Thyroid nodules and thyroid cancer: Pathology review

Definitions & Key takeaways

Thyroid nodules are lumps or growths that form in the thyroid gland, which is located in the neck. Thyroid nodules are relatively common and are often benign. They may cause no symptoms and be discovered incidentally during a physical exam or imaging study, or they may cause symptoms such as difficulty swallowing, hoarseness, or a visible lump in the neck.

Thyroid cancers, on the other hand, are less common than benign thyroid nodules, but the incidence of thyroid cancer has been increasing in recent years. There are several types of thyroid cancer, including papillary thyroid cancer, follicular thyroid cancer, medullary thyroid cancer, and anaplastic thyroid cancer.

The risk factors for thyroid cancer include a family history of thyroid cancer, radiation exposure, and certain genetic syndromes. Symptoms of thyroid cancer can vary, but may include pain in the neck or throat, difficulty swallowing or breathing, and hoarseness. Treatment for thyroid cancer depends on the specific type and stage of the condition. Options may include surgery to remove all or part of the thyroid gland, radiation therapy, and medication to regulate thyroid hormone levels.

Chapters:

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Case Study0:00–0:47

On the endocrinology ward, two individuals came in. Both individuals complained about feeling a lump on their necks, but reports no other symptoms.
The first one is 49 year old Dasha who as a child, lived close to Chernobyl. The other one is 27 year old Mike, who’s family history involves multiple endocrine neoplasia type 2A.
On exam, they each had a painless mass on their thyroid. Both people had normal T3, T4, and TSH levels.
They underwent thyroid echography, which showed cold nodules. Afterwards, fine-needle biopsies were done.
Both individuals had tumors on their thyroids. First, let’s refresh some info on the thyroid.

Physiology0:47–2:02

The thyroid gland is an endocrine gland located in the neck. The thyroid gland is made up of thousands of follicles, which are small spheres lined with follicular cells.
Follicular cells convert thyroglobulin, a protein found in follicles, into two iodine-containing hormones, tri-iodo-thyronine or T3, and thyroxine or T4.
Once released from the thyroid gland, these hormones enter the blood and bind to circulating plasma proteins. Once inside the cell T­4 is mostly converted into T3, at which point it can exert its effect.
T3, among other effects, speeds up the basal metabolic rate, increases cardiac output, stimulates bone resorption and activates the sympathetic nervous system.
The thyroid is also made up of parafollicular or C cells, which are near the follicles. These cells produce calcitonin, a hormone that lowers blood calcium levels by inhibiting osteoclasts.
Calcitonin also inhibits renal tubular cell reabsorption of calcium, allowing the calcium to be excreted in the urine. Now, DNA mutations can cause thyroid cells to become cancerous.

Pathology2:02–2:49

For example, a mutation might change a proto-oncogenes like RET and BRAF, which are genes that code for proteins that promote cell growth and proliferation, into oncogenes.
That would mean that the proteins force the cell to be stuck in the "on" position, always dividing, and that causes the thyroid cell to turn into a tumor.
There are other genes, called tumor suppressors, like TP53, that normally slow down cell division or make cells die if they divide uncontrollably.
DNA mutations might also turn off tumor suppressor genes, which allows thyroid cells that try to divide uncontrollably to go unchecked.
Let’s start by talking about thyroid adenomas which are benign and solitary growths of the thyroid. A high yield fact is that typically, these nodules are non-functional, so they don't produce thyroid hormones, and these are called "cold" nodules.

Thyroid adenoma2:49–3:24

In rare cases, the nodules can produce hormones regardless of TSH secretion, in which case they’re called hot, or toxic, nodules and they can lead to hyperthyroidism.
On histology, thyroid adenomas are follicular and there’s no capsular or vascular invasion. Moving on to thyroid carcinomas and there are 3 types: differentiated, medullary, and anaplastic.

Papillary carcinoma3:24–4:54

Let’s start talking about differentiated thyroid cancer, the cancer arises from follicular cells, and it's known as differentiated because the cancer cells look like normal thyroid cells.
Within the differentiated thyroid cancers there are two types of cancer that you’ll have to know for your exams: papillary carcinoma and follicular carcinoma.
Now, papillary carcinomas are the most common form of thyroid cancer and this is high yield! Thankfully they have an excellent prognosis.
They are associated with RET/PTC rearrangements and BRAF gene mutations as well as exposure to ionizing radiation during childhood.
The name “papillary” refers to the fact that these tumors have finger-like prolongations of follicle cells known as papillae that tend to grow slowly towards nearby lymphatic vessels and invade nearby lymph nodes in the neck.
Under the microscope, the nuclei of papillary carcinomas cells contain very few proteins and a small amount of DNA, and that gives the appearance of an empty nucleus, sometimes called an “Orphan Annie eye” nucleus based on an old famous cartoon character.
Another feature are psammoma bodies, which are calcium deposits within the papillae and you absolutely have to remember this for your exams.

Follicular carcinoma4:54–5:30

The second type, follicular carcinomas, represent the second most common form of thyroid cancer and they have a good prognosis.
This type of thyroid cancer is associated with the activation of RAS oncogene and PAX8-PPAR-gamma translocations which promotes proliferation.
In follicular carcinomas, the tumor develops from the follicular cells and grows until it breaks through the fibrous capsule.
Unlike papillary thyroid carcinomas, from there, follicular carcinomas can invade into nearby blood vessels and spread to other parts of the body.

Medullary thyroid carcinoma5:30–6:37

So moving beyond the differentiated thyroid cancers, there are medullary thyroid carcinomas which arise from C-cells. Most of the time, it forms because of a spontaneous mutation in the RET oncogene, and it’s usually a single carcinoma in one lobe of the thyroid.
Another high yield fact is that it’s associated with a hereditary condition called multiple endocrine neoplasia, or MEN, type 2A and 2B.
In these conditions, one or more of the endocrine glands like the thyroid gland, parathyroid gland, and adrenal gland develop tumors.
Under the microscope, medullary thyroid carcinoma is made up of spindle-shaped cells, which are called that because they’re long and skinny , like a spindle that’s used to spin fibers into thread.
C-Cells in the tumor make excessive amounts of calcitonin which deposits between the C-Cells. As the calcitonin deposits, the resulting clumps of protein stick together and form fibrous deposits called amyloid around the C-cells, which can be seen with Congo red stain.
Finally, there are the anaplastic thyroid carcinomas which are associated with mutations in the TP53 tumor suppressor gene.

Anaplastic thyroid carcinoma6:37–7:13

Anaplastic thyroid carcinomas are rare form of thyroid cancer that usually appears in older individuals and has a poor prognosis.
The altered cells don’t look anything like normal thyroid cells. It may be that these tumors derive from an existing papillary or follicular cancer where the cells mutate even more and become unrecognizable.
They often grow beyond the fibrous capsule of the thyroid gland and invade nearby structures. Most often the first sign of thyroid cancer is a solitary painless nodule in the thyroid gland.

Signs7:13–7:44

Typically, hard and immovable nodules are more likely to be tumors. If the tumor gets too big or invades the larynx or esophagus, it can cause hoarseness and trouble swallowing.
Although thyroid adenomas can sometimes cause hyperthyroidism, thyroid cancers are non functional so they usually do not present with signs of hyper or hypothyroidism.
The diagnosis of thyroid cancer often begins with imaging studies, like a thyroid ultrasound, which can help identify a thyroid nodule.

Diagnosis & Treatment7:44–8:57

Calcitonin levels are usually elevated in medullary thyroid carcinomas. A radioiodine scan can also be useful, that’s where radioactive iodine is ingested and taken up by cells that make thyroid hormone.
Usually, thyroid tumors don’t make thyroid hormone, so they appear as “cold nodules”. The diagnosis of thyroid cancer is usually confirmed by doing a fine-needle aspiration, where a thin needle is used to take small tissue samples from the thyroid nodule.
Treatment often involves partial thyroidectomy, after which complications can appear: First, there can be hypothyroidism if a large portion of the organ is removed.
Hoarseness can occur due to damage to the right recurrent laryngeal nerve which innervates most of the muscles in the larynx.
There could also be damage to the external branch of the superior laryngeal nerve that innervates the cricothyroid which can prevent the person from raising the pitch of their voice.
Hypocalcemia can also occur due to removal of the parathyroid glands. Allright, as a quick recap, Thyroid adenomas are benign and solitary growths on the thyroid.

Review8:57–10:16

Most often they are non-functional but in rare cases, can cause hyperthyroidism. Next there are three main types of thyroid cancer: differentiated, medullary, and anaplastic.
Differentiated thyroid carcinomas arises from follicular cells. The most common are papillary carcinomas and they are associated with RET/PTC rearrangements and BRAF gene mutations as well as exposure to ionizing radiation during childhood.
On histology, there are “Orphan Annie eye” nucleus and psammoma bodies. The second is follicular carcinomas which are associated with the activation of RAS oncogene and PAX8-PPAR-gamma translocations.
Moving beyond the differentiated thyroid cancers, we have medullary thyroid carcinomas which arise from C-cells and are often associated with RET mutations and MEN type 2A and 2B.
Finally, there are the anaplastic thyroid carcinomas. These are a rare form of thyroid cancer that usually appears in older individuals and are associated with TP53 mutations.
The diagnosis of thyroid cancer is done with fine-needle aspiration and treatment often involves thyroidectomy. Back to our cases.

Summary10:16–11:00

Dasha came in with a lump in her neck and echography confirmed that it was a cold thyroid nodule. After doing a fine needle aspiration, histology showed, empty appearing nuclei with central clearing, the so-called “Orphan Annie eyes” and psammoma bodies.
Her history of living close to Chernobyl, by that we need that she may have been irradiated, plus histology suggests that she has papillary carcinoma.
Mike also came in with a cold thyroid nodule, but in this case, histology showed spindle-shaped cells and amyloid around C-cells.
His family history of MEN type 2A and histology suggests medullary carcinoma. If genetic testing were to be done, it will probably show RET gene mutations.