Pathology of the Thyroid Gland

Question 1

What is the pyramidal lobe of the thyroid? Where is it?

Answer 1

The lobe is a remnant of the thyroid’s descent via the thyroglossal duct. It will not always be present, but when it is, it will be on top of the isthmus

Question 2

What type of receptor is the TSH receptor? How do you know when the gland is very active, histologically?

Answer 2

Gs G-protein coupled receptor

Gland is very active when the cuboidal epithelium lying the thyroid follicles becomes more columnar

Question 3

What is the definition of thyrotoxicosis and what are some causes of primary hyperthyroidism?

Answer 3

Thyrotoxicosis - umbrella term meaning increased circulating levels of free T3 and T4

Primary hyperthyroidism:

1. Graves disease
2. Toxic adenoma
3. Toxic multinodular goiter

Question 4

What are is a cause of secondary hyperthyroidism? How about excessive release of stored thyroid hormones?

Answer 4

Secondary hyperthyroid = defect in pituitary or hypothalamus, i.e. TSH-secreting pituitary adenoma

Excessive release of stored hormones - thyroiditis

Question 5

What are typical clinical symptoms of hyperthyroidism? Why does a wide-eyed staring gaze happen? What is lid-lag?

Answer 5

Everything is faster since BMR is increased. Increased SANS since B1 adrenoceptors upregulated:
Heat intolerance, weight loss, tachycardia, arrhythmia, anxiety/tremor/insomnia, diarrhea

Staring gaze - due to excessive sympathetic activation of superior tarsal muscle, occurs with lid lag (eyes remain high during downgaze)

Question 6

What will happen to the bones and the reproductive system in women in thyrotoxicosis? Muscle mass?

Answer 6

Bones - osteoporosis due to excessive bone turnover

Reproductive - oligomenorrhea (light periods, irregular)

Muscle mass is decreased due to need for gluconeogenesis -> can lead to proximal myopathy

Question 7

What are the causes of primary hypothyroidism? Which is most common?

Answer 7

1. Autoimmune thyroiditis - Hashimoto’s, most common
2. Developmental disorders - i.e. thyroid agenesis
3. Iodine deficiency - common in developing work
4. Drugs - i.e. lithium / amiodarone
5. Thyroid ablation due to surgical resection / radiation

Question 8

What are the physical / mental features of cretinism?

Answer 8

Hypothyroidism in neonates

1. Mental retardation
2. Short stature with skeletal abnormalities
3. Coarse facial features
4. Enlarged, protruding tongue
5. Umbilical hernia

Question 9

What can myxedema refer to? This can be three things.

Answer 9

1. Hypothyrodism in late childhood or early adulthood. Most common refereence.
2. Pretibial myxedema - symptom of Graves’ hyperthyroidism with fibroblastic proliferation of shins
3. Coarsening of facial features with enlargement of the tongue due to deposition of GAGs which occurs in myxedema.

Question 10

Do hypo or hyperthyroidism cause hypercholesterolemia? What are the other signs of myxedema in an adult?

Answer 10

Hypothyroidism causes HYPERcholesterolemia (fucks with your lipids), while hyperthyroidism causes HYPOcholesterolemia

Other signs of hypo:
-Fatigue, slowed cognition, cold intolerance, weight gain, decreased exercise capacity, constipation
(opposite of hyper)

Question 11

What is the farthest inferiorly and superior thyroid tissue can be found?

Answer 11

Can be found at foramen cecum -> lingual thyroid

Can be found far down below the sternum -> substernal thyroid

Question 12

What is a thyroglossal duct cyst? How will it present?

Answer 12

Cyst formation from remnants of thyroglossal duct

-> Will present with a midline mass anterior to the trachea.

Question 13

What condition is most likely to cause pain in the thyroid?

Answer 13

Something that stretches the capsule very rapidly

-> i.e. acute infectious thyroditis

Question 14

What are some causes of acute and chronic infectious thyroiditis?

Answer 14

Acute - bacteria

Chronic - mycobacteria or fungi

Question 15

What HLA is associated with Hashimoto’s thyroiditis and who tends to get it, including age?

Answer 15

Associated with HLA-DR5
High five to Luke for being a sick dude!!

Usually occurs in middle aged women (40s-50s), happens in women 20:1

Question 16

What is the pathogenesis of Hashimoto’s thyroiditis? What antibodies are present and are they the cause of disease?

Answer 16

Sensitization of autoreactive CD4+ cells to thyroid antigens, causing activation of immune system.

CD8 T cells -> perforin/granzymes / Fas pathways.
Cytokine-mediated -> macrophage activation via IFNy
Antibody-dependent cell-mediated cytotoxicity via NK cells -> probable minor role of antibodies, more of a marker.

1. Antithyroglobulin antibodies
2. Anti-thyroperoxidase antibodies

Question 17

How does the thyroid appear microscopically in Hashimoto’s? What cells are characteristically seen?

Answer 17

Replacement of thyroid parenchyma with a diffuse mononuclear inflammatory infiltrate causing follicular atrophy
-> looks like a lymph node

Hurthle cell change - characteristic of this disease -> eosinophilic metaplasia of follicular cells, as they have no colloid to hold onto anymore.

Question 18

How does someone with Hashimoto’s initially present / what does it devolve into? Is it tender or painless?

Answer 18

Present with transient thyrotoxicosis due to inflammatory cell lysis, but eventually hypothyroidism will occur

The gland will be PAINLESS since the enlargement / inflammation isn’t that acute

Question 19

What is the patient at increased risk for if they have Hashimoto’s?

Answer 19

Marginal zone B cell lymphoma -> since the thyroid basically becomes like a lymph node

Question 20

What is the pathogenesis of Subacute Granulomatous Thyroiditis and what is it also called?

Answer 20

Also called De Quervain thyroiditis

Pathogenesis: Viral infection -> antigen-induced, CD8 T-cell mediated injury to thyroid follicular cells
-> It is a type of infectious thyroiditis, but we put it in its own class because of its unique histology

Question 21

What will be seen on histological study of De Quervain’s Thyroditis?

Answer 21

The lysis of the follicular cells causes colloid to be exposed to the surrounding environment which is not normally exposed
-> Causes mononuclear inflammation and formation of multinucleated giant cells / nonnecrotizing granulomas around collections of thyroid follicle.

Question 22

How does de Quervain’s thyroiditis progress clinically? Is it painful?

Answer 22

Self-limiting infection, but still an infection -> painful expansion of thyroid. Think deQuerVAIN’s = PAIN.

Transient thyrotoxicosis due to gland lysis, followed by hypothyroidism and eventual return to normal thyroid function.

Question 23

What is Subacute Lymphocytic Thyroiditis and who tends to get it? What is the pathogenesis?

Answer 23

Also called Painless thyroditis (vs de Quervain), it is an auto-immune mediated lymphocytic infiltrate, so it is more common in women. (Note: all thyroid conditions are more common in women)

However, it is especially common in POSTPARTUM women

Question 24

What does the thyroid look like in subacute lymphocytic thyroiditis and is it painful? What’s the clinical progression?

Answer 24

Thyroid looks mildly enlarged with a lymphocytic infiltrate, however it is subacute and vs de Quervain’s it is NONPAINFUL (autoimmune, non-infectious mediated)

Similar thyroid hormone level presentation as de Quervains: mild early thyrotoxicosis -> hypothyroid -> euthyroid resolution

Question 25

What is seen histologically in Riedel thyroiditis and what is the cause?

Answer 25

Think Riedel “fibrosing” thyroiditis -> thought to be an autoimmune mediated fibrosis of the thyroid gland with mild inflammatory infiltrate.

The fibrosis can extend to adjacent structures in the neck i.e. retroperitoneum.

Question 26

What can you confuse Riedel thyroiditis with and why? How does it present?

Answer 26

Simulates an invasive neoplasm such as anaplastic carcinoma since it invades surrounding structures with fibrosis

Presents as a “hard as wood” / rock hard PAINLESS goiter, some may be hypothyroid. But patients are generally too young to have anaplastic carcinoma and there are no malignant cells on biopsy.

Question 27

Who tends to get Graves’ disease and what HLA markers make you more susceptible to it?

Answer 27

Tends to occur in women of childbearing age (younger than Hashimoto’s)

Associated with HLA-DR3 and HLA-B8. Think of a mnemonic you fker.

Also associated with CTLA4 gene variants (loss of lymphocytic immune tolerance)

Question 28

What is the pathogenesis of Graves’ disease? What is the most common antibody?

Answer 28

Loss of localized CD4+ T cell tolerance -> production of auto-antibodies to TSH receptor
TSI = thyroid-stimulating immunoglobulin is most common antibody, though other may be present

Question 29

What causes the eye symptoms of Graves’ disease?

Answer 29

Orbital fibroblasts express the TSH receptor. They are stimulating by TSI antibodies, as well as cytokines from CD4 T cells (TNF-alpha, IFN-y) to proliferate
-> increased GAG synthesis and fatty infiltration in retro-orbital space = osmotic swelling and proptosis.

Question 30

What is seen histologically in Graves’ disease?

Answer 30

Diffuse thyroid hyperplasia, with thyroid follicles lined by tall columnar epithelium (very active). There will also be a lot of white areas near the edges of the colloid (“scalloping”) indicating rapid reuptake of produced thyroid.

B cell infiltrate will also B present.

Question 31

What is the skin manifestation of Graves’ disease? What causes it?

Answer 31

Pretibial myxedema - due to activation of dermal fibroblasts with the TSH receptor. Similar mechanism as infiltrative ophthalmopathy / proptosis

Question 32

What is the true definition of a goiter?

Answer 32

A goiter is a process by which impaired thyroid hormone synthesis leads to increased TSH secretion and thus thyroid follicular hyperplasia. It does not refer to Hashimoto’s or graves’ which is a “goitrous enlargement” where the thyroid is enlarging due to a pathologic process (i.e. inflammatory infiltrate, or nonstop stimulation of thyroid release)

Question 33

What is the spectrum in which true goiter which it exists in? What is meant by “toxic”?

Answer 33

Starts as a Diffuse, nontoxic goiter (i.e. patient remains euthyroid), but may progress overtime to a multinodular goiter with multiple hypertrophied nodules producing thyroid hormone.

Thyroid nodules become “toxic” when they become TSH-independent and start secreting T3/T4 without TSH stimulation

Question 34

What is the general underlying mechanism of goiter which causes diffuse -> multinodular?

Answer 34

There is some reason for impaired thyroid hormone synthesis, which leads to increased TSH secretion.

Persistent TSH stimulation causes variable response of thyroid follicular epithelial cells (initially diffuse, becomes nodular). This leads to uneven hyperplasia + areas of involution = nodules. Rupture of follicles / blood vessels causes hemorrhage / fibrosis of the bland, with dystrophic calcification. Surrounding areas are variably active -> multinodular

Question 35

What are the etiologies of goiter?

Answer 35

1. Iodine deficiency - most common in developing world
2. Hereditary enzyme defects in thyroid synthesis -> more TSH is needed to stimulate gland -> goiter
3. Ingestion of goitrogens -> i.e. brussel sprouts, cabbage, cauliflower
4. Idiopathic need for increased TSH to maintain euthyroid.

Question 36

When looking at “goiter” thyroid gland histologically, which cells are responding to TSH well with follicular hyperplasia vs not?

Answer 36

Responding well -> many follicular cells with tall epithelium, and minimal colloid in the center of their follicles (don’t have time to let the colloid build up)

Responding poorly -> thyroid follicles lined by flattened cuboidal epithelium, will have TONS of colloid stored up but not responding to TSH to release it.

Question 37

What is the hormonal thyroid state of most people with goiter?

Answer 37

Goiter -> clinically euthyroid, but have a goiter to maintain that euthyroid state.

Those with “toxic” multinodular goiter will have autonomous nodules and may present with hyperthyroidism

Question 38

How does a thyroid neoplasm usually present on clinical exam? Do they produce hormone?

Answer 38

Usually presents as a solitary, palpable thyroid nodule

These are usually benign nodules, and most commonly they do not produce hormone.

If they produce hormone, they are far more commonly benign than malignant.

Question 39

What is hot nodule vs a cold nodule? Which one is more likely malignant?

Answer 39

Based on the amount of radioactive iodine uptake. Hot = lots of uptake.

As just explained, hot nodules as in a goiter or Graves disease (more diffuse) are usually benign.

“Cold” nodules, or low uptake, are usually benign as well, but warrant biopsy. These ones can be malignant.

Question 40

What is the mechanism of biopsy of thyroid neoplasms?

Answer 40

Fine needle aspiration -> gland is too vascular to do a tissue biopsy, you’d legit bleed out.

Question 41

What is a benign neoplasm of the thyroid called, and what does it look like histologically? How can it be differentiated from a carcinoma?

Answer 41

Thyroid adenoma, usually a follicular adenoma with proliferation of thyroid follicles.

These have a well-circumscribed capsule. Differentiated from a follicular carcinoma via lack of invasion through capsule or vasculature.

Question 42

Can follicular adenomas produce hormone?

Answer 42

Yes. Although it’s benign, a very small % of these lesions will be functioning and produce thyrotoxicosis. These are “hot” lesions.

Question 43

What two types of thyroid carcinoma are associated with RET mutations. Which one is associated with an MEN, and what cell is it derived from?

Answer 43

1. Papillary carcinoma - associatied with RET fusion protein
2. Medullary carcinoma of thyroid (Parafollicular / C cell derivation) - associated with RET mutation, in MEN2A and MEN2B syndromes.

Question 44

What are the three types of thyroid carcinoma derived from follicular cells, which one is most common, and what mutations are associated with them?

Answer 44

1. Papillary carcinoma - most common, associated with RET mutation
2. Follicular carcinoma - associated with RAS mutations. Similar to follicular adenoma.
3. Anaplastic carcinoma - no mutation in particular

Question 45

What is the primary risk factor for papillary carcinoma of the thyroid and who tends to get it?

Answer 45

Risk factor: Exposure to ionizing radiation in childhood (i.e. lymphoma, acne treatment, nuclear radiation)

Tends to be seen in younger females

Question 46

What is the histologic appearance of papillary carcinoma and how is the diagnosis definitively made?

Answer 46

Typically a papillary growth structure, with psammoma bodies (since a papillary carcinoma).

Diagnosis definitively made based on nuclear features of the cancer, even in the absence of papillary growth pattern:

“Orphan Annie Eyes” - Empty-appearing nuclei with chromatin on the edge, and intranuclear grooves with a ground-glass appearance of the nucleus.

Question 47

Where does papillary thyroid carcinoma spread to and what is the prognosis?

Answer 47

Generally spreads to cervical lymph nodes regionally, the prognosis is very good even despite this.

Question 48

What is the risk factor for follicular carcinoma of the thyroid and how must diagnosis be made?

Answer 48

Increased prevalence in areas of endemic iodine DEFICIENCY.

Diagnosis is made via biopsy with detection of invasion through the capsule or into the vasculature! Need to biopsy the entire sample to tell
-> this is the reason why fine needle aspiration for a follicular adenoma is insufficient to rule out cancer.

Question 49

What is the pattern of spread of follicular carcinoma of the thyroid carcinoma and its prognosis?

Answer 49

Despite being a carcinoma, this is one of the few carcinomas which spreads hematogenously to lungs / bone. Remember this because it infiltrates VASCULAR structures (seen in lab). Other examples of carcinomas which do this are RCC, HCC, and choriocarcinoma.

Prognosis is actually pretty good, depending on tumor stage.

Question 50

Who tends to get anaplastic carcinoma and what must you differentiate it from? What is the prognosis?

Answer 50

Tends to occur in older patients. Need to differentiate from Riedel thyroditis which occurs in younger patients.

Cells are very anaplastic, prognosis is bone bad (100% mortality). Worst cancer ever.

Question 51

What symptoms does anaplastic carcinoma usually present with and why?

Answer 51

Rapidly enlarging neck mass with dysphagia, dyspnea, and sometimes dysarthria

• > local invasion of trachea -> dyspnea. Esophagus -> dysphagia.
• > dysarthria due to recurrent laryngeal nerve which wraps around thyroid, causing hoarseness

Question 52

What type of malignancy is Medullary carcinoma of the thyroid? How does this correlate with the histologic appearance of the malignant cells? What serum value should be measured before treatment?

Answer 52

It is a neuroendocrine tumor -> C cells are neuroendocrine cells

Expect to see salt and pepper chromatin because it is a neuroendocrine malignancy.

Serum value of calcitonin should be measured before treatment -> can monitor recurrence

Question 53

Is medullary carcinoma usually single or multiple? What symptoms can be seen?

Answer 53

Usually single -> most patients with this condition have it sporadically

May be multiple in the case of MEN2 -> familial RET mutations can lead to multiple masses. Warrants prophylactic thyroidectomy.

Question 54

Other than salt and pepper chromatin, what else can be seen histologically on examination of a medullary thyroid carcinoma?

Answer 54

Amyloidosis -> due to accumulated AE amyloid derived from calcitonin.