What Does an NRAS Mutation in a Thyroid Nodule Mean?

A gene is a segment of DNA that holds the instructions for building the proteins that make our bodies work. Occasionally, a gene can undergo a change, known as a mutation, which alters these instructions. The NRAS gene belongs to a family of genes called RAS, which play a part in regulating how cells grow and divide. When a mutation occurs in the NRAS gene within the thyroid—a gland in the neck that controls metabolism—it can lead to the formation of a thyroid nodule, or a lump in the gland.

The Function of the NRAS Gene in Thyroid Cells

In a healthy thyroid, the NRAS gene produces a protein that acts like a switch for cell growth. It receives signals from outside the cell that tell it when to turn “on,” prompting the cell to divide, and when to turn “off.” This controlled process ensures that new cells are made only when needed to replace old ones, maintaining the thyroid’s normal structure and function.

A mutation can cause this finely tuned NRAS switch to become stuck in the “on” position. This is similar to a car’s gas pedal getting stuck, causing the engine to keep running at full throttle. When the NRAS protein is permanently activated, it continuously tells the thyroid cells to grow and divide, disrupting the normal balance of cell turnover.

The result of this uncontrolled proliferation is the formation of a thyroid nodule, which is a localized growth of cells. These cells accumulate, creating a lump that can sometimes be felt in the neck or seen on imaging scans. The specific type of growth that develops depends on other cellular and genetic factors.

Diagnosis and Molecular Testing

The discovery of an NRAS mutation often begins with the detection of a thyroid nodule, either by the individual, a doctor during a physical exam, or incidentally during an imaging test. The standard next step is a procedure called fine-needle aspiration (FNA). During an FNA, a doctor uses a very thin needle to withdraw a small sample of cells from the nodule for examination under a microscope.

In many cases, the pathologist can determine if the nodule is benign (non-cancerous) or malignant (cancerous). However, in about 20-30% of cases, the FNA results are “indeterminate,” meaning the cells have features that are not clearly benign or malignant. Categories such as Atypia of Undetermined Significance (AUS) or Follicular Lesion of Undetermined Significance (FLUS) indicate this uncertainty.

This diagnostic ambiguity is where molecular testing becomes valuable. For nodules with indeterminate cytology, the cell sample collected during the FNA can be sent for further analysis to look for specific genetic mutations. Tests like ThyroSeq or Afirma analyze the DNA and RNA from the nodule’s cells to identify mutations in genes known to be involved in thyroid cancer, including NRAS, HRAS, and BRAF.

Finding an NRAS mutation provides more precise information about the nodule’s potential behavior. The presence of an NRAS mutation in a cytologically indeterminate nodule can increase the likelihood of malignancy, helping to guide the next steps in management and treatment.

Thyroid Conditions Associated with NRAS Mutations

Discovering an NRAS mutation in a thyroid nodule does not automatically mean a person has cancer. The mutation is linked to a spectrum of thyroid conditions, ranging from completely benign growths to low-risk cancers. The most common possibilities include follicular adenomas, which are non-cancerous tumors that do not invade surrounding tissues.

Another possibility is a low-risk neoplasm called Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features (NIFTP). NIFTPs were once classified as a type of cancer but were reclassified because they have an extremely low risk of adverse outcomes. These tumors are encapsulated and do not show invasive behavior.

An NRAS mutation can also be found in malignant tumors, most commonly follicular thyroid cancer and the follicular variant of papillary thyroid cancer (FVPTC). These are considered differentiated thyroid cancers, which means the cancer cells still resemble normal thyroid cells to some extent. They tend to be slow-growing and are often confined to the thyroid gland.

Management and Treatment Approaches

The management plan for an NRAS-positive thyroid nodule is tailored to the individual, based on the specific diagnosis, nodule size, and other clinical factors. One option, particularly for small, slow-growing nodules that are likely benign or very low-risk, is active surveillance. This involves monitoring the nodule with regular ultrasounds to ensure it is not growing or changing in a concerning way.

For nodules where the risk of malignancy is higher or for those that are causing symptoms, surgery is the primary treatment. A thyroid lobectomy, the removal of one half of the thyroid gland, is a common approach. This procedure can be both diagnostic, providing a definitive pathologic diagnosis, and therapeutic, removing the nodule entirely. If the final pathology confirms a low-risk cancer, a lobectomy is often sufficient treatment.

In cases where the nodule is larger, shows signs of spreading, or if the final pathology indicates a more aggressive cancer, a total thyroidectomy might be recommended. Knowing a nodule is NRAS-positive helps doctors and patients decide on surgery, such as a lobectomy, to get a definitive diagnosis and treatment at the same time.

Prognosis for NRAS-Positive Thyroid Nodules

The long-term outlook for an NRAS-mutated thyroid nodule is very favorable. Many of these nodules are benign or low-risk neoplasms like NIFTP, which have an excellent prognosis following removal. Even when the nodule is malignant, the associated cancers are usually slow-growing and have a high cure rate with appropriate treatment.

Studies show that patients treated for these types of cancers have high survival rates, with no recurrence or metastasis detected during long-term follow-up after surgery. The presence of an NRAS mutation alone is not associated with aggressive tumor behavior.