Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP)

by Jason Wasserman MD PhD FRCPC
February 21, 2024

Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is a slow-growing tumour in the thyroid gland. This tumour was previously classified as a type of thyroid cancer but is now considered to be on the border between benign (noncancerous) and malignant (cancerous) tumours.

Until 2016, NIFTP was called non-invasive encapsulated follicular variant papillary thyroid carcinoma (EFVPTC). At that time, it was also considered a type of thyroid cancer. The tumour was described as non-invasive because the entire tumour was surrounded by a capsule and the tumour cells were not seen spreading into or invading the normal thyroid tissue. The name and classification were changed after several large, scientific studies found that patients diagnosed with non-invasive EFVPTC could be cured with surgery alone.

Can the tumour cells in non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) spread to lymph nodes and other parts of the body?

NIFTP has a very low malignant potential which means it is very unlikely to spread to lymph nodes or other parts of the body. In addition, most patients with non-invasive follicular thyroid neoplasm with papillary-like nuclear features are cured by surgery alone.

However, for a small number of patients initially diagnosed with NIFTP, tumour cells will be found later in a lymph node or other part of the body. Tumour cells that spread to a lymph node or other part of the body are called metastasis. When this happens, likely, a small area of tumour capsule invasion was not seen when the tumour was examined. In this situation, the original diagnosis may need to be changed.

What causes non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP)?

The specific causes of NIFTP, like many thyroid tumours, are not fully understood. However, it is believed that genetic mutations and environmental factors may play a role in its development. Exposure to radiation, particularly during childhood, is a known risk factor for thyroid tumours in general.

What are the symptoms of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP)?

NIFTP often does not present with any specific symptoms and is usually discovered incidentally during imaging studies for other reasons or as a palpable thyroid nodule during a physical examination. When symptoms do occur, they may include a noticeable lump in the neck, difficulty swallowing or breathing, or voice changes. However, these symptoms are not unique to NIFTP and can be associated with various thyroid conditions.

How is this diagnosis made?

The diagnosis of NIFTP can only be made after the entire tumour is removed and sent for examination under the microscope by a pathologist. This examination needs to be performed to make sure that the tumour cells do not cross the tumour capsule or spread into the normal surrounding thyroid tissue. The diagnosis cannot be made after a small tissue sample is removed from the thyroid gland in a procedure called fine-needle aspiration.

Microscopic features

When examined under the microscope, the tumour cells in NIFTP are often separated from the surrounding normal thyroid gland by a thin tissue barrier called a tumour capsule. If no capsule is seen, the tumour cells should still be separated from the normal thyroid gland by a small space.

Like the normal thyroid gland, NIFTP is made up of follicular cells that connect to form follicles. The term “papillary-like nuclear features” means that the tumour cells resemble the cells seen in another type of thyroid cancer called papillary thyroid carcinoma. These features which involve the nucleus of the cell (the part of the cell that holds the genetic material) include chromatin clearing (the nucleus looks clear or white), nuclear enlargement (the nucleus is larger than normal), irregular nuclear membranes (the outer layer of the nucleus is not smooth), and crowding (adjacent nuclei are overlapping or touching each other).

Genetic Alterations in non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP)

Several genetic alterations have been identified in NIFTP, which help differentiate it from more aggressive thyroid cancers:

• RAS mutations: The most common genetic changes found in NIFTP are mutations in the RAS family of genes. These mutations are also seen in other types of benign and malignant thyroid tumours.
• BRAF V600E mutations: While BRAF V600E mutations are commonly associated with more aggressive papillary thyroid carcinomas, their presence in NIFTP is rare. The absence of BRAF V600E mutations is one of the features that help in distinguishing NIFTP from more aggressive forms of thyroid cancer.
• PIK3CA and TERT promoter mutations: These mutations are less commonly associated with NIFTP and are more often found in aggressive thyroid cancers. Their presence in a thyroid nodule would likely argue against a diagnosis of NIFTP.

It’s important to note that the diagnosis of NIFTP is primarily based on histopathological examination, which involves a detailed microscopic examination of the tumour cells and their architecture. The presence of specific genetic alterations can support the diagnosis but is not solely determinative.

Lymphatic invasion

​Lymphatic invasion means that tumour cells were seen inside a lymphatic vessel. Lymphatic vessels are small hollow tubes that allow the flow of a fluid called lymph from tissues to immune organs called lymph nodes. Lymphatic invasion should not be seen in NIFTP.

Vascular invasion (angioinvasion)

​Vascular invasion (also called angioinvasion) is the spread of tumour cells into a blood vessel. Blood vessels carry blood around the body. Vascular invasion should not be seen in NIFTP.

Margins

​In pathology, a margin refers to the edge of tissue removed during tumour surgery. The margin status in a pathology report is important as it indicates whether the entire tumour was removed or if some was left behind. This information helps determine the need for further treatment.

Pathologists typically assess margins following a surgical procedure like an excision or resection, aimed at removing the entire tumour. Margins aren’t usually evaluated after a biopsy, which removes only part of the tumour. The number of margins reported and their size—how much normal tissue is between the tumour and the cut edge—vary based on the tissue type and tumour location.

Pathologists examine margins to check if tumour cells are present at the tissue’s cut edge. A positive margin, where tumour cells are found, suggests that some tumour cells may remain in the body. In contrast, a negative margin, with no tumour cells at the edge, suggests the tumour was fully removed. Some reports also measure the distance between the nearest tumour cells and the margin, even if all margins are negative.