Thyroid tests and papillary-follicular thyroid cancer follow-up successfully take advantage of the knowledge of how the normal thyroid gland functions.
The purpose of the gland and its various cells is to produce exactly the right amount of two thyroid hormones to maintain a balanced metabolism.
The balance of hormone levels circulating in the blood involves a feedback loop to two areas of the brain. The hypothalamus makes thyroid releasing hormone (TRH), which travels to TRH receptors in the pituitary gland. The hormone then stimulates the pituitary to release another hormone, the thyroid stimulating hormone (TSH), into the circulation. The thyroid gland itself has follicle cell receptors that allow the TSH to stimulate thyroid follicular cells to produce both thyroxine (T4) and triiodothyronine (T3). Thyroglobulin (Tg), produced only by the thyroid, is a precursor of both hormones T4 and T3.
The two thyroid hormones T4 and T3 then circulate in the blood and inhibit synthesis of the brain hormones, TRH and TSH, as well as the TRH receptor in the pituitary, as part of a negative feedback loop. As the level of one set of hormones rises, the other set decreases
After pathologic diagnosis of cancer, the first step in treatment is usually total thyroidectomy. Surgery results in removal of the tumor, thereby reducing the risk of recurrence and making it easier to treat a smaller number of any remnant cancer cells.
The second step takes advantage of thyroid gland function, and targets only thyroid cells that use iodine to manufacture thyroid hormones. Even after total thyroidectomy, thyroid cells could remain in the thyroid bed, in cervical lymph nodes, or be located in metastases.
Radioactive iodine (I-131) is administered, and taken up only by functioning thyroid cells, whether normal or neoplastic. The functioning cells are killed by the radiation in the iodine, but there is not enough radiation to kill other tissues of the body. Radioactive Iodine (I-131) ablation of thyroid cancer cells was the first great success in targeted cancer treatment.
Once there are presumably no more thyroid cells, future scans make detecting a recurrence of cancer possible at an early stage.
The third step of treatment is replacement of the now-missing essential hormones. Thereafter, good follow-up means testing to detect any recurrences.
Thyroxine (T4) is easily monitored and replaced by Synthroid or other formulations which act identically to natural thyroxine.
Thyroxine, natural or exogenous, does two things: first, it restores the patient to the euthyroid state; and second, Thyroxine suppresses the pituitary hormone, TSH, by being part of the normal feedback loop from thyroid to hypothalamus to pituitary. Low levels of TSH are advantageous because any remnant cancer cells will not be stimulated to grow. After years of controversy, most writers agree that replacement of triiodothyronine (T3) is not needed. Frequently, the brand name for exogenous T3 seen in attending physicians’ reports is Cytomel.
Good follow-up means looking for possible thyroid cancer recurrences, and one key to this is ultrasound scans of the neck. Ultrasound is useful for all pathologic types of recurrent cancer in the neck. Knowledge of cell function, however, can aid in detection of recurrences of papillary/follicular types of cancer in all areas of the body, including the neck. The fact that these thyroid cells take up iodine and/or produce hormones creates another way to look for recurrences.
The only cells in the body that produce thyroglobulin are thyroid cells. This is true whether the cells are normal or cancerous. Almost all differentiated papillary, papillary-follicular, or follicular cancer cells make thyroglobulin, and they are by far the commonest type of thyroid cancers. Measuring Tg is an excellent way to test for success of ablation or recurrence of thyroid cancers in the vast majority of patients. Thyroglobulin is a very convenient tumor marker.
Pre-surgical measurement of Tg will show if the patient’s cancer cells are producing thyroglobulin and enhances the usefulness of Tg as a tumor marker in that particular patient. Circulating pretreatment levels of 100 ng/ml of thyroglobulin are usually found in persons with thyroid cancer. Unfortunately, thyroglobulin (Tg) is not by medullary, undifferentiated papillary/follicular, or anaplastic thyroid carcinomas and one must fall back on the mainstay of neck ultrasound for follow up.
If no TSH is being produced (due to replacement and or suppressive therapy), any cancer cells that exist will not be stimulated to make thyroglobulin. This presents a dilemma, as the patient needs and gets thyroid hormone (usually Synthroid), but then there may be no thyroglobulin available to act as a tumor marker.
TSH stimulation is needed for thyroid cells to begin functioning again. Then serum thyroglobulin levels can be used to detect cancer cell recurrence in the most prevalent types of thyroid carcinoma. Serial thyroglobulin levels are more useful, as a change in the Tg level over time compensates for problems intrinsic to the test itself. It is also best to use the same laboratory when comparing results because of the technical difficulty faced by the laboratories.
Another result in a patient who is not producing TSH is that any existing thyroid cells will not be taking up iodine to make thyroglobulin. If cells are not taking up the iodine: first, doctors cannot use a radioactive iodine tracer (I-123) for a total body scan; and second, nor will the cells take up the iodine of I-131 to achieve radiation therapy.
Obviously, to follow patients by scanning or to treat recurrences with I-131, they must regain the TSH that was suppressed by needed therapy.
The I-123 or the radioactive iodine uptake (RAIU) test was the only method of detecting recurrent carcinoma outside the neck before tests for thyroglobulin became available. Though it is an older test it is still very effective. Nuclear scanning takes advantage of iodine uptake by functioning thyroid cells and can detect even a small cluster of cells. It is useful when thyroglobulin levels are obscured by anti-thyroglobulin antibodies or when there was a sub-total thyroidectomy performed that allows continued production of thyroglobulin. I-123 has a shorter half-life than I-131 (a half day vs. 8.1 days), so use of I-123 exposes the body to less radiation for less time and the type of radiation differs.
There are two ways to increase TSH in a suppressed patient – an old and a new method.
The old choice was to withdraw thyroxine therapy to make patients produce their own TSH in response to a fairly sudden hypothyroid state. A sudden hypothyroid state is not akin to natural hypothyroidism. Acute T4 withdrawal makes patients feel much sicker than gradual hypothyroid disease and they could be ill for weeks from sudden lack of T4. If very severe it may be termed ‘Myxedema Madness’.
The newer choice is simply to give the patient exogenous Recombinant Human TSH (rhTSH), which has been available since the late 1990s. Thyrotropin alpha (rhTSH) has an amino acid sequence that is identical to human pituitary thyroid stimulating hormone. Commercially, Thyrogen®, a highly purified rhTSH, is synthesized by recombinant DNA technology. When given rhTSH, the patients are not ill; they are not hypothyroid; they keep taking their replacement hormone; but they have lots of circulating TSH from rhTSH. If a patient has any differentiated thyroid cells, the cells will produce thyroglobulin and take up iodine to do so. Using rhTSH is much faster, with far less morbidity than the old method of waiting for the patient’s body to respond to iatrogenic hypothyroidism. Recombinant TSH nicely circumvents the thyroid hormone- hypothalamic- pituitary negative feedback loop.
Thyrogen (rhTSH) is administered intramuscularly, usually in two doses 24 hours apart. Thyroglobulin (Tg) may be produced if recurrent cancer cells exist; then Tg can be measured 72 hours after the last dose. If needed, imaging or further ablation may be done in two stages during the same time period.
Anti-thyroglobulin antibodies (ATA) are not uncommon and unfortunately interfere with accurate measurement of thyroglobulin, making this valuable tool more difficult to assess. Anti-thyroglobulin antibodies occur with Hashimoto's thyroiditis or Graves' disease and Tg-specific antibodies aid in the diagnosis of these diseases. Anti-thyroglobulin antibodies may also be present in apparently healthy euthyroid individuals (~12.5%). Additionally, ATAs will be present in approximately 25% of thyroid cancer patients. As treatment succeeds in thyroid cancer, thyroiditis, or autoimmune thyroid disease, the autoantibodies diminish with time. For the most accurate use of the thyroglobulin level, it is advisable that both Tg and ANA should be tested each time and the pattern analyzed by an endocrinologist or head and neck surgeon.
Medullary thyroid cancer, undifferentiated papillary/ follicular and anaplastic thyroid cancers do not produce thyroglobulin or thyroid hormones, so they do not take up iodine. These characteristics exclude most of the follow-up tools and treatments discussed above. Fortunately, ultrasound of the neck is sensitive for finding residual local disease in medullary and anaplastic cancers. As well, serum Calcitonin is a good marker for Medullary thyroid cancer and useful for detection of metastases. After total thyroidectomy calcitonin should be below the normal range.
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