The thyroid gland is an endocrine gland in
the neck that produces thyroid hormones. If the cells of the thyroid gland start to divide
uncontrollably, then that’s considered a thyroid cancer. Normally, the hypothalamus, which is located
at the base of the brain, secretes thyrotropin-releasing hormone, or ΤRH, into the hypophyseal portal
system – which is a network of capillaries linking the hypothalamus to the anterior pituitary.
The anterior pituitary then releases a hormone of its own, called thyroid-stimulating hormone,
thyrotropin or simply TSH. TSH stimulates the thyroid gland which is a gland located
in the neck that looks like two thumbs hooked together in the shape of a “V”. The entire
gland is covered in a thin, tough membrane called the fibrous capsule. If we zoom into
the thyroid gland, we’ll find thousands of follicles, which are small hollow spheres
whose walls are lined with follicular cells, and are separated by a small amount of connective
tissue. Follicular cells convert thyroglobulin, a protein found in follicles, into two iodine-containing
hormones, triiodothyronine or T3, and thyroxine or T4. Once released from the thyroid gland,
these hormones enter the blood and bind to circulating plasma proteins. Only a small
amount of T3 and T4 will travel unbound in the blood, and these two hormones get picked
up by nearly every cell in the body. Once inside the cell T­4 is mostly converted into
T3, at which point it can exert its effect. T3 speeds up the basal metabolic rate. So
as an example, they might produce more proteins and burn up more energy in the form of sugars
and fats. It’s as if the cells are in a bit of frenzy. T3 increases cardiac output,
stimulates bone resorption – thinning out the bones, and activates the sympathetic nervous
system, the part of the nervous system responsible for our ‘fight-or-flight’ response. Thyroid
hormone is important – and the occasional increase is like getting a boost to fight
off a zombie or to stay warm during a snowstorm! Thyroid hormones are also involved in a number
of other things, like controlling sebaceous and sweat gland secretion, hair follicle growth,
and regulating proteins and mucopolysaccharide synthesis by skin fibroblasts. 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.
Osteoclasts are bone cells that break down bone tissue which frees up the calcium to
enter the bloodstream. Calcitonin also inhibits renal tubular cell reabsorption of calcium,
allowing the calcium to be excreted in the urine. 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, such as PTEN 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. Over time,
a thyroid cell that divides uncontrollably, will lead to a lump of cells within the thyroid,
called a nodule. Most often, nodules are non-functional, so they don’t produce thyroid hormones, and
these are called “cold” nodules. Now, there are three main types of thyroid cancer: differentiated,
medullary, and anaplastic. In differentiated thyroid cancer, the cancer arises from follicular
cells, and it’s known as differentiated because the cancer cells look and act like normal
thyroid cells. Within the differentiated thyroid cancers there are three groups: papillary,
follicular, and Hṻrthle cell carcinoma. The first group, papillary carcinomas, represents
the most common form of thyroid cancer and is associated with RET and BRAF gene mutations
as well as exposure to ionizing radiation during childhood, as seen in kids near the
Chernobyl nuclear power plant accident. 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. The second type, follicular carcinomas, also
known as follicular adenocarcinomas, represent the second most common form of thyroid cancer.
This type of thyroid cancer is more frequent associated with countries where people have
low dietary iodine , but is also with the activation of RAS oncogene or the deactivation
of the tumor suppressor gene PTEN. In follicular carcinomas, the tumor develops from the follicular
cells and grows until it breaks through the fibrous capsule. From there, follicular carcinomas
can invade into nearby blood vessels and spread to other parts of the body like the lungs,
liver, bone, and brain, but interestingly they don’t typically invade nearby lymph
nodes. The third type, Hṻrthle cell carcinoma,
is a rare type of cancer and it’s considered a variant of follicular carcinoma. A tumor
can often cause immune cell to attack it, causing inflammation. Follicular cells in
the thyroid become adapt to cellular stress like inflammation by becoming Hṻrthle cells.
They do so by increasing the production of mitochondria which fills up their cytoplasm
and gives it a granular appearance and stains pink. These cells are also seen in disorders
like Hashimoto’s thyroiditis that where the thyroid is also inflamed. Like in follicular
carcinomas, Hṻrthle cells form neoplastic tumors that breaks through the fibrous capsule
and invade via the bloodstream. So moving beyond the differentiated thyroid
cancers, there are the medullary thyroid carcinomas which arise from C-cells. There’s a higher
concentration of C-cells in the upper ⅓ of the thyroid medulla which is where these
tumors usually arise. 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. But
sometimes it can arise as part of an inherited mutation like in familial medullary thyroid
carcinoma, which runs in families, and in those cases, there can be multiple carcinomas
across both lobes. It can also be 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. Calcitonin is a protein hormone, so as the calcitonin deposits, the
resulting clumps of protein stick together and form fibrous deposits called amyloids
around the C-cells. Tumors formed by C-cells can also release other hormones like serotonin
and vasoactive intestinal peptide which can cause increased gastrointestinal motility. Finally, there are the anaplastic thyroid
carcinomas. These are a rare form of thyroid cancer, named for having altered cells that
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. Under the microscope, anaplastic carcinomas typically contain spindle-shaped
cells as well as pleomorphic giant cells which are enlarged cells which vary in shape. These
cancers are the most aggressive compared to the other thyroid cancers. They often grows
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. Typically, the 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. Thyroid cancers are non functional so they
usually do not present with signs of hyper or hypothyroidism. In medullary thyroid carcinoma,
release of vasoactive intestinal peptide leads to diarrhea and increased serotonin levels
leads to flushing of the skin. The diagnosis of thyroid cancer often begins
with imaging studies, like a thyroid ultrasound, which can help identify a thyroid nodule.
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’re
“cold nodules”. The best way to be sure is to use fine-needle aspiration, where a
thin needle is used to take small tissue samples from the thyroid nodule, to identify the type
of tumor. The treatment of thyroid cancer depends mostly
on the type of cancer and how it has spread. Options include partial thyroidectomy where
the affected part is removed, or total thyroidectomy where the entire thyroid is removed, followed
by thyroid hormone replacement. All right, as a quick recap, thyroid cancer
is a cancer that forms in the thyroid gland. And it arises from either follicular cells
or C cells. There are three main types of thyroid cancer: differentiated, medullary,
and anaplastic. All the differentiated types arise from follicular cells and the most common
type is papillary carcinoma. Medullary carcinoma arise from the C-cells of the thyroid which
produce calcitonin. Diagnosis usually begins with a thyroid ultrasound and it’s confirmed
with a fine-needle aspiration. Treatment consists in a total or partial thyroidectomy.

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