A Practical Guide to Biomarkers for Thyroid Cancer

If you've ever had a thyroid nodule flagged on ultrasound or a lab result that made your stomach drop, you're not alone. Thyroid cancer is common, usually slow-growing, and increasingly diagnosed through routine imaging. The good news: modern biomarkers make it far easier to figure out which nodules are harmless, which cancers need treatment, and how well treatment worked.¹ Think of biomarkers as the dashboard on your car: numbers and signals, each telling you something specific, but only truly useful when read together.

What we mean by "biomarkers" in thyroid cancer

A biomarker is any measurable signal that reflects a biological process. In thyroid cancer, biomarkers help at three main moments: deciding which nodules need a biopsy, clarifying diagnosis when biopsy is inconclusive, and tracking for recurrence after treatment.² Some are blood tests, some come from a fine-needle aspiration (FNA) sample, and some are taken from imaging that behaves like a functional test.

There are several types of thyroid cancer, and each leans on different biomarkers:

• Differentiated thyroid cancer (DTC): papillary and follicular types
• Medullary thyroid cancer (MTC)
• Anaplastic thyroid cancer (ATC)

Knowing the subtype matters because it changes which biomarkers are useful and how they're interpreted.³

The first fork in the road: ultrasound and TSH

Most thyroid cancers begin as nodules found by chance. Your first biomarker is usually not a blood test, but the ultrasound pattern itself. Radiologists use systems like TI-RADS or ATA ultrasound patterns to estimate malignancy risk based on features such as microcalcifications, irregular margins, solid structure, marked hypoechogenicity, a taller-than-wide shape, and suspicious lymph nodes.⁴ ⁵ These features don't diagnose cancer on their own; they rank risk and guide whether a nodule should be biopsied and at what size threshold.

Alongside imaging, thyroid-stimulating hormone (TSH) provides context.¹ TSH nudges thyroid cells to grow and make hormone. Higher TSH within the reference range is associated with a slightly higher risk that a nodule is malignant in some studies, while a low TSH suggests an overactive nodule that is rarely cancerous. TSH also becomes important later when personalizing follow-up, because your care team may adjust TSH targets to match your risk level after treatment.

Fine-needle aspiration: the cornerstone test

If ultrasound suggests a nodule deserves a closer look, the next step is a fine-needle aspiration. FNA draws out cells for a pathologist to review. Results are reported using the Bethesda System, which groups findings into categories from benign to malignant, with two "gray zones" in the middle that are called indeterminate.² Here's why that matters:

• Benign: routine follow-up per ultrasound risk
• Malignant or suspicious for malignancy: surgery is usually recommended
• Indeterminate (AUS/FLUS or follicular neoplasm): risk varies

Indeterminate results used to lead to a lot of diagnostic surgeries. Now, molecular testing on the same FNA sample can clarify the risk and help avoid unnecessary operations.⁶

Molecular testing on indeterminate nodules

When cytology is unclear, molecular testing looks for gene mutations, fusions, or gene expression patterns associated with cancer. Two broad approaches are used:² ⁷

• Mutation and fusion panels: identify changes like BRAF V600E, RAS mutations, RET or NTRK fusions, and TERT promoter variants
• Gene expression classifiers: analyze RNA expression patterns to estimate the likelihood of benign behavior

Mutation panels tend to be "rule-in" tools: finding a strongly oncogenic mutation (for example, BRAF V600E in a papillary pattern) raises the probability of cancer and can support proceeding to surgery. Gene expression classifiers tend to be "rule-out" tools: a benign expression signature can safely support observation.⁶ Large validation studies have shown that these tools reduce diagnostic surgery for benign nodules, though performance varies across assays and institutions, and results need to be interpreted alongside ultrasound and clinical context.

Molecular results can also forecast behavior. Certain combinations, like TERT promoter changes with BRAF or RAS, are linked to more aggressive disease.⁸ That kind of genomic "weather report" becomes useful when planning surgery extent and follow-up intensity.

Biomarkers by thyroid cancer type

Differentiated thyroid cancer (papillary and follicular)

For DTC, the workhorse biomarkers are thyroglobulin and anti-thyroglobulin antibodies after surgery, with selective use of molecular markers up front to refine risk.⁹

Before surgery

• Molecular markers on FNA can help confirm cancer and anticipate aggressiveness. BRAF V600E is common in papillary thyroid cancer; RAS mutations are more typical in follicular-pattern lesions.⁸ ¹⁰
• Ultrasound features and FNA remain the central diagnostic tools.

After surgery

• Thyroglobulin (Tg): a protein made by normal thyroid cells and most DTC cells. After total thyroidectomy (and if radioiodine ablation is performed), Tg should be very low or undetectable.⁹ ¹¹ Detectable or rising Tg suggests residual thyroid tissue or recurrent disease.
• Anti-thyroglobulin antibodies (TgAb): these antibodies can interfere with Tg assays and falsely lower or elevate readings, depending on the method.⁹ If TgAb are present, their trend becomes a surrogate marker. Falling antibodies suggest less tumor burden; rising antibodies raise suspicion for residual disease.
• TSH: personalized targets for TSH suppression are based on recurrence risk. The goal is to reduce the stimulus for any remaining thyroid cancer cells.

A practical analogy: Tg is a smoke alarm for differentiated thyroid cancer after thyroid tissue is removed. If the alarm is quiet and stays quiet, you breathe easier. If it starts to chirp upward, your team looks for the source.

Imaging as a functional biomarker

• Radioiodine scans take advantage of thyroid cells' iodine-handling machinery. If your tumor cells still trap iodine, radioiodine can both image and treat them. A positive scan plus a rising Tg suggests iodine-avid disease that may respond to radioiodine; a rising Tg with a negative scan can prompt other imaging.
• FDG PET-CT becomes more informative when tumors lose iodine avidity. In that scenario, PET positivity correlates with a higher risk of progression.

Medullary thyroid cancer

Medullary thyroid cancer comes from C cells, which make calcitonin. Its biomarker toolkit is unique:

• Calcitonin: the primary marker for MTC. Levels correlate with tumor burden; the doubling time over months to years is a strong prognostic signal.¹² ¹³
• Carcinoembryonic antigen (CEA): a secondary marker that often tracks with calcitonin, especially in advanced disease.¹²
• RET genetic testing: all patients with MTC should be evaluated for germline RET variants, because some cases are part of a hereditary syndrome (MEN2).³ Finding a germline variant affects family screening and surgical planning.

Controversy you should know: routine calcitonin screening for all thyroid nodules is standard in parts of Europe but not universally recommended in the United States. Instead, it's often used selectively based on ultrasound, cytology, or family history. Guidelines differ by region, so your care team will tailor the approach.

Anaplastic thyroid cancer

Anaplastic thyroid cancer is rare and aggressive. Traditional thyroid biomarkers like Tg and calcitonin are not useful here. Molecular profiling looks for alterations such as BRAF V600E, TP53, or TERT promoter changes to guide systemic therapy choices.⁸ Imaging and clinical course dominate decision-making.

Putting the biomarkers to work after treatment

After surgery for differentiated thyroid cancer, your clinician will typically establish a new baseline over the first several months. This is when Tg, TgAb, TSH, and imaging settle into a pattern. From there, the story is told by trends, not single snapshots.

For differentiated thyroid cancer

• Undetectable Tg (with negative TgAb) suggests no residual disease. Continued low or undetectable levels are reassuring.⁹ ¹¹
• Detectable but low Tg that stays stable can be watched with ultrasound and labs. Some remnant thyroid tissue can persist without clinical significance.
• Rising Tg prompts a search for where, using neck ultrasound first, then targeted cross-sectional imaging or radioiodine or PET depending on iodine avidity and risk profile.
• If TgAb are present, their slope is the signal. Declining antibodies over time usually parallel favorable response; rising antibodies prompt closer imaging.

For medullary thyroid cancer

• Calcitonin and CEA are followed at regular intervals. The actual number matters less than the doubling time.¹² ¹³ Short doubling times suggest more active disease.
• Neck ultrasound and cross-sectional imaging are used when markers rise or symptoms appear.

One practical tip: stick with the same lab and assay whenever possible. Different assays have different calibration, especially for Tg and calcitonin. Consistency makes your trend line trustworthy.

When imaging itself behaves like a biomarker

Ultrasound is the frontline tool for the neck. Postoperative ultrasound looks for suspicious lymph nodes and thyroid bed changes. Subtle clues matter: microcalcifications in a lymph node, rounded shape, lost fatty hilum, or cystic change can suggest metastatic spread.⁴ When the lab signal nudges higher, ultrasound is the first "flashlight" we shine.

Beyond the neck, CT or MRI evaluates deeper or chest structures when risk increases. Radioiodine whole-body scans identify iodine-avid disease in DTC. FDG PET-CT acts as a metabolic readout in more aggressive or radioiodine-refractory disease. These aren't random images; they are chosen to answer specific questions that arise from lab trends.

Assay pitfalls and how to avoid being fooled

All tests live in the real world, and the real world is messy. Three common issues can trip up interpretation:

• Biotin interference: High-dose biotin in hair, skin, and nail supplements can make some immunoassays read falsely high or low. Many prenatal or beauty supplements contain biotin at levels high enough to interfere. If a result looks out of character, your team may ask about supplements and repeat the test after a pause.
• Anti-thyroglobulin antibodies: TgAb can mask true Tg levels.⁹ If TgAb are present, labs often report both Tg and TgAb, and clinicians rely on trends or use mass spectrometry-based Tg assays in select cases to avoid antibody interference.
• Heterophile antibodies and assay differences: Rarely, nonspecific antibodies in blood can cause spurious results. Also, switching labs can shift baselines. When in doubt, repeat testing with a different method or confirm with imaging.

How biomarkers inform treatment choices without making the decisions for you

Biomarkers don't operate in a vacuum. They plug into guideline-based frameworks from organizations like the American Thyroid Association and the National Comprehensive Cancer Network.³ Here's how they shape decisions without dictating them:

• Surgery extent in DTC: Molecular markers and ultrasound findings can suggest the need for total thyroidectomy versus lobectomy. For instance, features linked to aggressive biology support more comprehensive surgery. This is weighed against tumor size, location, and your health profile.
• Radioiodine use: Postoperative risk stratification uses pathology, Tg, and imaging to decide whether radioiodine ablation adds value. Not all DTC needs it. The aim is to match therapy intensity to recurrence risk.
• TSH targets: After treatment, TSH levels may be kept lower for a period to reduce growth stimulus. Over time, targets are relaxed as risk diminishes. It's personalized and periodically revisited.
• Systemic therapy for advanced disease: Genomic alterations like RET or NTRK fusions and BRAF V600E can identify candidates for targeted therapies. These decisions balance benefit, side effects, and overall goals of care.

Credibility cue: Multiple large cohort studies show that a dynamic, response-to-therapy approach — adjusting surveillance and treatment based on biomarker and imaging trends over time — more accurately predicts outcomes than initial stage alone.

Special situations across life stages

Pregnancy

• Thyroid physiology shifts during pregnancy, and common supplements can interfere with testing. hCG can lower TSH early on; prenatal vitamins often include biotin, which can skew some immunoassays.
• Radioiodine is contraindicated in pregnancy and breastfeeding. Ultrasound and selective labs are the main tools during this window.
• For known DTC, many patients can safely defer definitive therapy until after delivery; biomarkers help monitor stability.

Pediatrics and young adults

• Thyroid cancers in children often present with nodal disease but still have excellent long-term outcomes.
• The same biomarkers are used, with care to minimize radiation exposure from imaging.

Older adults

• Comorbidities and competing risks shape how intensively biomarkers drive interventions.
• TSH targets may be set with more caution due to cardiac and bone health considerations.

Medullary thyroid cancer nuances you might miss

Calcitonin isn't just a number — its change over time is the real message. Doubling time offers prognostic weight.¹² ¹³ CEA adds another layer, especially when calcitonin behavior changes with tumor differentiation. Imaging escalates when markers rise. If a germline RET variant is discovered, first-degree relatives may be offered testing; that's a biomarker ripple effect that extends to family health.

When to consider additional molecular profiling

If you're facing recurrent or metastatic disease, or if your initial tumor showed aggressive features, comprehensive tumor profiling can uncover actionable alterations.⁸ For DTC that is refractory to radioiodine, profiling may find RET, NTRK, BRAF, or other changes that open doors to targeted therapies. In MTC, somatic RET or RAS mutations are common and can inform options. In anaplastic disease, profiling often directly guides systemic therapy strategy.

Important caveat: not every alteration predicts response, and not every detected mutation is a driver. Results belong in a multidisciplinary discussion with your team.

What about lifestyle and labs?

Unlike cholesterol or glucose, day-to-day lifestyle choices don't usually swing thyroid cancer biomarkers in a meaningful way. The big exception is supplements that interfere with assays, particularly biotin. Hydration and typical exercise don't change thyroglobulin or calcitonin in a reproducible way. Sleep, nutrition, and movement matter for overall health and treatment tolerance, but they aren't levers for these specific cancer markers. That said, consistent routines help keep testing conditions similar, which makes trends cleaner.

Real-world scenarios to make it concrete

Scenario 1: A 1.6 cm solid hypoechoic nodule with microcalcifications is biopsied and called "indeterminate." A mutation panel shows BRAF V600E.⁸ ¹⁰ Your team explains that this substantially nudges risk toward papillary thyroid cancer and may favor definitive surgery over watchful waiting. Post-op, Tg is undetectable, and ultrasound is clean — a reassuring response pattern.

Scenario 2: You had a lobectomy for a low-risk papillary cancer. With half your thyroid intact, Tg is not expected to be undetectable, so the care plan leans on ultrasound and stable Tg levels over time.⁹ TSH targets are not as stringent because your recurrence risk is low.

Scenario 3: A patient treated for medullary thyroid cancer has calcitonin that begins to rise slowly. The level itself is modest, but the doubling time is short.¹³ That trend triggers earlier imaging and a tighter follow-up interval, catching small nodal disease when it's most manageable.

Questions that help you get the most out of biomarker testing

• Which biomarkers are most informative for my cancer type and stage?
• What does my trend over time show, and are we using the same assay each visit?
• Do any of my supplements or medications interfere with these tests?
• If a result changes our plan, what specific next step does it trigger?
• Would molecular profiling refine my risk or open therapy options if I recur?

Key limitations to keep in mind

Biomarkers are powerful, but none are perfect. Thyroglobulin can be unreliable in the presence of antibodies; calcitonin can be elevated by benign conditions like renal impairment or proton pump inhibitor use; ultrasound depends on operator skill; molecular panels can return variants of uncertain significance. Labs and imaging complement one another, and interpretation relies on the full clinical picture. When something doesn't fit, the answer is often to recheck, confirm with a different method, or correlate with imaging rather than rushing to a conclusion.

A quick glossary

• TSH: pituitary hormone that stimulates the thyroid
• FNA: fine-needle aspiration biopsy of a nodule
• Bethesda: standardized cytology categories that estimate cancer risk
• Thyroglobulin (Tg): protein marker made by normal thyroid and most DTC cells
• Anti-thyroglobulin antibodies (TgAb): antibodies that can interfere with Tg measurement; their trend can act as a surrogate signal
• Calcitonin: hormone made by C cells, the primary marker for medullary thyroid cancer
• CEA: a general tumor marker that tracks with medullary thyroid cancer
• Radioiodine avidity: a tumor's ability to take up iodine, useful for imaging and therapy in DTC
• Molecular profiling: testing tumor or FNA material for genetic changes to refine diagnosis, risk, or therapy options

The bottom line

Biomarkers in thyroid cancer are not just box-checking — they are the language your tumor speaks. Ultrasound patterns start the conversation, FNA and molecular testing clarify the plot, and post-treatment markers like thyroglobulin or calcitonin tell you how the story is unfolding. Follow the trends, use consistent assays, and interpret everything in context. With a steady, guideline-informed approach, biomarkers can help you and your care team make smart, timely decisions while avoiding unnecessary interventions.