Pathology of the Thyroid Gland Flashcards
What is the pyramidal lobe of the thyroid? Where is it?
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
What type of receptor is the TSH receptor? How do you know when the gland is very active, histologically?
Gs G-protein coupled receptor
Gland is very active when the cuboidal epithelium lying the thyroid follicles becomes more columnar
What is the definition of thyrotoxicosis and what are some causes of primary hyperthyroidism?
Thyrotoxicosis - umbrella term meaning increased circulating levels of free T3 and T4
Primary hyperthyroidism:
- Graves disease
- Toxic adenoma
- Toxic multinodular goiter
What are is a cause of secondary hyperthyroidism? How about excessive release of stored thyroid hormones?
Secondary hyperthyroid = defect in pituitary or hypothalamus, i.e. TSH-secreting pituitary adenoma
Excessive release of stored hormones - thyroiditis
What are typical clinical symptoms of hyperthyroidism? Why does a wide-eyed staring gaze happen? What is lid-lag?
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)
What will happen to the bones and the reproductive system in women in thyrotoxicosis? Muscle mass?
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
What are the causes of primary hypothyroidism? Which is most common?
- Autoimmune thyroiditis - Hashimoto’s, most common
- Developmental disorders - i.e. thyroid agenesis
- Iodine deficiency - common in developing work
- Drugs - i.e. lithium / amiodarone
- Thyroid ablation due to surgical resection / radiation
What are the physical / mental features of cretinism?
Hypothyroidism in neonates
- Mental retardation
- Short stature with skeletal abnormalities
- Coarse facial features
- Enlarged, protruding tongue
- Umbilical hernia
What can myxedema refer to? This can be three things.
- Hypothyrodism in late childhood or early adulthood. Most common refereence.
- Pretibial myxedema - symptom of Graves’ hyperthyroidism with fibroblastic proliferation of shins
- Coarsening of facial features with enlargement of the tongue due to deposition of GAGs which occurs in myxedema.
Do hypo or hyperthyroidism cause hypercholesterolemia? What are the other signs of myxedema in an adult?
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)
What is the farthest inferiorly and superior thyroid tissue can be found?
Can be found at foramen cecum -> lingual thyroid
Can be found far down below the sternum -> substernal thyroid
What is a thyroglossal duct cyst? How will it present?
Cyst formation from remnants of thyroglossal duct
-> Will present with a midline mass anterior to the trachea.
What condition is most likely to cause pain in the thyroid?
Something that stretches the capsule very rapidly
-> i.e. acute infectious thyroditis
What are some causes of acute and chronic infectious thyroiditis?
Acute - bacteria
Chronic - mycobacteria or fungi
What HLA is associated with Hashimoto’s thyroiditis and who tends to get it, including age?
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
What is the pathogenesis of Hashimoto’s thyroiditis? What antibodies are present and are they the cause of disease?
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.
- Antithyroglobulin antibodies
- Anti-thyroperoxidase antibodies
How does the thyroid appear microscopically in Hashimoto’s? What cells are characteristically seen?
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.
How does someone with Hashimoto’s initially present / what does it devolve into? Is it tender or painless?
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
What is the patient at increased risk for if they have Hashimoto’s?
Marginal zone B cell lymphoma -> since the thyroid basically becomes like a lymph node
What is the pathogenesis of Subacute Granulomatous Thyroiditis and what is it also called?
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
What will be seen on histological study of De Quervain’s Thyroditis?
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.
How does de Quervain’s thyroiditis progress clinically? Is it painful?
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.
What is Subacute Lymphocytic Thyroiditis and who tends to get it? What is the pathogenesis?
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
What does the thyroid look like in subacute lymphocytic thyroiditis and is it painful? What’s the clinical progression?
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
What is seen histologically in Riedel thyroiditis and what is the cause?
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.
What can you confuse Riedel thyroiditis with and why? How does it present?
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.
Who tends to get Graves’ disease and what HLA markers make you more susceptible to it?
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)
What is the pathogenesis of Graves’ disease? What is the most common antibody?
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
What causes the eye symptoms of Graves’ disease?
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.
What is seen histologically in Graves’ disease?
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.
What is the skin manifestation of Graves’ disease? What causes it?
Pretibial myxedema - due to activation of dermal fibroblasts with the TSH receptor. Similar mechanism as infiltrative ophthalmopathy / proptosis
What is the true definition of a goiter?
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)
What is the spectrum in which true goiter which it exists in? What is meant by “toxic”?
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
What is the general underlying mechanism of goiter which causes diffuse -> multinodular?
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
What are the etiologies of goiter?
- Iodine deficiency - most common in developing world
- Hereditary enzyme defects in thyroid synthesis -> more TSH is needed to stimulate gland -> goiter
- Ingestion of goitrogens -> i.e. brussel sprouts, cabbage, cauliflower
- Idiopathic need for increased TSH to maintain euthyroid.
When looking at “goiter” thyroid gland histologically, which cells are responding to TSH well with follicular hyperplasia vs not?
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.
What is the hormonal thyroid state of most people with goiter?
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
How does a thyroid neoplasm usually present on clinical exam? Do they produce hormone?
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.
What is hot nodule vs a cold nodule? Which one is more likely malignant?
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.
What is the mechanism of biopsy of thyroid neoplasms?
Fine needle aspiration -> gland is too vascular to do a tissue biopsy, you’d legit bleed out.
What is a benign neoplasm of the thyroid called, and what does it look like histologically? How can it be differentiated from a carcinoma?
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.
Can follicular adenomas produce hormone?
Yes. Although it’s benign, a very small % of these lesions will be functioning and produce thyrotoxicosis. These are “hot” lesions.
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?
- Papillary carcinoma - associatied with RET fusion protein
- Medullary carcinoma of thyroid (Parafollicular / C cell derivation) - associated with RET mutation, in MEN2A and MEN2B syndromes.
What are the three types of thyroid carcinoma derived from follicular cells, which one is most common, and what mutations are associated with them?
- Papillary carcinoma - most common, associated with RET mutation
- Follicular carcinoma - associated with RAS mutations. Similar to follicular adenoma.
- Anaplastic carcinoma - no mutation in particular
What is the primary risk factor for papillary carcinoma of the thyroid and who tends to get it?
Risk factor: Exposure to ionizing radiation in childhood (i.e. lymphoma, acne treatment, nuclear radiation)
Tends to be seen in younger females
What is the histologic appearance of papillary carcinoma and how is the diagnosis definitively made?
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.
Where does papillary thyroid carcinoma spread to and what is the prognosis?
Generally spreads to cervical lymph nodes regionally, the prognosis is very good even despite this.
What is the risk factor for follicular carcinoma of the thyroid and how must diagnosis be made?
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.
What is the pattern of spread of follicular carcinoma of the thyroid carcinoma and its prognosis?
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.
Who tends to get anaplastic carcinoma and what must you differentiate it from? What is the prognosis?
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.
What symptoms does anaplastic carcinoma usually present with and why?
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
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?
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
Is medullary carcinoma usually single or multiple? What symptoms can be seen?
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.
Other than salt and pepper chromatin, what else can be seen histologically on examination of a medullary thyroid carcinoma?
Amyloidosis -> due to accumulated AE amyloid derived from calcitonin.
