Monitoring for Thyroid Cancer after Thyroidectomy

concepts of monitoring for thyroid cancer recurrence

After treatment for thyroid cancer, we begin a process of monitoring for recurrence. Recurrence of thyroid cancer is in general an uncommon event but, should it occur, is best detected and treated early. Finding a lump in the neck or elsewhere, either by physical exam or by radiologic imaging is one possible way a recurrence may become apparent. Of course, not every lump or bump is necessarily a recurrence of thyroid cancer, but if one is identified, further evaluation to determine the identity of the lump may include some form of biopsy, typically an ultrasound guided fine needle aspiration biopsy.

Other techniques of identifying recurrence are based on the biochemical behavior of thyroid cells. Thyroid cancer cells often retain some of the functions of normal thyroid cells. As there are two different types of cells in the thyroid gland (follicular cells that form papillary and follicular thyroid carcinoma and parafollicular c-cells that give rise to medullary thyroid carcinoma), the biochemical strategy of detecting tumor recurrence is based on the original type of thyroid cancer. Follicular cells that make papillary and follicular thyroid cancer may take up iodine and normally produce a molecule called thyroglobulin. Radioiodine uptake scanning may anatomically localize thyroid cancer cells, and the presence of thyroglobulin may be detected with blood work. Parafollicular C-cells that make medullary thyroid cancer may produce a molecule called calcitonin, which may be detected by a blood draw.

It is important to note that cancers evolve, and each time a cell divides into two cells, the new (daughter) cells may have more mutations than the parent cell. After numerous generations, the descendant cells may act less and less like the original tissue. Thus, at some point, thyroid cancer cells may continue to act like cancer but stop acting like thyroid tissue in some ways, such as their ability to make proteins (such as thyroglobulin or calcitonin) made by the original cells, or behaviors such as taking up iodine.

Thyroglobulin assays

As noted above, there are two different cell types in a thyroid gland—follicular cells that make thyroid hormone and thyroglobulin and parafollicular C-cells that make calcitonin. When monitoring for a type of thyroid cancer that arose from a follicular cell (such as papillary and follicular thyroid cancer), one may make use of thyroglobulin testing (assays). In essence, thyroglobulin assays are used because no other tissue in the body other than follicular cells of the thyroid makes thyroglobulin, and so an individual who has no thyroid tissue anywhere in their body should have a thyroglobulin level of zero. In actuality, a laboratory does not report thyroglobulin levels as zero, but rather as “undetectable” or as a value something like “ <1 ng/mL” which is practically the same as a zero result.

If a person with papillary or follicular thyroid cancer has had their entire thyroid gland removed, and if no thyroglobulin is detectable in the blood several weeks after surgery, then one may typically proceed with cautious optimism that there is no evidence for recurrent cancer with periodic thyroglobulin assays. Values remaining undetectable over time further suggests no recurrence of cancer. If the values are initially undetectable and then show a rising trend over time (not just a single datum, but a trend), then recurrence is presumed and the question becomes where is the recurrence. Thyroglobulin may take time to change from being undetectable to becoming detectable because if only a single cell or microscopic cluster of cancer cells remains after treatment, they may produce thyroglobulin at undetectable quantities until time has passed and each cell divides to make two cells, then these two become four, and so on until a population of cells large enough to create detectable thyroglobulin has formed. In this scenario, the group of thyroid cells producing thyroglobulin may be in the surgical bed where the thyroid is normally found, or it may be in a lymph node or the lung. The cell or microscopic cluster of cells that grew to produce detectable quantities of thyroglobulin would have been present from the day of surgery, but were not detectable by thyroglobulin assay until adequate growth had occurred. If the growth of thyroid cells producing this newly detectable thyroglobulin is located in the thyroid bed, then one would not necessarily know without further investigation whether these cells are normal thyroid cells or thyroid cancer cells, either of which could have been left behind at the time of surgery. On the other hand, if the population of cells making thyroglobulin is in a lymph node, the lung, or somewhere else in the body that does not normally have thyroid tissue, then we can know that these cells descended from thyroid cancer that had spread to this location before growing.

If a person has not had their entire thyroid removed, then the remaining thyroid tissue will produce detectable thyroglobulin. This does not necessarily mean that thyroid cancer still exists, as a remnant of normal thyroid gland would make thyroglobulin. One example of this is when a person underwent a hemithyroidectomy and isthmusectomy, leaving the entire other thyroid lobe intact. Another example is if the entire thyroid gland was intended to be removed, but was not, as in the case of an extension of thyroid tissue that was not visualized and removed during surgery. A third example is when all grossly visible thyroid tissue was removed, but enough microscopic rests of thyroid cells remain attached to the trachea or surrounding tissues to produce detectable thyroglobulin. In this third case, treatment with radioactive iodine may kill these remaining thyroid cells.

If thyroid cancer has spread to other parts of the body, such as a lymph node or lung, then this metastatic disease may produce thyroglobulin.

Antibodies against thyroglobulin

Some individuals have circulating immune proteins called antibodies that specifically bind to thyroglobulin. The percentage of people with these anti-thyroglobulin antibodies, also called TgAb and anti-Tg antibodies, is about 10% in normal individuals, but the percentage increases amongst those with follicular or papillary thyroid cancer. The accuracy of quantitative thyroglobulin testing is significantly affected when the individual has antibodies against thyroglobulin, almost always leading to falsely low readings for thyroglobulin concentration.

Testing for the presence and concentration of anti-thyroglobulin antibodies is typically performed simultaneously to a thyroglobulin assay. When TgAb is present, the reading of thyroglobulin is considered inaccurate.

This conundrum may be partially circumvented by monitoring the trend in thyroglobulin levels over serial measurements as well as monitoring the trend in antibodies to thyroglobulin themselves. Persistence of anti-thyroglobulin antibodies raises suspicion of persistent or recurrent papillary or follicular thyroid cancer, whereas declining anti-thyroglobulin antibody concentrations may indicate a reduced amount of thyroid cancer or the absence of thyroid cancer.

RadioIodine scan and Radioiodine ablation

Follicular cells, which give rise to papillary thyroid carcinoma and follicular thyroid carcinoma, normally take in iodine from the blood. This is used in making thyroid hormone. As long as a particular strain of papillary or follicular thyroid carcinoma retains this behavior, detecting a relatively small cluster of thyroid cancer cells may be accomplished by giving the patient some radioactive iodine, allowing it to circulate and then concentrate in thyroid cells, and then performing a radioiodine uptake scan to look for concentrated areas of the radioactivity from the radioactive iodine. This technique works best when there is no remainder of normal thyroid cells left in the neck after thyroid surgery, because a patch of residual normal thyroid tissue can act like a sponge soaking up most of the radioactive iodine, and leaving little left to collect in any separate focus of thyroid cancer in a lymph node or other location, such as the lung. This is the reason that removing all of the thyroid gland, not just one lobe and the central isthmus, is needed before utilizing radioactive iodine as a method of detection of recurrence.

In the technique described above, the radioactivity in radioactive iodine may be detected by a nuclear medicine scan called a radioiodine uptake scan. When 131-I is used in higher doses, the radiation emitted from radioactive iodine can also be used as a form of treatment, called radioiodine ablation therapy. This clever technique also capitalizes on the way that iodine concentrates in thyroid tissue, including most papillary and follicular thyroid cancers. A higher dose of radioactive iodine may be administered, allowed to concentrate in thyroid cells, and then emit their radiation to only the specific area where the radioactive iodine has collected. This radiation can (ideally) kill the thyroid cells that themselves incorporated the radioactive iodine, sparing the normal tissues even a little further away.

Calcitonin assay

Only one type of cell in the body produces the hormone calcitonin. This cell is the parafollicular c-cell, which is the type of cell within the thyroid that can progress to become medullary thyroid carcinoma. Thus, the presence of calcitonin in the blood indicates the presence of at least a small cluster of parafollicular c-cells or their evil counterpart, medullary thyroid carcinoma. The technique of monitoring blood concentrations of calcitonin is most effective when calcitonin is undetectable in the period after surgical treatment. In this scenario, there are either zero or near zero cells producing calcitonin. If, as time goes on, calcitonin becomes detectable in the blood, and especially if the calcitonin level continues to rise on subsequent blood draws, growth of parafollicular c-cells (or medullary thyroid carcinoma cells) is suspected. While this, in theory, might result from regrowth of normal thyroid parafollicular c-cells, it is usually considered evidence of a growing patch of medullary thyroid carcinoma somewhere in the body unless proven otherwise. Situations in which the blood calcitonin level does not drop to undetectable after surgery for medullary thyroid carcinoma are less clear, since a small focus of normal thyroid tissue left in the neck after attempted total thyroidectomy could account for the continued production of calcitonin. Alternatively, a focus of medullary thyroid cancer that had spread to another area, such as a lymph node, could also potentially account for the continued production of calcitonin. In this scenario, efforts to differentiate between residual normal thyroid and the presence of metastatic medullary thyroid carcinoma may be undertaken, including possibly monitoring the trend of the calcitonin level, which would be expected to rise in the presence of (growing) metastatic medullary thyroid cancer but remain stable if caused only by normal thyroid tissue.

Other Blood testing

Additional blood testing may be utilized, such as for alkaline phosphatase, which becomes elevated in situations including spread of cancer to bone.

Ultrasound

Ultrasonography is a low risk and relatively inexpensive method for surveying an anatomic region for a mass such as that from thyroid cancer. Ultrasound is limited in that bones block transmission of the sound waves, and thus areas within bones such as within the chest, cannot be evaluated by ultrasound. Additionally, as a practical matter, it can be difficult to have an ultrasound of the thyroid “bed” (where the thyroid is normally located) and the sides of the neck (lateral neck) on the same day due to radiologist preferences. If a lymph node looks suspicious and is big enough (usually about 8–10 mm or more), a needle biopsy may be done.

CT

Computed tomography (CT) imaging has a role in evaluation after treatment for thyroid cancer, though its role is best in specific situations. CT is not typically undertaken as a way to determine whether thyroid cancer has recurred, but it may be of use in localizing and characterizing recurrence once discovered. CT imaging is helpful for evaluation of the chest, where ultrasound and MRI have limited roles, and in the neck when cancer invasion into surrounding structures is suspected. The contrast material used with a CT scan is iodine based. As such, iodine avid tissue, such as thyroid tissue absorbs this contrast well, which can facilitate identification of areas of thyroid cancer on the CT images. CT scans show bone detail well, and thus bony metastases are well characterized by CT imaging. One specific consideration with use of CT with contrast, however, is that thyroid tissue becomes less able to absorb additional iodine after the iodine load in the contrast. Therefore, any planned treatment with radioactive iodine would need to take place at least two months after a CT with contrast, when the thyroid tissue will have become “avid” for iodine once again.

MRI

Magnetic Resonance Imaging (MRI) also offers its own advantages in evaluation of suspected thyroid cancer recurrence. MRI is especially good at differentiating between different types of soft tissue, and therefore may highlight an area of cancer spread not apparent on other types of imaging. MRI is, however, more susceptible to degradation in image quality with patient movement during the scan, therefore limiting its application when looking for tumor in constantly moving tissue, such as the lungs.

PET-CT

Fluoro-deoxy-glucose positron emission tomography coupled with a non-contrast CT scan (PET-CT) imaging is not typically used for routine surveillance for thyroid cancer recurrence. In certain situations, such as when a papillary or follicular thyroid cancer has lost its ability to absorb iodine, rendering an iodine scan ineffective, then a PET-CT may be considered to assess for the location(s) of thyroid cancer spread.