Thyroid

The thyroid gland is a butterfly-shaped gland located in the front of the neck, just below the larynx. It consists of two lobes, one on each side of the trachea, connected by a thin piece of tissue called the isthmus. As the thyroid gland is formed it moves from the base of the tongue to its final position in the neck via the thyroglossal duct. Because of this migration, the thyroid gland can sometimes be found in other locations, such as higher up in the neck or even in the chest, known as an ectopic thyroid gland. Most often you end up with a small strip of thyroid gland extending superiorily from the isthmus, also called the pyramidal lobe.
Histologically the thyroid gland is made up of spherical structures called follicles, which are lined with a single layer of epithelial cells called follicular cells. The follicles are filled with a substance called colloid, which contains the precursor to thyroid hormones. (T3 and T4). Surrounding the follicles are parafollicular cells (also known as C-cells), which produce the hormone calcitonin. Between the follicles are connective tissue and blood vessels allowing for efficient transport of hormones.
Histology:

1. Follicular cells (epithelial cells) take up iodine and release it into the colloid where it is used to make precursers of T3 and T4. Which is then taken up by the follicular cells, again, cleaved by proteases, and released into the blood stream as T3 and T4.
2. Colloid contains thyroglobulin, a protein that is used to make thyroid hormones.
3. Parafollicular cells (C-cells) produce the hormone calcitonin, which inhibits osteoclast activity (cells that break down bone and release calcium into the blood), and also promote the excretion of calcium and phosphate in the kidneys. This results in a decrease in blood calcium levels.

How to activate the thyroid gland: The journey start in the hypothalamus where the thyroid receptor hormone (TRH) is secreted. This hormone than stimulates the anterior pituitary gland to secrete thyroid stimulating hormone (TSH). TSH travels to the thyroid where it connects to a transporter on the outer side of the follicular cells, which then activates a channel called the sodium-iodide symporter (NIS). This channel then takes up iodine and along with natrium transports it from the blood into the follicular cell. The iodine is oxidized within the cell and transferred into the lumen of the follicle or the colloid. Here the iodine is combined to tyrosine inside a protein called thyroidglobulin, becoming MIP and DIP. MIP and DIP are then combined to form T3 and T4, which are still bound to the thyroglobulin. When the body needs thyroid hormones, the follicular cells endocytose ("eat") some of the colloid containing the thyroglobulin with T3 and T4 attached. The vesicle containing the colloid fuses with a lysosome, where proteases cleave T3 and T4 from the thyroglobulin. The free T3 and T4 are then released into the bloodstream. In the blood, most of T3 and T4 are bound to carrier proteins, such as thyroxine-binding globulin (TBG), transthyretin, and albumin. Only a small fraction of T3 and T4 are free and biologically active. T4 is converted to the more active T3 in peripheral tissues by the enzyme deiodinase. T3 then enters cells and binds to thyroid hormone receptors in the nucleus, where it regulates gene expression and affects metabolism, growth, and development.

Thyroid Scintigraphy

Thyroid scintigraphy is a nuclear imaging technique that uses small amounts of radioactive material to evaluate the function and structure of the thyroid gland. The patient is injected with a small amount of radioactive iodine or technetium, which is taken up by the thyroid gland. A special camera, collimator, is used to detect and gather the radiation emitted by the radioactive material, and you are able to visualise the gland. As the radioactive material is also taken up by the salivary glands, most often they can be visualised as well.
Pros:

1. Great way to easily assess the thyroid tissue function

Cons:

1. Cannot detect lesions under 1 cm.
2. Cannot detect cold/hypofunctioning lesions if there is normal thyroid tissue in front or behind (here a SPECT/CT would be preferred, as you can then inspect the uptake in 3-D).
3. Radioactive material is used.

Symptoms:

Fatigue
Weight gain
Cold intolerance
Constipation
Hair thinning
Brain fog and depression
Bradycardia
Dry skin
Myxedema (swelling of the skin and underlying tissues)

Symptoms:

Anxiety
Heart palpitations
Heat intolerance
Tremors
Weight loss
Increased appetite
Swelling and darkening of shins
Thyroid enlargement (goiter)
Fatigue
Muscle weakness
Increased sweating
Frequent bowel movements, sometimes diarrhea
Menstrual irregularities
Exophthalmos (bulging eyes) - specific to Graves disease, an autoimmune reaction in the tissues around the eyes. Rare to see now due to early treatment.

• Prevalence: ~10% of all diagnosed thyroid cancers, but prevalence varies greatly according to study and population (from 5% to even 30%). Generally good prognosis, but worse than papillary thyroid carcinoma. More aggressive and more likely to metastasize via the bloodstream (to lungs and bones) than papillary thyroid carcinoma.
• Risk: radiation exposure, iodine deficiency.
• Histology: follicules made up of cuboidal cells (like normal thyroid follicles), but the lesion is surrounded by a fibrous capsule that is often thickened and sometimes irregular. The follicles can be small or large and the cells can be arranged in a microfollicular, trabecular, or solid pattern. The cells can have varying degrees of atypia, with enlarged nuclei and prominent nucleoli. The diagnosis of follicular carcinoma is based on the presence of capsular and/or vascular invasion, which can be difficult to assess on fine-needle aspiration biopsy. Therefore, a surgical excision is needed to make the diagnosis.
  - positive for thyroglobulin and TTF-1, and many other markers.
• Genetics: most often you will find mutations in the RAS gene and/or the PAX8-PPARγ1 translocation. Both of these mutations lead to activation of the MAPK and PI3K/AKT signaling pathways, which promote cell growth and division.

• Prevalence: 80-90% af all diagnosed thyroid cancers. Excellent prognosis. Aggressiveness seems to be uncertain, as autopsy studies have shown about 10% of people have small papillary thyroid carcinomas that never caused any symptoms or problems during their lifetime.
• Risk: increased risk in those who have been exposed to radiation or have a history of thyroid disease (such as goiter).
• Histology: is mostly based on nuclear morphology; the nuclei overlap each other and are enlarged and elongated/oval with central clearing (often referred to as Annie´s eyes). The nuclei can have grooves and inclusions. The cells are often arranged in papillary structures, hence the name, with fibrovascular cores. You can also sometimes see psammoma bodies (concentric calcifications).
  - positive for thyroglobulin and TTF-1.
• Genetics: most often caused by mutations in the BRAF gene (especially BRAF V600E) or RET/PTC rearrangements. Both of these mutations lead to activation of the MAPK signaling pathway, which promotes cell growth and division. BRAF V600E seems to be associated with a more aggressive form of papillary thyroid carcinoma, with a higher risk of recurrence and metastasis.

• Prevalence: about 5% of all thyroid cancers diagnosed, but rapports range from 1-10%. 25% of the cases are hereditary (MEN2A, MEN2B or familial medullary thyroid carcinoma (FMTC)). The prognosis is worse than for papillary and follicular thyroid carcinoma, but better than for anaplastic thyroid carcinoma.
• Risk: generally radiation exposure and those with congenital mutation in the RET-gene (MEN2A, MEN2B or FMTC).
• Histology: the cancer originates from the parafollicular cells or the "C-cells" and is therefore a neuroendocrine tumor as the C-cells are of neural crest origin. The cells are often arranged in solid nests, trabeculae, sheets or even follicles, and the cells can have a variety of shapes, including spindle-shaped, polygonal, or plasmacytoid. The cytoplasm can be granular ("salt and pepper") or clear, and the nuclei can be round or oval with prominent nucleoli. Amyloid deposits are often present in the stroma, which can be detected with Congo red staining. Sometimes you will find mucin.
  - positive for calcitonin, CEA, chromogranin A and synaptophysin.
• Genetics: certain mutations in the RET gene cause hereditary syndrome MEN2A, MEN2B and Familial MTC, which is associated with a high risk of developing medullary thyroid carcinoma. These mutations lead to activation of the RET tyrosine kinase receptor, which promotes cell growth and division. Sporadic cases of medullary thyroid carcinoma can also have mutations in the RET gene, as well as in other genes such as RAS and BRAF.

• Prevalence: 1-2% of all thyroid cancers and rare. Highly aggressive and locally invasive.
• Risk: as it is so rare, the risk factors are not well understood.
• Histology: the cells are undifferentiated and can have many different shapes and sizes, including spindle-shaped, giant, or squamoid. The cells can be arranged in sheets, nests, or trabeculae, and the cytoplasm can be abundant or scant. The nuclei are often pleomorphic and hyperchromatic, with prominent nucleoli. Mitoses are often numerous, and necrosis is common. The tumor can invade surrounding tissues, including blood vessels and nerves.
  - often positive for p53, Ki-67 (high proliferation index), and cytokeratins, but negative for thyroglobulin and TTF-1.
• Genetics: associated with many somatic mutations, for example in TERT (telomere gene), TP53 (oncogene), BRAF, RAS, and PIK3CA. These mutations lead to activation of various signaling pathways, including MAPK and PI3K/AKT, which promote cell growth and division. Considered somatic (and not hereditary) in most cases.