testing

Molecular testing looks for changes (mutations or rearrangements) in the DNA of the tumour cells. These tests are often done using a method called next-generation sequencing (NGS), which allows many genes to be tested at once. Molecular testing is sometimes used to help understand how a thyroid tumour developed and how it might behave.

In encapsulated angioinvasive follicular thyroid carcinoma, the most common molecular findings include:

• RAS mutations: Found in up to 30% of follicular thyroid carcinomas. These mutations affect genes that control cell growth (such as NRAS, HRAS, or KRAS). RAS mutations are common in both benign and malignant follicular-patterned thyroid tumours and are not specific for cancer.

• PAX8::PPARG gene rearrangement: This abnormal fusion between two genes is found in 10–40% of follicular thyroid carcinomas. Tumours with this change may occur in younger patients and may be more likely to show aggressive behaviour.

• TERT promoter mutations: Found in about 15% of follicular thyroid carcinomas, especially those with distant metastases (spread to other organs). These mutations are linked to more advanced disease and worse prognosis.

• PIK3CA and PTEN mutations: These are part of a signalling pathway that helps control cell growth. These mutations are more common in follicular thyroid carcinoma than in benign thyroid tumours.

• EIF1AX mutations: Found in a small number of cases, often in combination with RAS mutations.

• DICER1 and NF1 mutations: Rare but may be seen in tumours related to inherited syndromes.

• TSHR (thyroid-stimulating hormone receptor) mutations: Rarely seen, especially in tumours that produce excess thyroid hormone (causing hyperthyroidism).

It’s important to know that no single genetic mutation confirms the diagnosis of encapsulated angioinvasive follicular thyroid carcinoma. The diagnosis is still made by carefully examining the tumour under the microscope. Molecular testing provides additional information that may help predict the behaviour of the tumour and guide future treatment.

What is the treatment for encapsulated angioinvasive follicular thyroid carcinoma?

Treatment usually begins with surgery to remove the affected lobe of the thyroid or the entire thyroid gland (total thyroidectomy). Depending on the amount of vascular invasion and the risk of spread, additional treatment may include:

• Radioactive iodine therapy to destroy any remaining thyroid tissue or microscopic cancer cells

• Thyroid hormone replacement therapy to maintain normal hormone levels and suppress tumour growth

• Monitoring with regular blood tests and imaging

If the tumour shows extensive vascular invasion or has spread to other parts of the body, more intensive treatment and closer follow-up may be needed.

What is the prognosis for encapsulated angioinvasive follicular thyroid carcinoma?

The prognosis depends on the extent of vascular invasion and whether the cancer has spread:

• Limited vascular invasion (< 4 foci): Excellent prognosis, similar to minimally invasive follicular carcinoma

• Extensive vascular invasion (≥ 4 foci): Higher risk of recurrence and spread, especially to the lungs or bones

• The presence of TERT promoter mutations or distant metastases is associated with a higher risk of poor outcomes

Long-term follow-up is important, as some tumours may recur or spread many years after initial treatment. However, many patients are cured with surgery and radioactive iodine.

Pathologic stage (pTNM)

The pathologic stage for encapsulated angioinvasive follicular thyroid carcinoma can only be determined after the entire tumour has been surgically removed and examined under the microscope by a pathologist. The stage is divided into three parts: tumour stage (pT) which describes the tumour, nodal stage (pN) which describes any lymph nodes examined, and metastatic stage (pM) which describes tumour cells that have spread to other parts of the body. Most pathology reports will include information about the tumour and nodal stages. The overall pathologic stage is important because it helps your doctor determine the best treatment plan and predict the outlook for recovery.

Tumour stage (pT)

• T0: No evidence of primary tumour.
• T1: The tumour is 2 cm (about 0.8 inches) or smaller in its greatest dimension and confined to the thyroid.
  • T1a: The tumour is 1 cm (about 0.4 inches) or smaller.
  • T1b: The tumour is larger than 1 cm but not larger than 2 cm.
• T2: The tumour is larger than 2 cm but not larger than 4 cm (about 1.6 inches) and is still inside the thyroid.
• T3: The tumour is larger than 4 cm or has minimal extension beyond the thyroid gland.
  • T3a: The tumour is larger than 4 cm but is still confined to the thyroid.
  • T3b: The tumour shows gross extrathyroidal extension (it has spread into the muscles outside of the thyroid).
• T4: This indicates advanced disease.
  • T4a: The tumour extends beyond the thyroid capsule to invade subcutaneous soft tissues, the larynx (voice box), trachea (windpipe), esophagus (food pipe), or recurrent laryngeal nerve (a nerve that controls the voice box).
  • T4b: The tumour invades prevertebral space (area in front of the spinal column), and encases the carotid artery or the mediastinal vessels (major blood vessels).

Nodal stage (pN)

• N0: No regional lymph node metastasis (the cancer hasn’t spread to nearby lymph nodes).
• N1: There is metastasis to regional lymph nodes (near the thyroid).
  • N1a: Metastasis is limited to lymph nodes around the thyroid (pretracheal, paratracheal, prelaryngeal/Delphian, and/or perithyroidal lymph nodes).
  • N1b: Metastasis to other cervical (neck) or superior mediastinal lymph nodes (lymph nodes in the upper chest).

Questions to ask your doctor

• How many blood vessels were involved?

• Will I need radioactive iodine treatment?

• Has the tumour spread outside the thyroid gland?

• What follow-up tests will I need?

• Are there any genetic mutations that affect my treatment or prognosis?

• Do I need to see a specialist in thyroid cancer or genetic counselling?

Other helpful resources

American Thyroid Association (ATA)

American Cancer Society