Let’s talk just very briefly about thyroid irradiation. Potential sources for thyroid irradiation include external beam irradiation or radioiodine fallout. There was a lot of childhood irradiation being done back in the 40’s and 50’s and there were many many cases of thyroid cancer noted in the adults of children who were exposed, for reasons that would certainly not be considered medically appropriate uses of radiation in this day and age. It is clear to me that children are more radio-sensitive than adults. Now we have radioactive fallout. Catastrophe; I’m sure many of you remember this. This was shortly after the Chernobyl reactor accident, and it truly has been a catastrophe in any number of different ways, not the least being sort of an epidemic of especially childhood thyroid cancer cases with fairly aggressive courses that have been noted. Beginning about four years after – it was a fairly short latency, actually – after the reactor accident. I guess hopefully we will never see another Chernobyl but on the other hand, as the events in Japan last week have proven, by no means are we going to be free from the potential risk of catastrophic nuclear accidents in the future.

Familial syndromes associated with papillary thyroid cancer: there are familial papillary thyroid cancer syndromes but a specific familial papillary gene has not been identified. Papillary cancer is seen in increased frequency with some GI syndromes, Gardener’s syndrome, familial polyposis, Cowden syndrome. Carney complex is the combination of myxomas, nodular adrenal cortical disease, Sertoli cell, testicular carcinomas and thyroid malignancies are also seen with increased frequency in that. A couple of pathologic variants of papillary thyroid cancer may be noted at the time of surgery, and sort of going from less aggressive to more aggressive are an encapsulated papillary thyroid cancer variant, the so-called follicular variant. These are tumors in which there is no gross papillary element present in the tumor, but the cytology of the individual cells is consistent with the papillary form. This has about an equal biologic behavior to ordinary papillary thyroid cancer. Of somewhat greater concern are the diffuse sclerosing variants, tall cell variant. There is another variant known as the columnar variant, which may be sort of a variant of tall cell variant, and an insular form which is fairly aggressive is also seen. So a couple of less common variants can be seen.

Follicular thyroid cancer accounts for about 15% of the thyroid cancer in the United States, and as I mentioned, more common in areas of chronic iodine deficiency. We touched on the issue that follicular carcinoma cannot be distinguished from follicular adenoma by aspiration, and so if that quandary remains, in general I will recommend surgery to the patient. The general spread of follicular carcinoma is by hematogenous spread to lung, bone, liver and brain. A specific variant form that is though to be a variant of follicular carcinoma is the so-called Hurthle cell carcinoma. Hurthle cells, which may be seen in a variety of different thyroid lesions, including many non-neoplastic conditions. So the presence of Hurthle cells is not in and of itself specifically a marker of a thyroid neoplasm. But occasionally one will see neoplasms which consist predominantly of oxyphilic cells with sort of a granular cytoplasm and this defines the Hurthle cell variant. One of the important issues in terms of Hurthle cell carcinomas, is that in comparison to follicular or papillary carcinoma, it is considerably less likely to take up radioiodine and therefore in one sense is effectively a surgical disorder. Many, although not all, investigators report a worsened prognosis compared to follicular carcinoma. It would hardly be surprising if this was in fact the case based on the fact that it appears to be a less differentiated tumor. But it’s not been a universal finding in all studies.

So with that, let’s talk a little bit about thyroid cancer itself. A variety of different types. Differentiated cancers arising from thyroid follicular cells are of course papillary or follicular cancers.  The less differentiated is the anaplastic, which fortunately we see very rarely. Arising from an embryologically distinct population of C cells is medullary thyroid cancer. I’ll talk very briefly about it towards the end. I don’t know if the speakers, when they were talking about some of the other islet cell neoplasms, discussed this at all or not. Finally, there are sort of non-thyroid thyroid things. Non-Hodgkin’s lymphoma can present as a goiter or a thyroid nodule occasionally. Metastatic disease and some other less common lesions. But we are going to focus on the differentiated follicular-derived thyroid cancers. About 17,000 cases are diagnosed yearly in the U.S. and the incidence of diagnosed cases has been increasing. It’s not clear to me if this represents some true alteration in the incidence of the disease, or whether this is in part a reporting issue of previously undiagnosed cases, since thyroid cancer often will be fairly indolent. The disease is more common in women than in men.

The most common form of thyroid cancer that we see in this country, and in general in areas of iodine sufficiency, is papillary thyroid cancer. Probably accounts for 80-85% of the thyroid cancers that we see in the United States. Papillary thyroid cancer can be noted as an incidental finding. Occasionally one will undergo a thyroidectomy and a microscopic focus or maybe several microscopic foci of papillary thyroid cancer will be found almost as an incidental finding. It would appear that that form of microscopic papillary thyroid cancer is probably of little clinical concern, since the finding is that these things are found on autopsy series in unsuspected patients much more frequently than they present clinically. So there are probably several people in this room who are harboring microscopic foci of papillary cancer and very likely you will never know about it. Papillary cancer can be multifocal throughout the thyroid gland, or bilateral. The general spread of thyroid cancer is local invasion spread to cervical lymphatics and then distant metastases, particularly to the lung.

Risk factors for papillary cancer; thyroid irradiation. Papillary cancer is seen with increased frequency as a second malignancy in individuals with a history of childhood cancer. This in part may be related to the irradiation issue. It may be in part related to general genetic factors with regard to tumor predisposition. There is some argument as to whether or not Grave’s disease, because of its sort of the endogenous thyroid stimulation is a risk factor. Dietary iodine increases the relative risk of papillary thyroid cancer but decreases the risk of follicular cancer. If you look at areas of the world that are iodine deficient you tend to see more follicular thyroid cancer relative to the United States.

Thyroid cancer is most frequently going to present as a solitary thyroid nodule. These are by no means uncommon findings. In the Framingham study, just the health surveillance study, the prevalence of these nodules was close to 10% in women. The important figure that I tell my patients when I first see them is that the a priori odds of a solitary thyroid nodule being a cancer is actually not that high; only about 5-10% of thyroid nodules are ultimately going to prove to be malignant.

Clinical risk factors: the important risk factors, issues that would make one highly suspicious, a nodule that is growing rapidly. Say, over a period of weeks to months. A family history of a familial syndrome, multiple endocrine neoplasia or perhaps medullary thyroid cancer. Not by any means a common situation and in fact I would hope not to be seeing anybody with that history at this point, for reasons that we’ll discuss. Among the physical characteristics, a nodule that is very hard, that appears to be fixed to adjacent structures. Very rarely there will be vocal cord paralysis present. Obviously the presence of clinically suspicious lymph nodes or the occasional patient who would present with frank metastatic disease. But in fact, most of the time when patients come to see me with a thyroid nodule they are asymptomatic and there is very little a priori reason to feel that they either do or do not have a thyroid cancer.

This is kind of a busy algorithm. It’s reproduced in your notes. The important point here is that from my perspective the single most important test, in terms of evaluating solitary thyroid nodule, is a thyroid aspiration. Frequently I will do that at the time of the initial visit, even if I know nothing else about laboratory studies or anything like that. Oftentimes a biopsy will provide enough information to make a treatment decision right off the bat. If the biopsy is highly suspicious for being a papillary cancer, you don’t need at that point to do a lot of scanning or imaging studies. On the other hand, if the biopsy is very reassuring about this being a colloid nodule, for example, or perhaps chronic thyroiditis or something like that, you also don’t need to do a whole lot. The one area to keep in mind in which the biopsy can be difficult is where the cytologist reports back the biopsy findings as being suspicious for a follicular neoplasm. The problem here is that on an aspiration cytology level, a follicular neoplasm, that aspirate will not distinguish a follicular carcinoma from a follicular adenoma. So those are the areas that can be a difficulty. It’s in those patients that I’ll get a scan because occasionally the nodule will be hot and if we know the nodule to be hot on scan, we know it’s not a follicular carcinoma. So that’s the one situation in which a scan is particularly useful in distinguishing a cancer from an adenoma. Otherwise, if the scan shows it to be cold then most of those patients are going to be indeterminate and I would recommend surgery for most of those patients because there won’t be any other less invasive procedures that will be definitive.