This comprehensive review explains that thyroid nodules are extremely common, with most being benign, but proper evaluation is crucial to rule out cancer (present in 4.0-6.5% of nodules). The article details a step-by-step diagnostic approach starting with a physical exam and blood tests, followed by ultrasound imaging, and potentially a fine needle aspiration (FNA) biopsy, which is the gold standard test. It also covers new molecular tests that can help with uncertain biopsy results and provides clear management guidelines based on the specific findings for each patient.

A Patient's Guide to Thyroid Nodules: Modern Diagnosis and Management

Table of Contents

• Background: Understanding Thyroid Nodules
• Diagnosis and Evaluation of Thyroid Nodules
• History and Physical Examination
• Laboratory Tests
• Imaging Studies
• Fine Needle Aspiration Biopsy (FNA)
• Understanding Your Cytology (Biopsy) Results
• New Molecular Marker Tests
• Management and Treatment Options
• Conclusion and Key Takeaways
• Source Information

Background: Understanding Thyroid Nodules

A thyroid nodule is a distinct lump or lesion within the thyroid gland that can be seen as separate from the rest of the thyroid tissue on imaging scans. These nodules are incredibly common, but how often they are found depends greatly on the method used to look for them.

During a physical exam where a doctor feels the neck (palpation), nodules are found in 2–6% of people. However, when using more sensitive ultrasound technology, the discovery rate jumps to 19–35%. Autopsy studies show that many people have nodules that were never detected during their life, with prevalence rates ranging from 8% to a staggering 65%.

Most patients discover a nodule themselves, or a clinician finds it during a routine exam. A growing number are found incidentally—meaning by accident—when a patient gets an imaging test like an ultrasound, CT scan, MRI, or PET scan of the neck for another reason. The main goals of evaluating a nodule are to rule out thyroid cancer (which is found in 4.0 to 6.5% of all nodules), determine if it is overproducing thyroid hormone, and check if it is large enough to cause symptoms like trouble swallowing.

Diagnosis and Evaluation of Thyroid Nodules

Thyroid nodules can be caused by a variety of conditions, both benign (non-cancerous) and malignant (cancerous). It's important for patients to understand the possibilities to contextualize their own diagnosis.

Common benign causes include colloid nodules, Hashimoto’s thyroiditis, simple cysts, follicular adenomas, and subacute thyroiditis. The cancerous causes include several types of thyroid cancer:

• Papillary Cancer (the most common type)
• Follicular Cancer
• Hurthle Cell (oncocytic) Cancer
• Anaplastic Cancer
• Medullary Cancer
• Thyroid Lymphoma
• Cancers that have spread from other parts of the body (with kidney, lung, and head/neck cancers being the most common sources)

The initial evaluation for any patient with a thyroid nodule must include a detailed history and physical exam. The first lab test should always be a measurement of serum Thyroid-Stimulating Hormone (TSH). A thyroid ultrasound is also essential for all patients to confirm the nodule's presence and characteristics. For nodules that meet certain size and appearance criteria, the next step is a fine needle aspiration (FNA) biopsy.

History and Physical Examination

Your doctor will take a comprehensive history, focusing specifically on risk factors that can increase the chance a nodule is cancerous. It is vital to tell your doctor if any of the following apply to you, as they significantly increase malignancy risk:

• History of childhood head or neck irradiation
• Total body irradiation for a bone marrow transplantation
• Exposure to ionizing radiation from fallout in childhood or adolescence
• Family history of papillary thyroid cancer (PTC), medullary thyroid cancer (MTC), or a known thyroid cancer syndrome (e.g., Cowden’s syndrome, familial polyposis, Carney complex, Multiple Endocrine Neoplasia [MEN] 2, Werner syndrome)
• A nodule that is enlarging or growing rapidly
• The presence of swollen cervical lymph nodes
• A nodule that feels fixed to the surrounding tissue
• Vocal cord paralysis or a new hoarse voice

You will also be asked about symptoms of an underactive or overactive thyroid and local pressure symptoms like difficulty swallowing, trouble breathing, a persistent cough, or a change in your voice. The physical exam will assess the size, texture, and features of the nodule and check the neck lymph nodes. Smaller nodules (usually under 1 cm) or those located deep in the neck can be difficult to feel during an exam.

Laboratory Tests

Serum TSH: This is a critical first test for all patients with a thyroid nodule. If your TSH level is low, it suggests your thyroid may be overactive, and the next step is a radionuclide thyroid scan. Importantly, research shows that a TSH level that is high, or even at the high end of the normal range, is associated with an increased risk and a more advanced stage of cancer if a nodule is malignant.

Serum Calcitonin: The routine use of this test is controversial. Some studies, mostly from Europe, suggest it can help find medullary thyroid cancer (MTC) earlier, but these often used a drug called pentagastrin to make the test more accurate, which is not available in the U.S. The test can have false positives due to other conditions and medications, and false negatives can occur in rare cases. Therefore, major guidelines do not have a definite recommendation for or against its routine use.

Serum Thyroglobulin (Tg): This test is not recommended for evaluating a new thyroid nodule. Thyroglobulin can be elevated in many benign thyroid conditions and is neither sensitive nor specific enough to reliably diagnose cancer.

Serum TPO Antibodies: This test, which checks for autoimmune thyroid disease, is also not necessary for the initial evaluation of a thyroid nodule.

Imaging Studies

Radionuclide Thyroid Scan (Scintigraphy): This test is only used if your TSH level is low. It determines if the nodule is "autonomous" or hyperfunctioning (overproducing hormone). The scan uses a small amount of radioactive iodine or technetium. Nodules are classified as:

• Hot: Uptake is greater than normal tissue (very low cancer risk).
• Warm: Uptake is equal to normal tissue.
• Cold: Uptake is less than normal tissue (higher cancer risk, but most are still benign).

Thyroid Sonography/Ultrasound: This is a non-invasive, essential imaging test for any patient with a known or suspected nodule. It provides detailed information about the nodule itself and the surrounding neck structures. The ultrasound assesses:

• Size and location
• Composition (solid, cystic, or mixed)
• Echogenicity (how bright or dark it appears)
• Margins (smooth or irregular)
• Presence of calcifications (small specks of calcium)
• Shape (whether it is taller than it is wide)
• Blood flow (vascularity)

Certain features on ultrasound are strongly associated with a higher risk of cancer. These suspicious characteristics include:

• A shape that is taller than it is wide (the feature with the highest predictive value)
• Solid and hypoechoic (darker than surrounding tissue)
• Irregular or blurry margins
• Microcalcifications (tiny white specks)
• No visible halo around the nodule

Fine Needle Aspiration Biopsy (FNA)

FNA is the gold standard procedure for evaluating thyroid nodules. It is a safe, accurate, and cost-effective office procedure where a thin needle (23 to 27 gauge) is used to extract cells from the nodule for examination under a microscope. It can be done by feeling the nodule (palpation-guided) or, more commonly and accurately, using ultrasound guidance to see the needle in real-time. Ultrasound guidance is preferred, especially for nodules that are difficult to feel, mostly cystic, or located at the back of the gland.

The decision to perform a biopsy is based primarily on the nodule's size and its ultrasound appearance. Current guidelines recommend a conservative approach to avoid unnecessary procedures. The general recommendations are:

• Biopsy Recommended:
  • Nodules ≥1 cm with intermediate or high suspicion ultrasound patterns.
  • Nodules ≥1.5 cm with low suspicion ultrasound patterns.
  • Nodules ≥2 cm with very low suspicion patterns (like spongiform); observation is also an option here.
• Biopsy Not Required: Nodules that do not meet the above criteria, including most nodules smaller than 1 cm and purely cystic nodules.

There are important exceptions. A biopsy should be considered for any sized nodule if there are suspicious lymph nodes in the neck or if the patient has significant high-risk clinical factors. Additionally, nodules discovered on a PET scan (which are "PET-positive") have a high cancer rate of 40-45%, so a biopsy is recommended if they are larger than 1 cm.

Understanding Your Cytology (Biopsy) Results

The cells from your FNA are analyzed by a cytopathologist and reported using a standardized system, most commonly the Bethesda System. This system places results into one of six categories, each with a specific risk of malignancy and recommended next steps:

1. Nondiagnostic or Unsatisfactory (1-4% cancer risk): The sample didn't have enough cells for a diagnosis. This happens in about 15% of biopsies and is often due to a very cystic nodule or a bloody sample. The usual next step is a repeat ultrasound-guided FNA.
2. Benign (0-3% cancer risk): This is the most common result, found in about 70% of biopsies. It includes conditions like colloid nodules and thyroiditis. No immediate further testing or surgery is needed, but ongoing ultrasound monitoring is recommended.
3. Follicular Lesion of Undetermined Significance (FLUS) or Atypia of Undetermined Significance (AUS) (5-15% cancer risk): This "indeterminate" category means the cells look atypical but aren't clearly benign or cancerous. It accounts for 10-15% of biopsies and presents a management challenge.
4. Follicular Neoplasm or Suspicious for a Follicular Neoplasm (FN/SFN) (15-30% cancer risk): Another indeterminate category where the cells look like they could be a follicular tumor. The only way to know if it's benign (adenoma) or cancerous (carcinoma) is to surgically remove it and examine the entire capsule surrounding the nodule.
5. Suspicious for Malignancy (60-75% cancer risk): The cells are highly suspicious for cancer but not absolutely diagnostic. Diagnostic surgery is almost always recommended.
6. Malignant (97-99% cancer risk): The cells are diagnostic of cancer, most commonly papillary thyroid carcinoma. Surgery is required.

New Molecular Marker Tests

For the indeterminate categories (Bethesda categories III and IV), new molecular tests have been developed to provide more information and help patients and doctors decide between surgery and monitoring. These tests are run on cells collected during the FNA.

Afirma Gene Expression Classifier (GEC): This test analyzes the mRNA of 167 genes. It acts as a "rule-out" test with a high sensitivity of 92% and a high negative predictive value of 93%. This means if the test result is "benign," there is a 93% chance the nodule is truly not cancerous. However, its positive predictive value is low (48-53%), so a "suspicious" result is less reliable. A benign GEC result still carries about a 5% risk of malignancy.

7-Gene Genetic Mutation Panel: This test looks for specific mutations (in genes like BRAF, RAS) and rearrangements known to be associated with thyroid cancer. It acts as a "rule-in" test with very high specificity (86-100%) and a very high positive predictive value (84-100%). If this test is positive, there is a very high chance the nodule is cancerous.

It is crucial to understand that these are supplementary tests. None can decisively confirm or rule out cancer with 100% accuracy in all cases. Their performance can also vary based on how common cancer is in the population being tested. These tests are expensive, and current guidelines note that they can be considered but do not strongly recommend for or against their routine use. The field is evolving rapidly, and these recommendations may change.

Management and Treatment Options

Management is tailored to the individual based on their TSH level, risk factors, nodule size, ultrasound features, and most importantly, the FNA biopsy results.

Hyperfunctioning (Autonomous) Nodules: If the nodule is causing hyperthyroidism (overactive thyroid), treatment options include radioactive iodine therapy or surgery. If it's only causing a slightly low TSH (subclinical hyperthyroidism), treatment depends on the patient's age and risk for complications like atrial fibrillation or osteoporosis.

Benign Nodules: Most patients with a benign biopsy do not need surgery. They enter a surveillance program with periodic thyroid ultrasounds. The frequency of monitoring depends on the initial ultrasound appearance:

• High suspicion pattern: Repeat ultrasound and possibly FNA within 12 months.
• Low/Intermediate suspicion pattern: Repeat ultrasound in 12-24 months.
• Very low suspicion pattern (e.g., spongiform): Repeat ultrasound at 24 months or longer.

Indeterminate Nodules (FLUS/AUS and FN/SFN): This is where decision-making gets more complex. Options include:

• Repeat FNA: Can provide a more definitive diagnosis in some cases.
• Molecular Testing: As discussed, can help estimate cancer risk to guide the choice between surgery and monitoring.
• Diagnostic Surgery: Removing half (lobectomy) or all (total thyroidectomy) of the thyroid gland is a definitive way to get a diagnosis, as the entire nodule can be examined by a pathologist.

Suspicious or Malignant Nodules: Surgery is the standard treatment for these diagnoses. The extent of surgery (lobectomy vs. total thyroidectomy) depends on the type and size of the cancer, patient age, and other factors.

Conclusion and Key Takeaways

Thyroid nodules are a common medical finding, and the vast majority are benign. The modern approach to diagnosis is highly structured, relying on ultrasound characteristics and FNA biopsy to stratify risk and guide management. For patients, the most important steps are undergoing a proper initial evaluation and understanding their specific biopsy results.

The emergence of molecular testing offers new tools for managing the challenging "indeterminate" biopsy results, though they are not yet perfect or universally recommended. Ultimately, the management plan should be a shared decision between the patient and their endocrinologist, considering all the clinical, imaging, and cytological information available.

Source Information

Original Article Title: Thyroid nodule update on diagnosis and management
Authors: Shrikant Tamhane and Hossein Gharib
Publication: Tamhane and Gharib, Clinical Diabetes and Endocrinology (2016) 2:17
Note: This patient-friendly article is based on peer-reviewed research and aims to comprehensively translate the original scientific content for educational purposes.