Thyroid Cancer (TC)

At a Glance

Cancer arising from the thyroid gland’s unique cells (i.e., follicular or para-follicular C-cells) comprises less than 2% of all cancers, but accounts for 32,000-37,000 annual new cases of cancer in the United States and 90% of all endocrine cancers. It occurs predominantly in women (3:1) and appears in this incidence because of smaller lesions detected and other factors. Causal factors include radiation exposure, especially in childhood, and some genetic or familial disorders, but most cases are sporadic.

Thyroid cancer (TC) is divided into:

Differentiated forms, which include Papillary (PTC, including mixed papillary and follicular types) and Follicular (FTC, including those with Hürthle cells), each comprising 78% and 17% of TC’s and arising from follicular cells.

Medullary carcinoma (MTC) arises from para-follicular or C-cells, which are part of the neuroendocrine system and secrete calcitonin but may also secrete CEA, ACTH, serotonin, melanin, and prostaglandins. MTCs account for 4% of TCs.

Anaplastic carcinoma (ATC; 1% or less of TCs) may arise de novo but are believed to represent dedifferentiation or multiple additional mutations in previous papillary or follicular carcinomas.

PTCs and FTCs are generally curable, but in 15% of patients can recur or persist up to 20 years from presentation, and 5% may die from their tumors.

MTCs have a worse prognosis and can spread early to involve lymph nodes and have distant metastases. They have common association with genetic or familial syndromes, such as MEN-2A and MEN-2B, but most are sporadic.

ATCs are aggressive tumors with most patients dying within 6 months of presentation. They spread locally and metastasize.

Symptoms of TC depend on the type of tumor.

Differentiated forms may have no apparent symptoms, but most patients are discovered in the work up of a nodule. Up to 90% of the population by a certain age may have thyroid nodules, depending on whether they are palpated or discovered by other studies, and 99% of nodules are benign. TCs may be discovered incidentally on the work-up of a nodule, usually by fine needle aspiration (FNA) or by functional assessment (“cold” nodule).

Signs or symptoms indicating malignancy are related to the size, growth rate, or spread of a tumor and include:

Lump in the neck

Enlarged lymph nodes

Hoarse voice with vocal cord pressure

Dysphagia or difficulty swallowing with esophageal pressure

Neck or throat pain

Hard, “woody” mass with anaplastic carcinoma

Para-neoplastic syndrome with MTC (usually Cushing’s or carcinoid syndromes)

Hypercalcemia or diarrhea with MTC

Signs related to metastases, usually lung, liver, bone, or brain, such as dyspnea, bone pain, lethargy

Previously diagnosed TC or familial syndrome with chemical or physical signs of tumor growth or spread

Patients at high risk for TC may be followed with specific chemical tests, and any change in those may suggest tumor formation or recurrence.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Tissue diagnosis is the mainstay or gold standard for TC of any type. One of the problems with either FNA, large needle aspiration biopsy (LNAB), or surgical biopsy may be with indeterminate results or inadequate samples. This problem is most common in FNA material in which up to 30% of results may be so classified.

Thyroglobulin (TG), a glycoprotein unique in the body to thyroid follicular cells, can be used to follow differentiated carcinomas. It is generally not used in the initial diagnosis of those tumors, since it is also secreted by normal follicular epithelium. However, some suggest that initial TG levels might be helpful to show if the tumor can secrete TG. The problem with this approach is that normal thyroid tissue, before surgery or ablation, may cause initially detectable TG levels.

Anti-thyroglobulin antibodies (TG Ab) may also be a unique follow-up marker for differentiated carcinomas but are used primarily to assess results of TG assays.

Calcitonin (CT) levels, if sufficiently elevated, may be diagnostic of an MTC but can also be elevated in other conditions.

Calcitonin may be used to follow patients for recurrent or persistent MTC and may be used in patients at high risk for MTC to see if a tumor or precursor lesion is developing (e.g., C-cell hyperplasia).

Procalcitonin (PCT) may be an alternative to calcitonin testing because of stability issues, but more studies are needed to define threshold levels and comparison of results between assays.

There are no chemical tests to diagnose or follow ATC. Some markers for other tumors that may mimic anaplastic tumors (e.g., lymphoma) may be used to exclude those diagnoses.

Molecular markers may be used to resolve some indeterminate biopsy cases or indicate a worse prognosis lesion.

Tests for circulating TC cells detected by DNA amplification of thyroglobulin micro-RNA are considered experimental at this time.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Thyroglobulin (TG) Testing

TG is a heterogeneous glycoprotein, unique to thyroid follicular cells, but it may vary between normal and malignant forms.

It may take 1 month or more to clear TG after complete surgery or ablative treatment.

Any normal remaining thyroid cells may secrete TG if the tissue is not completely suppressed, so TG should not be used for follow-up if unsuppressed thyroid tissue is present.

TG is usually tested by immunoassays; results can vary because of molecule heterogeneity, antibody or epitope specificity, and assay conditions or lack of standardization.

There may be “hook” effect with very high levels of TG that overwhelm the assay’s ability to measure levels. This may be less common with newer assays.

To compare follow-up testing, the same assay should be used for each test for an individual patient.

The functional sensitivity of a test must be known to assess cut off points for positive and negative results.

Anti-TG antibodies may interfere with results and should be tested with each TG sample.

There are different generations of tests. Older tests may be less sensitive and require stimulation with recombinant human TSH (rhTSH) or withdrawing thyroid hormone suppression (THW) to see detectable or comparable TG levels.

Newer assays may be sensitive enough to not require stimulation or withdrawal of suppression to measure TG levels.

A provider needs to know what generation of test is used and how reliably sensitive it is.

TG secretion by a tumor may change over time. As tumors dedifferentiate, they may lose the ability to secrete TG and it is no longer a useful marker.

The level of TG may correlate with tumor mass, but there may be undetectable TG with recurrent or persistent tumor and there may be detectable TG with no tumor noted on iodine scans if the tumor does not concentrate iodine.

Anti-thyroglobulin antibodies (TG Ab)

Anti-thyroglobulin antibodies are present in 10% of the general population but 20% of patients with TC.

It may take 3-5 years for TG Ab to clear from a patient after treatment, but up to 20 years in a patient with autoimmune disease.

TG Ab are tested by immuno-assays that can show variability like TG assays.

TG Ab can spuriously affect TG results, usually by competing for and decreasing TG in immunoassays (IA), but may increase TG results in radio-immuno assays (RIA).

Testing should be run simultaneously with TG assays to evaluate TG levels.

There may be no reproducible lower level at which TG Ab do or do not interfere with TG assays.

There may be positive levels without TG detectable, and these may be an independent marker for tumor recurrence or persistence.

Rising or persistent levels should be evaluated for tumor recurrence or persistence.

Calcitonin (CT)

It is tested by immunoassays that vary by antibody specificity and epitope specificity.

Patients should be followed using the same assay.

It degrades rapidly at room temperature and even in the refrigerator, affecting assay results. Samples must be frozen quickly.

At high levels of CT, endogenous fragment formation may affect assay levels.

Cut off values vary according to a specific assay, so they must be assay specific.

It can be stimulated by pentagastrin, but those stimulated values may be assay-specific so comparing results across assays may not be possible.

Very high levels may be diagnostic of a MTC, but many factors cause false-positive results. These include active immune thyroiditis, hyperparathyroidism, lactation, mastocytosis, neonates, other neuroendocrine tumors or possibly leukemia, renal failure, sepsis, massive trauma, noninfectious inflammatory conditions, and proton pump inhibitor drugs.

C-cell hyperplasia is a precursor lesion to MTC and can show elevated CT levels which overlap with MTC.

Small or micro MTCs may have lower CT levels.

PCT, the precursor to CT, may be a more stable and reliable marker, but more studies are needed to confirm this and what levels should be used for cut of values. Inter-assay variability should be considered.

What Lab Results Are Absolutely Confirmatory?

Definitive tissue diagnosis is confirmatory, perhaps with immuno-histochemical (IHC) testing to confirm cell type (e.g., C-cells in MTC) or to exclude other cell types (e.g., ATC). There is mixed literature for which IHC tests are useful in differentiated TC.

Very high levels of CT may be confirmatory in known or highly suspect cases of MTC (e.g., familial syndromes), but one must know cut offs or reference ranges for individual CT assays.

Combinations of tissue results with chemical or molecular testing and radiographic studies may be sufficient to guide further treatment in compatible clinical circumstances (e.g., an atypical FNA, with elevated TG levels and a positive radio-iodine scan in a patient with prior treated follicular carcinoma).

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Newer approaches to confirming a TC diagnosis or evaluating prognostic implications involve molecular tests. As part of its 2009 guidelines for patients with thyroid nodules and differentiated TC, the American Thyroid Association recommended that a panel of molecular markers may be considered for patients with indeterminate cytology to guide management. This panel includes BRAF, RAS, RET/PTC, and PAX/PPAR gamma markers.

One marker, the BRAF V600E mutation, indicates a more aggressive course in papillary thyroid carcinoma (PTC). How to manage these results is being studied.

Use of these and other markers will improve over time, improve the diagnostic accuracy, and allow individualized surgical and post-surgical treatment.

Marker specifics include:

BRAF V600E mutation noted in papillary, poorly differentiated, and anaplastic carcinomas, indicating a more aggressive course and heralding treatment failure or the need for more aggressive treatment.

RET proto-oncogene rearrangements are expressed in C-cells and MTC.

RET/PPC rearrangement may be specific for PTC, classical pattern, and may be seen in younger patients with radiation exposure. It may indicate a less aggressive course.

RAS mutations are associated with follicular cells and may be present with PTC showing a follicular variant or FTC but may also be present in follicular adenomas or clonal nodules and may suggest nodules that need complete excision to prevent progression to malignancy.

PAX8/PPAR gamma rearrangement is present in some FTCs and may be associated with vascular invasion or follicular adenomas that may progress to FTC.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Molecular tests can be affected by having adequate tissue, standardization of methods and interpretation, and use of proper methods for different issue types or sources. They are also expensive and require adequate population studies to confirm the usefulness or applicability of results.

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