Classical options were to observe the nodule closely with repeat ultrasounds and consider surgery if any changes / growth was noted vs surgery upfront to get a definitive diagnosis.
More recently molecular analysis studies have become available to help further rule out the risk for cancer.
Instead of describing how thyroid cells grossly appear under a microscope, molecular analyses look much deeper into the cells for DNA mutations, gene rearrangements, and changes to microRNA (miRNA) expression profiles which are the root causes for cells to become malignant.
- Examples in the U.S. include ThyroSeq, ThyGeNEXT + ThyraMIR, and Afirma.
Molecular analysis works best to rule out cancer for Bethesda III – Atypia of Undetermined Significance (AUS) and Bethesda IV – Follicular Neoplasm (FN), where the relative risk for cancer is low (16 and 23%, respectively).
- When no abnormalities are found, the risk for cancer is typically very low, ranging from ~1-5%, making it much safer to recommend ultrasound surveillance moving forward.
- ~65% of Bethesda III (AUS) and IV (FN) end up testing negative for malignancy.
- If abnormalities are discovered, typically the risk for cancer is >50-60% and the recommendation for surgery is more confident.
- Occasionally the results are not conclusive enough to decrease or increase the % risk prior to the analysis, and the decision to observe vs operate becomes an individualized one for the patient.
- A special note on RAS mutations:
- Unlike other DNA alterations causing thyroid cancers, the presence of a RAS DNA mutation does not always mean the nodule is cancerous at the time of the biopsy.
- Instead, the presence of a RAS mutation indicates the nodule will always have the potential to become cancerous and at time of the diagnosis can exist anywhere along the progression of a benign thyroid nodule to thyroid cancer: Benign follicular adenoma -> pre-cancerous NIFTP -> Follicular Thyroid Cancer (FTC) or Follicular Variant of Papillary Thyroid Cancer (fvPTC).
- Therefore, when RAS mutations are present on molecular analysis, the nodule in question has the potential to be cancerous at that time of diagnosis, or if not cancerous at that time, a high risk of developing into cancer in the future if not removed surgically.
- Additional RNA testing with some molecular analyses can further rule out the presence of cancer at the time of biopsy.
- Surgery (especially if the patient is younger or the nodule has been growing) or an intensified ultrasound surveillance program should be heavily considered when RAS mutations are identified.
- The widespread availability of molecular analysis over recent years has substantially decreased the number of ‘diagnostic’ thyroid surgeries that were previously being performed.
Molecular analysis is not as effective for and should not be used to rule out cancer with a Bethesda V – Suspicious for Malignancy diagnosis, where the risk for cancer is already very high (65%).
Sometimes molecular analysis can be considered when the diagnosis is Malignant:
- The purpose would not be to rule out cancer, but instead to identify changes associated with aggressively behaving cancers which would then impact a patient’s decision for active surveillance, extent of surgery, use of radioactive iodine (RAI) following surgery, and potential targeted molecular therapies for distant metastatic spread.
- Low risk DNA alterations:
- RAS and RAS-like mutations (NRAS, KRAS, HRAS, PAX8/PPARG); gene expression alterations (e.g. PTEN mutations, PPARG fusion); copy number alterations of a focal chromosol type.
- Intermediate risk DNA alterations:
- BRAF V600E mutations; BRAF-like mutations and gene fusions (e.g. RET fusions, RET/PTC); copy number alterations of genome haploidization (GH) type.
- High risk DNA alterations:
