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Thyroid nodules and thyroid cancer: Pathology review

Thyroid nodules and thyroid cancer: Pathology review


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USMLE® Step 1 style questions USMLE

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A 45-year-old woman is evaluated for voice changes after thyroid surgery. The patient was diagnosed with papillary thyroid cancer and subsequently underwent thyroidectomy. Immediately after the surgery, she noticed some mild voice changes, but the doctor informed her that this is usually transient due to local edema and will likely self-resolve. Currently, the patient describes only mild voice and pitch changes but denies any dysphagia. On physical examination, sensation of the mucosa above the glottis is intact. After evaluation, the doctor suspects an isolated unilateral paralysis of the cricothyroid muscle. Which of the following nerves demonstrated in the picture below was most likely injured during the surgery?


Content Reviewers:

Yifan Xiao, MD

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.

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.

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.

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.

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.

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.

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.


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.

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