Summary
Thyroid cancer is classified firstly into differentiated types or undifferentiated (also called anaplastic) carcinomas, secondly there is group of medullary carcinomas and lastly there are the lymphomas. Differentiated carcinoma is so-called because the cancer looks (down the microscope) like the thyroid gland tissue from which it has derived.
There are two types: the commoner papillary type (60% of all thyroid cancer) and the follicular type (17% of the total). The importance of distinguishing the differentiated histology is that these are the types of thyroid cancer which retain the ability to concentrate iodine. If the iodine is made into a radioactive iodine isotope, then this radio-iodine is a tumour specific lethal weapon. It is the differentiated types of thyroid cancer that form the majority of cancers of this gland and correct management is attended by high cure rates.
Anaplastic or undifferentiated carcinomas of the thyroid retain little of the features of the original thyroid gland as discerned down the microscope. They tend to be faster growing and metastasising (spreading to other tissues) and have a worse outlook overall; furthermore, they do not concentrate iodine and so the radio-iodine option has no role in their management.
Medullary carcinoma of the thyroid is an unusual type of thyroid carcinoma completely unrelated to the other types. It is derived from the so-called C-cells which normally produce the calcium lowering hormone (calcitonin). If allowed to metastasise, it carries a bad outlook.
Thyroid lymphoma is almost invariably a high grade B cell lymphoma with a tendency to spread to other parts of the lymphoid system and bone marrow (see lymphoma section) a lower grade B cell MALT lymphoma, which has a lower tendency to spread outside the thyroid gland.
Causes
Iodine deficiency leads to the benign overgrowth of the thyroid to produce ‘goitres’ and this has led clinicians to study the relationship between environmental iodine availability and thyroid cancer. It has been demonstrated that follicular carcinoma (see below) is more common in regions of low environmental iodine whereas papillary carcinoma (see below) is as common or even more common in iodine avid as deprived regions.
Radioactive iodine pollution in the atmosphere is probably more carcinogenic and fall-out from nuclear accidents, bombs, or emissions from power stations are risks for the later development of thyroid cancer. Indeed, after exposure to nuclear fall-out containing radioactive iodine it is recommended to ingest ‘cold’ (non-radioactive) iodine to swamp the thyroid and so dilute the amount of radioactive isotope concentrated by the gland for this reason.
Total body exposure to ionising radiation of whatever source is also predisposing to thyroid cancer after an interval of some years.
Thyroid cancer is considerably more common in females than it is in males in all parts of the world, although the ratio female:male varies from 2:1 to 4:1.
There is a small incidence in childhood and then a significant incidence in young adult women before the incidence slowly and progressively rises as age increases.
There are a few very rare hereditary causes of thyroid cancer and medullary thyroid cancer (see below) occurs in the multiple endocrine neoplasia syndrome along with other primary tumours.
Thyroid lymphoma tends to occur in the elderly who have suffered autoimmune thyroiditis for a long time previous to the development of the lymphoma, and the inference is that the immune lymphocytes invading the gland in the benign thyroiditis have eventually turned malignant to become a lymphoma.
Anaplastic thyroid cancer (see below) is also a disease that tends to occur in the elderly; it is not an iodine avid cancer and therefore radioactive iodine therapy has no role (as indeed it does not in neither thyroid lymphoma nor medullary cancer).
Incidence
There is a wide variation in incidence of thyroid cancer across the world with a low incidence in the UK (circa 1 case per 100,000 of population) to high incidences such as 15 per 100,000 of population in Iceland. These differences are thought to be more due to differences in environment than to hereditary or racial causes; but see next section.
The thyroid is the only gland in the body which concentrates the salt iodine (an integral part of the thyroid hormone molecule) and the relationship between thyroid cancer incidence in iodine rich geographical regions, such as most maritime vicinities, and those with iodine lack (e.g. mountainous terrains of Switzerland, famous in the last century for its goitrous populations) has been studied with interest.
Symptoms & diagnosis: Thyroid cancer
The patient almost invariably complains of a swelling in the neck in the thyroid region. Sometimes this is inside the thyroid gland and such lumps characteristically rise upwards towards the mouth on swallowing as the thyroid is tethered to the larynx which moves up on swallowing so taking the thyroid with it. On other occasions, the lump is in an adjacent lymph node to thyroid and indicates spread of the tumour to the neck lymph nodes. In the figure photo, one can clearly see that the young woman has a lump adjacent to her larynx on her left (but just to the right as one looks at the photo) which was indeed spread of a papillary cancer of the thyroid to a neck lymph node.
Rarely, the patient presents with breathlessness due to spread to the lungs or bone pains due to spread of the cancer to the skeleton.
Diagnosis
The doctor will first run a thyroid ultrasound scan to specifically distinguish between a cyst and a solid lump; the ultrasound will also serve to tell if the thyroid is a goitrous gland within which the lump that has brought the patient to medical attention is just a prominent one of many nodules, the so-called multinodular goitre (which is rarely a malignant condition).
An isotope scan will inform the doctor as to whether the nodule is functioning like a normal thyroid gland, which is very rare indeed in cancers.
Next, the doctor may opt to obtain needle cytology of the lump (were a fine needle is placed within the lump and tissue aspirated for examination under the microscope). If this test demonstrates cancer (carcinoma or lymphoma) then it is a useful test. However, a negative result is less reliable at excluding thyroid carcinoma as some cancers look very similar indeed to the normal thyroid tissue and the sample obtained at cytology is often inadequate to distinguish.
Where doubt exists the patient is usually put up for surgery and a formal hemi-thyroidectomy is performed where the half of the thyroid containing the lump is removed. If it contains differentiated thyroid cancer (see below) then a completion thyroidectomy (the removal of the rest of the gland) is performed at a subsequent operation a couple of weeks later.
Stages
The most important fact to establish is whether the thyroid carcinoma is confined to the gland. An ultrasound of the thyroid and neck has already probably been done and is an accurate first procedure to delineate the thyroid tumour and identify abnormal lymph nodes. An MRI scan of the neck is also useful, particularly for demonstrating any local extensions of the primary growth.
A CT scan may be useful. Especially if the thyroid tumour extends down into the chest but there is an iodine load involved in the contrast that is used in neck CT scanning, and this may make difficult subsequent iodine therapy if this is necessary within a few weeks of the CT scan.
The commonest sites of distant spread for thyroid carcinoma are the lungs and the bones (usually in that order). Therefore, a chest x-ray or Ct (with the above caveat over iodine loading) of the thorax and a bone isotope scan are used in staging.
For differentiated carcinoma, the radical surgical operation (see below) will often be recommended whatever the staging shows and the operative specimen yields further staging information as to whether the tumour had spread outside the gland or not. By these means, the patient is classified as having intracapsular or extracapsular disease.
The measurement of the serum tumour marker (thyroglobulin) is not useful at this time.
In medullary carcinoma cases, the staging is much the same but there is a hormone marker of disease presence in the form the hormone calcitonin (which as has been said above is the normal physiological product of the thyroid C cells). This hormone marker is almost invariably raised in this disease and the level should fall back to normal levels after curative surgery.
By contrast, lymphoma staging is that for any high grade lymphoma (see lymphoma section), but PET scanning and bone marrow exam amongst other tests will be ordered.
Treatment & outcomes: Thyroid cancer
In patients with differentiated thyroid cancer, radical surgery (thyroidectomy) involving the total removal of the thyroid gland is advocated in most cases. ( In cases of early thyroid cancer – confined to one lobe of the gland and in younger patients – in whom the overall prognosis for cure is high – it is acceptable and indeed standard practice to remove only the affected lobe of the thyroid (hemi-thyroidectomy or lobectomy); the patient is then monitored without radio-iodine scanning (vide infra). In other cases and all those with advanced disease, radical thyroidectomy – removal of the whole gland is indicated.
Several points need to be made. The first is that a radical thyroidectomy is rarely complete, as the surgeon has to preserve the parathyroid glands that subserve the body’s calcium homeostasis and live within the confines of the thyroid capsular compartment; (these are different from the C cells that are an integral part of the thyroid itself). Furthermore, the surgeon has to preserve the nerves to the larynx which run through the thyroid compartment. In order to preserve both these structures, the surgeon is almost never able to safely remove the last normal thyroid cells. This is of importance as residual thyroid tissue remains and will show up on subsequent radio-iodine tracer scans and confuse the doctors; the residual thyroid tissue will also lead to a measurable thyroglobulin in the blood, again confusing the doctors. These facts provide the important reason for the radio-iodine ablation dose -vide infra
The second main point to make is that, in differentiated thyroid cancer, radical thyroidectomy may still be indicated even when there is metastatic carcinoma because it will only be possible to target high doses of radio-iodine onto the tumour cells when the higher avidity normal thyroid tissue has been ablated, and the simplest way of achieving a debulking of the normal thyroid is to take it out surgically.
The rationale of the radio-iodine treatment programme needs to be discussed: the thyroid cell need to concentrate iodine in themselves to make thyroid hormone. Each molecule of l-thyroxine contains four atoms of iodine and consequently, to make thyroid hormone, the thyroid cells need to uptake iodine from the blood in far higher concentrations than any other cell type in the body. They have acquired an iodine ‘trap’ and concentrate iodine 40X more than any other cell type in the body. This iodine ‘trap’ is utilised in the treatment of thyroid cancer because differentiated thyroid cancer cells tend to retain this trap mechanism in their cell membranes. The ‘trap’ does not distinguish between the various (radioactive versus non-radioactive) isotopes of iodine.
These principles do not apply to anaplastic (undifferentiated) carcinoma, to medullary thyroid carcinoma or lymphoma of the thyroid, as these cell types do not possess an iodine trap mechanism.
Following radical thyroidectomy, and in patients with differentiated thyroid carcinoma, there follows an ‘ablation dose’ of radioiodine which is specifically aimed at obliterating the normal thyroid remnant (and taking advantage of the fact that the normal thyroid cell residuum is highly avid for up taking the radioactive isotope of iodine). There is no point in such radioiodine ablation in the other types of thyroid carcinoma. The dose is most effective when the pituitary hormone: TSH is high and the TSH stimulating hormone : TRH (Thyrogen) is given intramuscularly for two consecutive days before the radio-iodine dose to ensure this is so.
Such TRH stimulation (to ensure high TSH levels at the time of radio-iodine administration is also used before any therapy dose as it maximises the uptake of the therapeutic 131-iodine into any thyroid cancer. The whole radio-iodine (131-I) programme for advanced/metastatic thyroid cancer is predicated on the basis that differentiated thyroid cancer retains the ability to uptake iodine. This is true in the majority of thyroid cancers -at least for a time. However, the uptake is less avid than in normal thyroid tissue and so it is important that the normal thyroid tissue is ablated, as it would otherwise compete successfully against the cancer for uptake). Much larger doses of 131-iodine are administered to treat thyroid cancer than are used to ablate the normal thyroid remnant after thyroidectomy (again because of the lesser avidity of cancer).
For the radioiodine ablation dose, the patient is admitted to a specially designated hospital side room where, in solitary confinement for 1-2 days, the patient remains after swallowing the radioiodine capsule. The radioiodine decays with a half life of 8 days and is excreted in the urine (but also in saliva and other body secretions) hence the solitary confinement whilst the radioactivity is high.
Female patients must not be pregnant and all patients must remain in the room until their whole body radiation dose is below acceptable and legal limits. After discharge, the patient must avoid close contact with children or pregnant women or travel by air flights (where they may be seated next to such individuals) for two weeks. These facts worry some patients but they may be re-assured that these precautions are just exceeding safe precautions and the patient is not discharged until the legal limits on dose have been measured and are acceptable for normal circulation in the adult population. The risk for the patient himself/herself is minimal.
Following radical thyroidectomy for any thyroid carcinoma (of whatever subtype), the patient is placed on thyroid hormone replacement, necessarily because the normal thyroid tissue has been removed. In the case of differentiated thyroid cancer (papillary and follicular variants) the dose of thyroid hormone replacement is high enough to fully suppress the pituitary TSH (the hormone from the pituitary that controls thyroid secretion, but which can act as a growth promoter for differentiated thyroid cancer).
For the other forms of thyroid cancer in where surgery is performed, notably medullary thyroid cancer, the replacement dose is just to keep the free thyroxine blood level in the normal range.
In differentiated thyroid cancer, the follow up of patients relies on the serial review of the neck both clinically and by ultrasound and by radio-iodine tracer scans: (very small doses delivered after Thyrogen stimulation of TSH to increase sensitivity and then a nuclear medicine scan to show any sites in the body that have uptaken the isotope) and by serum thyroglobulin levels – which should be zero after the ablation of the normal thyroid gland. Thyroglobulin is a protein that is made only by normal thyroid tissue and so the blood level should be zero after ablation of all thyroid tissue. However, differentiated thyroid cancer secretes thyroglobulin and so thyroglobulin blood levels can be used as a cancer marker.
Later, the patient is kept on thyroid hormone: T4 (thyroxine) which suppresses the serum level of the pituitary TSH hormone (such that there is no pituitary drive to thyroid tissue, as TSH could theoretically stimulate differentiated thyroid cancer cells to divide).
Where there is no evidence of thyroid carcinoma outside the thyroid gland, the patients with differentiated thyroid carcinoma (papillary and follicular) are thereafter carefully monitored by clinical examinations and two other more specific tests. The first is the radioiodine tracer scan where a tiny dose of a radioiodine isotope is administered (usually orally) and then a whole body radio-iodine tracer scintiscan is performed to see if there is any iodine avid tissue remaining (which there should not be in a patient who has had a radical thyroidectomy and a radioiodine ablation of the normal post-surgical remnant).
The second specific test is a serum marker test and relies on the fact that there is a specific thyroid protein molecule that is secreted into the blood by normal and differentiated thyroid cancer cells; it is called ‘thyroglobulin’.
Some doctors will not always ablate the thyroid remnant with radioiodine after the operation (for example in low risk patients, e.g. the young women of less than thirty five years with an intrathyroidal papillary cancer) and just place the patients on TSH suppressive doses of thyroxine. They will monitor the thyroglobulin in follow-up whilst the patient is on thyroxine (T4); this may be acceptable practice in low risk patients but if these patients do subsequently relapse then it is necessary to ablate the thyroid normal remnant before the iodine therapy programme can get at the metastatic cells.
In a patient who has differentiated thyroid cancer and has undergone radical thyroidectomy and a radioactive ablation dose to eradicate the post-surgical remnant, there is a radioactive iodine whole body scan performed at three months post ablation and a further one six months later. If both these are negative for iodine up taking tissue and if the serum thyroglobulin is undetectable at these check points, then the patient is regarded as being without cancer and is thereafter followed by serial thyroglobulin levels and clinical examinations only. Should anything suspicious arise clinically (e.g. a node appear in the neck or a shadow on the chest x-ray) or a rise in the serum thyroglobulin occur, then the patient will have another radio-iodine whole body scan performed at that time.
It should be noted that both serum thyroglobulin measurements and the whole body radioiodine whole body scans are more sensitive measures when the patient has a high circulating serum TSH.
At the time of radio-iodine scanning or therapy doses of 131-iodine, the TSH is stimulated to be high by TRH (thyrotrophine releasing hormone – Thyrogen). This enhances the uptake of the radio-isotope.
Where there is metastatic differentiated thyroid cancer, and it is proven to be iodine avid on the radio-iodine whole body tracer scans, then the doctor will proceed to radio-iodine therapy once the normal thyroid remnant has been ablated. After Thyrogen stimulation to achieve high TSH levels in the blood (to increase the uptake of iodine by the cancer) large doses of 131-iodine (a beta and gamma photon emitting isotope) are delivered by an oral capsule (as the isotope is well absorbed from the gastrointestinal tract) in the specially designated radio-isotope room in hospital with all the proviso’s given above. The patient should not have taken an iodine rich diet in the weeks before therapy as the ‘cold’ iodine competes for uptake with the radio-isotope.
The doses of radioactive iodine are repeated (often at six month intervals) until the iodine avid, metastatic disease disappears on (post-treatment) imaging and stops up-taking any more iodine and the serum thyroglobulin becomes undetectable. In the figure above (at the start of this section), there is shown a radioactive iodine scan performed on a patient who has disease in the neck (the small black blobs at the top of the figure) and widespread uptake throughout both lungs (the two larger triangular black areas below and to either side of the figure). This patient has very iodine avid thyroid cancer that is recurrent in the neck and both lungs and underwent a successful course of multiple radio-active iodine therapy doses which achieved complete remission of the disease.
The adroit use of radioactive iodine therapy in this disease is most important to long term survival in patients who have disease outside the gland.
Where the thyroid cancer is locally invasive in the neck (e.g. it is infiltrating the muscles of the neck adjacent to the thyroid or is invading the larynx) then it is advisable to recommend a course of radiotherapy to the neck and this takes place in the post-operative period in addition to the radioactive ablation therapy.
Where the patient with differentiated thyroid cancer relapses in the neck lymph nodes only, then it is advisable to remove the affected lymph nodes prior to the radioactive iodine programme. When the disease is further afield (e.g. metastatic to lungs or bones) then surgery is obviously not appropriate and the therapy relies entirely on the radioactive iodine isotope therapy.
For all patients in between radioiodine therapy doses and long-term, the patient remains on thyroid hormone in generous dosage to ensure that the serum TSH remains fully suppressed.
For patients with undifferentiated/anaplastic thyroid cancer, the use of radical thyroidectomy is confined to those patients who have localised disease to the thyroid gland at presentation to the doctor. This is the minority of cases and most patients are recommended to receive radiotherapy to the neck as this disease is usually locally invasive at the time of presentation and tends to invade adjacent neck tissues and may throttle the patient if its progress in the neck is not stopped. High dose radiotherapy is usually the treatment offered to retard progress of the disease in the neck. Chemotherapy does not have a good track record in retarding the progress of undifferentiated thyroid cancer.
Medullary thyroid cancer patients are recommended to receive radical thyroidectomy if the disease is localised to the thyroid gland and the operation usually includes the central neck nodes of the neck. Post-operative radiotherapy is delivered if the diseases is invasive into other neck tissues. If the operation is successful, then the serum calcitonin will fall to the normal range. Where the disease has spread or relapsed (raised serum marker: calcitonin), then the use of isotopes of MIBG (a chemical that is specifically taken up by the medullary cancer cells in some cases) or octreotide can be introduced in high radioactively labelled dosage to deliver a radiation dose to the relapsed cancer in a comparable way to iodine-131 therapy in differentiated thyroid cancer. Orthodox chemotherapy does not have a good track record in retarding the progress of the disease.
Localised thyroid lymphoma is treated by a combination of chemotherapy (usually a short course of some three months) followed by a course of radiotherapy to the neck and upper chest (the next port of call / spread) of this lymphoma; the radiotherapy course usually lasts for four weeks and causes some tiredness and temporary difficulty in swallowing and skin soreness over the area. When the disease has spread further afield, then total reliance is on an aggressive chemotherapy programme (see lymphoma section). For localised MALT lymphoma, radiotherapy alone may suffice, as the chance of spread is less than with higher grade lymphomas.
What to do if the foregoing therapies have failed?
If the patient with differentiated thyroid cancer has failed the surgery and radio-iodine based programe then ‘smart’ Tyrosine Kinase Inhibitor therapy (TKI) is indicated and Sorafenib andLevatinib are the bet known drugs in this regard and are worthy of a trial. If these do not work, it is worth getting a genomic profile on the cancer by a fresh tumour biopsy or cell free DNA from a blood draw – to do Next Generation Sequencing (NGS) and genomic analysis of the cancer. For example, some (particularly papillary thyroid) cancers may have BRAF mutations that are driving the cancer to grow and one particular mutation of the V(aline to Glutamic acid) 600 mutation occurs in this type of cancer and disrupts the MAPK signalling pathway of regulation of cell divisions. When this particular mutation occurs in melanoma, the stimulus to melanoma growth can be blocked by inhibitors such as Vemurafenib and Dabrafenib. Unfortunately these Save have a lower chance of causing remissions in BRAF V600 mutations in V600 mutated papillary thyroid cancer (probably because of feedback loops in the MAPK signalling pathway) – but not negligible and the presence or absence of this mutation should be known, as should other mutations of potentially ‘druggable’ oncogenes.
In medullary carcinoma of the thyroid, the RET oncogene is frequently mutated (CLIP1-RET fusion positive) and the drugs : Vandetanib, Cabozantinib and LOXO292 can all have good effects causing at least partial remissions of the cancer – the latest drug: LOXO292 can have dramatic effects on metastatic disease, including on brain metastases. The radio-isotopes: MIBG and Octreotide are worth researching in the form of tracer scans for both isotopes, as this neuro-endocrine cancer can express uptake for both isotopes and then, using much higher doses than in the tracer scan, M131IBG or LU177-octreotate in high specific activity doses can be used for therapy in scan positive cases.
In anaplastic carcinoma of the thyroid, the mTOR genetic signalling pathway seems to be a driver to cell division and the drug: everolimus may have a good therapeutic effect.
Where the genomics has not proven useful in causing a durable remission, then the genomic profiling may give a clue as to whether the cancer may respond to immunotherapy. If there is evidence of hyper-mutation, or mismatch repair deficiency (which equates with increased mutation) then there is an increased chance of immunotherapy working on the cancer. Increased PDL1 expression is also an indicator that the immune system finds the cancer or be immunogenic and that inhibition of PD1 (on the lymphocyte surface) or its ligand (on the cancer cells): PDL1 – will lead to a response to particularly checkpoint PD1/PDL1 inhibition.
Credit: Dr. P. N. Plowman MD, The Oncology Clinic, 20 Harley Street, London W1G 9PH. (Advanced Genomics). Tel: +44-207-631-1632
Outcomes
The vast majority of patients presenting to the doctor with early, differentiated thyroid cancer will be cured. For example, the young woman with early papillary cancer has a greater than 90-95% chance of cure, but it is important that the algorithm of care outlined above is followed.
Similarly the chance of cure is good with modern therapy for thyroid lymphoma.
Unfortunately, the chance of surviving undifferentiated/anaplastic thyroid cancer is very much smaller and, despite the therapies outlined above, the majority of these patients die of their disease within one year.
Patients with medullary thyroid cancer have an overall 50% survival to 10 years and those with early stage disease and who have curative surgery, with the disappearance of raised serum calcitonin, are those who are likely to be in the cured cohort. With the new genomically targeted therapies, higher expectations are expected
Screening
Overall, thyroid cancer is a rare disease and a population based screening programme is not indicated.
However, people with a family history of medullary thyroid cancer, MEN (multiple endocrine neoplasia) syndrome or the rare other syndromes associated with a genetic predisposition to the disease must be screened. If a patient is diagnosed with medullary cancer, it is required that the doctor rules out the inherited MEN syndrome and screens for phaeochromocytoma and hyperparathyroidism (concomitants of the inherited syndrome).