Thyroid nodules are common, affecting a significant portion of the population. The initial evaluation of these nodules typically involves a physical examination, thyroid function tests, and an ultrasound to visualize the nodule’s characteristics. If the nodule appears suspicious based on its size or ultrasound features, a fine-needle aspiration (FNA) biopsy is often performed to collect cells for examination under a microscope. This process helps determine if the nodule is benign or malignant, guiding subsequent management decisions.
Understanding Thyroid Atypia of Undetermined Significance (AUS/FLUS)
A diagnosis of Atypia of Undetermined Significance (AUS) or Follicular Lesion of Undetermined Significance (FLUS) arises from a fine-needle aspiration biopsy of a thyroid nodule. This classification indicates that cells show atypical features, but are not distinct enough for a definite cancer diagnosis, nor are they clearly benign. Pathologists observe cellular irregularities that fall into an indeterminate category.
This diagnostic category is formally known as Category III within The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). The Bethesda System provides a standardized framework for interpreting thyroid biopsy results, classifying nodules into six categories based on their risk of malignancy. AUS/FLUS represents a heterogeneous group of thyroid lesions, positioned between benign and malignant diagnoses. This indeterminate nature signifies a degree of uncertainty, requiring additional evaluation to refine the risk assessment and guide patient care.
Quantifying the Malignancy Risk
The risk of malignancy associated with an AUS/FLUS diagnosis, as defined by Bethesda Category III, has historically been cited within a range of 5-15%. However, more recent studies have suggested that the actual malignancy rates can be higher, with some reports indicating ranges from 26.6% to 37.8%, and even up to 38% to 55% in certain comprehensive cancer centers. The 2017 Bethesda System estimates a malignancy risk of approximately 6-18% when non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is not considered malignant, and around 10-30% when NIFTP is included as malignant.
This risk is not static and can be influenced by several factors. Suspicious features identified during the initial ultrasound examination play a significant role in modifying the risk estimate.
Ultrasound Features
Irregular margins
Microcalcifications
Hypoechogenicity (appearing darker than surrounding tissue)
Increased vascularity within the nodule
Nodules that are “taller than wide”
Patient history can also contribute to the risk assessment.
Patient History Factors
Prior radiation exposure
Family history of thyroid cancer
Younger patient age
Additionally, the specific cytological features observed by the pathologist, such as the presence of nuclear atypia, can indicate a higher risk compared to other atypical patterns. Considering these combined factors helps to provide a more tailored risk stratification for each individual.
Advanced Diagnostic Tools
Following an initial AUS/FLUS diagnosis, several diagnostic approaches are employed to further clarify the malignancy risk. One common approach is a repeat fine-needle aspiration (FNA) biopsy, often recommended within 3 to 6 months. A repeat FNA can reclassify a significant portion of AUS/FLUS nodules, with studies showing that about 55% may be reclassified as benign, while a smaller percentage (around 6%) may be identified as malignant or suspicious for malignancy. However, approximately 26-30% of nodules may still remain in the indeterminate AUS/FLUS category after a repeat biopsy.
Molecular testing has emerged as a significant tool in assessing the risk of malignancy in AUS/FLUS nodules. These tests analyze genetic mutations or gene expression patterns within the thyroid cells obtained from the FNA sample. By identifying specific genetic markers, such as the BRAF V600E mutation, these tests can provide a more precise risk stratification, indicating either a low or high probability of malignancy. Molecular tests can help guide decisions by potentially reducing the number of unnecessary surgeries for benign nodules.
The initial ultrasound findings and the patient’s overall clinical picture are continuously integrated with the biopsy results and any molecular test outcomes. For instance, a nodule with highly suspicious ultrasound features that is classified as AUS/FLUS on FNA might prompt molecular testing or a repeat FNA to confirm the risk.
Management Pathways
Based on the refined risk assessment derived from advanced diagnostic tools, management pathways for AUS/FLUS nodules are highly individualized. For cases where the risk of malignancy is reclassified as low, active surveillance is a common strategy. This approach involves regular ultrasound monitoring of the nodule, typically every 6 to 12 months, along with ongoing clinical follow-up to observe for any changes in size or characteristics. Active surveillance aims to avoid unnecessary procedures for nodules that are unlikely to be cancerous or are slow-growing.
For nodules reclassified as higher risk, or when the indeterminate nature persists after further diagnostic evaluation, diagnostic surgery may be recommended. This often involves a thyroid lobectomy, where only the lobe containing the nodule is removed, allowing for a definitive pathological diagnosis. In some instances, a total thyroidectomy, involving the removal of the entire thyroid gland, may be considered, particularly if the risk of malignancy is substantial or if there are other concerning features. The choice between lobectomy and total thyroidectomy depends on the specific risk profile and extent of potential disease.
The final management decision is a collaborative process between the patient and their healthcare team, taking into account all factors. Patient preferences, other health conditions (comorbidities), and the specific risk profile of the nodule all contribute to determining the most appropriate course of action.