Download Pathology Chapter 24 p1107-1130 [4-20

Pathology Chapter 24: The Endocrine System (pages 1107-1130)
The thyroid gland has 2 bulky lateral lobes connected by a thin isthmus, usually below and anterior the
larynx
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The thyroid is divided by thin fibrous septae into lobules made of many follicles, which are filled
with thyroglobulin, which stains PAS positive
o The follicles are lined by epithelium
In response to things from the hypothalamus, thyrotrophs in the anterior pituitary release
thyroid-stimulating hormone (TSH, aka thyrotropin)
TSH then binds to its receptor on the thyroid follicle epithelium
o This causes a conformational change and activation of the receptor, allowing it to
associate with a G protein
o Activation of the G protein eventually results in an increase in intracellular cAMP, which
stimulates thyroid growth, and hormone making and release
When the thyroid stops listening to TSH and hyperfunctions, it’s called thyroid autonomy
Thyroid follicular epithelial cells convert thyroglobulin into mainly thyroxin (T4), and lesser
amounts of triiodothyronine (T3)
T4 and T3 are released into systemic circulation, where they reversibly bind to plasma proteins,
like thyroxine-binding globulin and transthyretin, for transport to peripheral tissues
o The binding proteins help to maintain serum unbound (“free”) T3 and T4 concentrations
within narrow limits so that is just enough to meet the tissues’ needs
In the periphery, most of the free T4 is deiodinated to T3
T3 then binds to thyroid hormone nuclear receptors in target cells with more affinity than T4
would, and has more activity than T4
When thyroid hormone interacts with its nuclear thyroid hormone receptor (TR), it forms a
complex that then goes to thyroid hormone response elements (TREs) in target genes
Thyroid hormone does things to increase the basal metabolic rate
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This includes triggering carb and lipid break down, and stimulating protein making in cells
One of the most critical roles of thyroid hormone is in brain development in the fetus and
newborn
Goitrogens are agents that can inhibit thyroid hormone making
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When goitrogens inhibit thyroid hormone making, it triggers TSH to be released and increase,
which leads to hyperplastic enlargement of the thyroid gland, called goiter
Propylthiouracil – drug that inhibits oxidation of iodide, causing a block in the making of thyroid
hormones
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Propylthiouracil also inhibits peripheral deiodination of circulating T4 to T3, fixing symptoms of
thyroid hormone excess
Giving people with a hyperfunctioning thyroid iodide, also blocks the release of thyroid hormones
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In large doses, iodide inhibits proteolysis of thyroglobulin (so the hormones aren’t cleaved off it)
o So the thyroid hormone is made and put into colloid, but not released inot the blood
Thyroid gland follicles also have parafollicular (C) cells, which make and release calcitonin
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Calcitonin promotes the absorption of calcium by the bones, and inhibits resorption of bone by
osteoclasts
Thyrotoxicosis is a hypermetabolic state caused by elevated levels of free thyroxine and T3
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Since thyrotoxicosis is usually caused by overfunctioning of the thyroid, it’s called
hyperthyroidism
Sometimes though, the thyroid isn’t overfunctioning, and the problem could be excessive
release of premade thyroid hormone (thyroiditis) or by an extrathyroidal source
o A lot of people use the terms hyperthyroidism and thyrotoxicosis interchangeably
The three most common cause of thyrotoxicosis are from hyperfunctioning of the thyroid:
o Diffuse hyperplasia of the thyroid- like in Grave’s disease
o Hyperfunctional goiter
o Hyperfunctional cancer of the thyroid
The symptoms from hyperthyroidism are from the hypermetabolic state it causes, and
overactivity of the symps
Excessive thyroid hormone increases the basal metabolic rate, making the skin soft, warm, and
flushed, due to increased blood flow and peripheral vasodilation to lose the heat
o This causes heat intolerance to be common
o The increased metabolic rate causes sweating to increase
o The increased metabolic rate can also cause weight loss despite an increased appetite
Heart changes are among the earliest and most consistent feature of hyperthyroidism
o Includes increased cardiac output, due to increased contractility and oxygen
requirements, tachycardia, palpitations, and enlarged heart
o Arrhythmias and heart failure are more common in older people
o Some people can develop reversible left ventricular dysfunction and “low output” heart
failure, called thyrotoxic or hyperthyroid cardiomyopathy
o Hyperthyroidism can make pre-existing heart problems worse
Neuromuscular problems from hyperthyroidism are signs of an overactive symp system,
including tremor, hyperactivity, emotional and anxiety issues, insomnia, and thyroid myopathy
(muscle weakness and decreased muscle mass)
Eye changes in thyroid conditions can be a wide, staring gaze and lid lag, due to symps
overstimulating the levator palpebrae – page 1109
o True thyroid opthalmopathy causing proptosis is only seen in Grave’s disease
In the GI, hyperthyroidism causes hypermotility, malabsorption, and diarrhea
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In the skeletal system, thyroid hormone stimulates bone resorption, which can cause
osteoporosis and easy fractures during chronic hyperthyroidism
Thyroid storm- medical emergency of severe abrupt hyperthyroidism
o Thyroid storm happens most often in people with underlying Grave’s disease
o Probably caused by an acute increase in cathecholamine levels, like during an infection,
surgery, or stopping antithyroid medicines, or any form of stress
o They usually present with a fever, and can progress to tachycardia and death by cardiac
arrhythmia
Apathetic hyperthyroidism- thyrotoxicosis in old people, where effects of aging blunt the
features of the hyperthyroidism
o Often not noticed until they’re losing weight or get blood work for heart problems
The measurement of serum TSH concentration is the most useful screening test for
hyperthyroidism
o Hyperthyroidism decreases TSH release right away, even before symptoms show up
o Once a low TSH is seen, free thyroxine is measured, and the diagnosis of
hyperthyroidism is confirmed if it is increased
If you inject them with TRH and see a rise in TSH after, it excludes secondary (pituitary)
hyperthyroidism
Once you’ve diagnosed them with hyperthyroidism, you can use radioactive iodine to see what
part of the thyroid is the problem, which can help you determine the cause
o Graves- increased uptake of the iodine
o Toxic adenoma- only increased uptake at one part
o Thyroiditis- decreased uptake
Quick drug summary:
o β-blockers- stop sympathetic symptoms
o Thionamide-blocks new hormone making
o Iodine-blocks release of the thyroid hormone
Hypothyroidism is usually a primary (intrinsic at the thyroid) condition, that can lead to goiter (enlarged
thyroid, from compensatory rise in TSH)
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Hypothyroidism is caused by anything that decreases the making of thyroid hormone
Hypothyroidism is somewhat common (up to 4 of people), and risk increases with age
o Hypothyroidism is way more common in women
Primary hypothyroidism can be congenital, acquired, or autoimmune
Congenital hypothyroidism is usually caused by endemic iodine deficiency in the diet
o Can also be an inborn error in thyroid hormone making (called dyshormonogenetic
goiter) at:
 Iodide transport into the thyrocytes
 Iodide organification - when iodide binds to the tyrosines of thyroglobulin (the
storage protein)
 Coupling to form active thyroid hormones
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Mutations to thyroid peroxidase are the most common cause of dyshormonogenetic
goiter
o Pendred syndrome- mutation to the gene for pendrin, causing hypothyroidism and
sensorineural defects
 Pendrin is an anion transporter on the apical surface of the thyrocyte
o Thyroid hormone resistance syndrome – the thyroid hormone receptor can’t bind
thyroid hormone
 Both thyroid hormones and TSH will be high in this case
Acquired hypothyroidism can be caused by surgery or radiation-induced destruction of the
thyroid
o Often a result of getting rid of too much thyroid when treating hyperthyroidism
Autoimmune hypothyroidism is the most common cause of hypothyroidism in parts of the
world that have plenty of iodine
o Most autoimmune hypothyroidism cases are Hashimoto thyroiditis
 Autoantibodies like anti-microsomal, anti-thyroid peroxidase, and antithyroglobulin are found
 Usually causes goiter
Secondary hypothyroidism is caused by a deficiency of TSH, or sometimes TRH
o Pituitary problem
Classical manifestations of hypothyroidism include cretinism and myxedema
o Cretinism- hypothyroidism in infancy or childhood
 Causes impaired skeletal system and CNS development, showing mental
retardation, shortness, coarse facial features, a protruding tongue, and
umbilical hernia
 The amount of retardation depends on when the kid is exposed to less thyroid
hormone
 Normally, mom thyroid hormones cross the placenta and are needed
for fetal brain development
 Mom hypothyroidism during the period of brain development is the
worst
o Myxedema- hypothyroidism in older children and adults
 Shows slowing physical and mental activity
 Shows fatigue, mental sluggishness (which both can resemble
depression), cold intolerance, weight gain
 Symps are decreased, so you get constipation and decreased sweating
 Often their skin is cool and pale because of decreased blood flow
 Decreased cardiac output happens, and can decrease exercise capacity and
cause shortness of breath
 Hypothyroidism also causes increase in total cholesterol and decrease in HDL
 They also have accumulation of ECM stuff, like glycosaminoglycans and
hyaluronic acid in the skin and viscera
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This causes edema, broadening and coarsening of facial features,
enlargement of the tongue, and deepening of the voice
Measuring TSH is the most sensitive screening test for hypothyroidism
o It will be increased in primary hypothyroidism
o TSH won’t be increased in secondary hypothyroidism, like a pituitary problem
o Thyroxine will always be decreased with any kind of hypothyroidism
Thyroiditis- inflammation of the thyroid gland
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Inflamed thyroids can cause neck pain and tenderness at the thyroid
o Infections can cause fever and other systemic signs too
Hashimoto thyroiditis
o Hashimoto thyroiditis is the most common autoimmune thyroiditis, and the most
common cause of hypothyroidism in parts of the world that get enough iodine
o Hashimoto thyroiditis is characterized by gradual thyroid failure due to autoimmune
destruction of the thyroid
o It’s most common from ages 45-65
o The autoimmunity destroys the thyroid
o More common in women, and in middle-aged people
o Commonly caused by mutations to CTLA4 and PTPN22 (both inhibit T cells)
o Most cases of Hashimoto thyroiditis will involve circulating antibodies against
thyroglobulin and thyroid peroxidase
o The autoimmunity causes apoptosis of thyrocytes, and their replacement with
inflammatory cells and fibrosis
o Ways autoimmunity can kill the thyroid cells:
 CD8+ caused death
 Cytokine caused death – excessive T cell activation leads to making of
cytokines from TH1, like interferon-γ, which causes macrophage to kill the
thyroid follicles
 Binding of anti-thyroid antibodies – includes anti-thyroglobulin and anti-thyroid
peroxidase
o Hashimoto shows goiter (enlarged thyroid) and lymphocytic inflammatory infiltrate
 Also shows atrophic thyroid follicles, lined with Hurthle cells (epithelial cells
with an eosinophilic, granular cytoplasm)
 Hurthle cells are characteristic of Hashimoto thyroiditis, and they are a
metaplastic response by the epithelium to ongoing injury
 Morphology also shows fibrosis only within the capsule of the gland, unlike
Reidel thyroiditis
 Classic Hashimoto thyroiditis shows increased interstitial connective tissue
o The classic presentation of Hashimoto thyroiditis would be a middle-aged woman
coming in with painless goiter and some degree of hypothyroidism
 The enlargement of the thyroid is symmetric
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Some cases can involve hasitoxicosis, where before the hypothyroidism begins,
antibodies destroy enough thyroid follicles to cause release of the colloid and all the
stored thyroid hormones, causing a temporary hyperthyroidism
o People with hashimoto thyroiditis are at risk for developing other autoimmune diseases
Subacute granulomatous thyroiditis (aka De Quervain thyroiditis)
o De Quervain (granulomatous) thyroiditis is the most common cause of thyroid pain
 Usually De Quervain is just a temporary thyroid inflammation and
hyperthyroidism that will go away in 6-8 weeks
o Another one more common in middle-age and women
o De Quervain thyroiditis is thought to be triggered by a virus, usually an upper
respiratory infection
o Occurs more often in the summer
o The thyroid may be unilaterally or bilaterally enlarged
o Instead of looking rubbery and brown like normal thyroid, De Qeurvain thyroiditis will
look yellow-white and firm
o Inflammation occurs, including multinucleate giant cells that give it the name
granulomatous
o They have high thyroid hormones, but unlike in Grave’s disease, radioactive uptake of
iodine is decreased (thyroiditis)
Subacute lymphocytic thyroiditis (aka painless thyroiditis)
o Usually brings them in for goiter and mild hyperthyroidism
o Again, more common in middle age, and women
o Postpartum thyroiditis is an example of a lymphocytic painless thyroiditis, that happens
in 5% of women
o Some of these patients can transition from hyperthyroid to hypothyroid
o Also includes Riedel thyroiditis, a rare one that causes fibrosis of the neck
o Only shows a lymphocytic infiltrate, other than that the thyroid looks normal
Grave’s disease – the most common cause of endogenous hyperthyroidism
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Characterized by 3 things:
o Hyperthyroidism
o Ophthalmopathy that causes exophthalmos (protruding eye)
o Dermopathy called pretibial myxedema
Most often occurs between 20-40 years of age
Women have Grave’s disease way more than men do
Grave’s disease and Hashimoto make up the two extremes of thyroid autoimmune disorders
o Grave’s – hyperthyroid, Hashimoto-hypothyroid
Like Hashimoto, Grave’s has also been linked to gene problems with CTLA4 and PTPN22
Grave’s disease is characterized by an autoimmunity to the TSH receptor
Grave’s results in many antibodies, including:
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Thyroid-stimulating antibody- an IgG that binds to the TSH receptor and mimics TSH,
causing continuous stimulation of the thyroid follicle to make thyroid hormone
 Almost all cases of Grave’s have thyroid-stimulating Ig, and they’re specific for
Grave’s disease, unlike the other 2 Ig’s seen
o Thyroid-growth stimulating Ig- also targets the TSH receptor and causes proliferation of
the follicle epithelium
o TSH-binding inhibitor Ig- bind and inhibit TSH, and can also mimic TSH
 So it can both stimulate and inhibit thyroid hormone making
The ophthalmopathy in Grave’s shows increased volume of the extraocular eye muscles and
connective tissues, caused by:
o T cells infiltrating the retro-orbital space
o Swelling of eye muscles
o Accumulation of ECM stuff, like HA and chondroitin sulfate
o Fatty infiltration
o All of these displace the eye forward and interfere with the function of the eye muscles
Morphology of Grave’s:
o Grave’s has a goiter from hypertrophy & hyperplasia of thyroid follicular epithelial cells
 The thyroid will be symmetrically enlarged
o Colloid in the follicles is pale – everything’s getting pushed out of it
o There’s a lymphocyte infiltrate of mainly T cells
o Treating with iodine causes involution of the epithelium and accumulation of colloid,
due to blocked thyroglobulin secretion
o Treating with propylthiouracil makes the hyperplasia and hypertrophy worse by
stimulating TSH secretion
o The heart can hypertrophy
The enlargement of the thyroid in Grave’s can be accompanied by an increased flow of blood
through the thyroid, causing an audible bruit
Grave’s causes symp overactivity that causes a characteristic wide, staring gaze, and lid lag
Graves causes exophthalmos-protrusion of the eyeball
Graves can cause pretibial myxedema (dermopathy), which will look scaly and thick
They’re at risk for other autoimmune diseases
Tests for Graves show increased free thyroid hormone, and decreased TSH
o Radioactive iodine uptake will be increased
Diffuse and multinodular goiters show impaired making of thyroid hormone, most often caused by a
dietary deficiency
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Causes a compensatory rise in TSH, causing hypertrophy and hyperplasia of the thyroid
follicular cells, causing a goiter
o So anything that stimulates the follicles (TSH, things that act like it like Grave’s) will
cause goiter
Usually, this is enough to return the person to a euthyroid (normal) state of thyroid hormone
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If it doesn’t work, you get hypothyroidism with a goiter
Diffuse nontoxic (simple) goiter - goiter without nodules
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More common in females
Can be called colloid goiter because the enlarged follicles are often filled with colloid
Endemic goiters happen in places where food supplies are low in iodine
o Less iodine means less thyroid hormone making and more TSH, causing goiter
o Some foods can interfere with thyroid hormone making and are called goitrogens
 Ex: cabbage, cauliflower, cassava
Goiter can also be caused by hereditary enzyme defects that interfere with thyroid hormone
making
Two morphologic phases to a diffuse nontoxic goiter:
o Hyperplastic phase- symmetric enlargement of the thyroid
o Colloid involution- when the colloid fills the follicles
Usually, the TSH increase makes them euthyroid (their thyroid hormone levels are
compensated)
o So any problems they have are from mass effects from the enlarged thyroid – page 1117
o So thyroid hormones are normal, but TSH would be high
Multinodular goiter
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All chronic simple goiters will convert to a multinodular goiter at some point
Multinodular goiters cause extreme enlargements, and are often confused with cancer
It’s thought that multinodular goiter can happen because of variations in the response of
follicular cells to external stimuli
o If some follicular cells have some sort of growth advantage, they can give rise to clones
of proliferating cells to form a nodule
o Nodules can grow without an external stimulus
o Mutations to the TSH signaling pathway that cause continuing activation of making TSH
can cause these nodules
The development of the nodule produces stress that can rupture follicles and vessels leading to
hemorrhage, scarring, and calcification
Multinodular goiters are multilobulated asymmetrically enlarged thryoids
Unlike cancers, multinodular goiter does not have a capsule between the hyperplastic nodules
and thyroid parenchyma
Symptoms of a multinodular goiter are caused by such a big mass
o It can compress airways and vessels in the neck or upper thorax
Most of them are euthryoid, or have subclinical hyperthyroidism (seen only as low TSH)
Plummer syndrome – the minority of cases where the nodule in a chronic goiter becomes
autonomous, causing hyperthyroidism
o There won’t be any eye problems, like there are in Graves
o Most of these nodules won’t become cancerous, but it’s possible
Single solitary nodules on an otherwise normal thyroid are more common in women, and happen more
as you get older
Most solitary nodules (growths) on the thyroid turn out to not be cancer, or to just be a benign
neoplasm
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1% of solitary thyroid nodules are malignant
The few cases that are cancerous have a good survival rate
Solitary nodules are more likely to be cancerous than multiple nodules
Nodules in younger people are more likely to be cancerous
Nodules in males are more likely to be cancerous
Nodules that take up radioactive iodine (hot nodules) are much more likely to be benign
Radiation to the head and neck increases the risk for thyroid cancer
You check a nodule for cancer by fine-needle aspirating it
Thyroid adenoma – page 1119
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Thyroid adenomas are usually solitary masses derived from the follicular epithelium
o So they’re often called follicular adenomas
Most adenomas are nonfunctional, but a minority can make thyroid hormones to cause
hyperthyroidism
o Those that do make thyroid hormone are called toxic adenomas, and don’t listen to
TSH
Half of thyroid adenomas have gain-of-function mutations to the TSH receptor, which allows
the follicular cells to secrete thyroid hormone without any TSH stimulation
o This includes mutations to the α-subunit of the G protein, coded by the GNAS gene
o These mutations are rare in follicular carcinomas, which is why most of these won’t
progress to carcinoma
The thyroid adenoma will be well separated from adjacent thyroid tissue by a well-defined
capsule
o This is important in telling the difference between adenoma, and multinodular goiters
or carcinomas, and a capsule is the hallmark of a follicular adenoma
It’s common to see hemorrhage, fibrosis, and calcification in thyroid adenomas, just like in
multinodular goiters
Sometimes, the neoplastic cells develop brightly eosinophilic granular cytoplasm, called oxyphil
or Hurthle cell change – page 1119 bottom right pic
o These ones act exactly like the adenomas that don’t develop this
Malignancy is more common in cold nodules than hot nodules (those that make thyroid
hormone)
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o Those that make thyroid hormone will take up radioactive iodine
You can only diagnose a follicular adenoma with histology because the diagnosis is the integrity
of the capsule
Usually, a follicular adenoma presents as a unilateral painless mass
o Larger ones can cause mass effect symptoms, like problems swallowing
Follicular adenomas have a great prognosis and don’t recur or metastasize
Most follicular adenomas won’t progress to carcinomas, but they are able to
o A minority of follicular adenomas has mutations to RAS, PIK3CA, or have a PAX8-PPARG
fusion gene, which are all mutations you also see in follicular carcinomas
Thyroid carcinomas
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Thyroid carcinomas are uncommon, and more common in women if it’s an adult
Most thyroid carcinomas, except medullary carcinomas, are derived from the thyroid follicular
epithelium, and most are well differentiated
The four major thyroid carcinomas are: papillary, follicular, anaplastic, and medullary
o Papillary thyroid carcinomas are by far the most common
The two common pathways where the follicular cancers (all except medullary) comes from are
the MAP kinase pathway, and the PI3/AKT pathway
o In normal cells, theses pathways are temporarily (transiently) activated by the binding of
a growth factor ligand to a receptor tyrosine kinase, causing autophosphorylation of the
receptor, causing signal transduction into the cell
o In carcinomas, a mutation leads to constant activation even when there’s no ligand
o Papillary carcinoma- usually activates the MAP kinase pathway
 Can do so by rearranging RET or NTRK1, which both encode receptor tyrosine
kinases, or by a mutation in BRAF
 Normally, the tyrosine kinase coded for by RET is not expressed in a thyroid
follicle cell
 Papillary cancers move the RET gene so that the tyrosine kinase will be
expressed in the thyroid follicle cells
 The RET gene is moved so that it fuses with the gene of something is
expressed normally
 There’s many genes it can fuse with, but in general it’s just called a
RET/papillary thyroid carcinoma (PTC) gene
 The now expressed tyrosine kinase then activates the MAP kinase
pathway
o Follicular carcinomas- often have an activating mutations to the PI3K/AKT pathway
 This includes activating mutations to RAS and PIK3CA, and inhibiting mutations
to PTEN tumor suppressor
 Follicular carcinomas also show fusion of the PAX8 gene with a peroxisome
proliferator gene (PPARG)
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Anaplastic (undifferentiated) carcinomas – very aggressive and lethal tumors that can
arise denovo, or from de-diferrentiation of the other forms
 They express more mutations and more often express them than the others
o Medullary carcinomas- usually involve RET mutations
The major environmental risk factor for thyroid cancer is ionizing radiation
o Iodine deficiency is also linked to increasing the risk for follicular cancers
Papillary carcinoma- by far the most common thyroid cancer
o Can happen at any age, but are most common between 25-50
o Most thyroid cancers from radiation are papillary carcinomas
o The hallmarks of a papillary carcinoma are – page 1121
 Branching papillae – have a fibrovascular stalk
 Nucleus with dispersed chromatin, giving a clear appearance called the
“ground glass” or “orphan annie eye” nuclei
 May also see intranuclear inclusions or grooves
 The diagnosis of papillary carcinoma is made base on these features in
the nucleus
 Psammoma bodies- calcified structures, almost never seen in follicular and
medullary carcinoma
 Signs of the tumor invading the lymphatics
o The follicular variant of papillary carcinoma- has the characteristic nucleus of a papillary
carcinoma, but looks follicular
 Most common variant of papillary carcinoma
 Has a mutation in BRAF and sometimes RAS, and less RET/PTC fusions
 It’s encapsulated and metastases less often than other papillary carcinomas
o Tall cell variant – has tall columnar cells with very eosinophilic cytoplasm lining the
papillary structures
 These ones invade the blood more and leave the thyroid more, and almost
always have BRAF mutations
o Diffuse sclerosing variant – includes fibrosis along with the papillary growth pattern
o Most papillary carcinomas present as asymptomatic thyroid nodules that can be moved
around freely
o Papillary carcinomas are cold masses
o Papillary carcinomas have a great prognosis
Follicular carcinoma – page 1123
o More common in women, and present at an older age than papillary carcinomas
o Follicular carcinomas are more common in places with dietary iodine deficiency
o Most follicular carcinomas are made of uniform cells forming small follicles containing
colloid, like normal thyroid
o Their nucleus doesn’t have the features that papillary carcinoma does, and there’s no
psammoma bodies
o Spread to the lymphatics is not common in follicular carcinoma, so they don’t go to
lymph nodes
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Follicular carcinomas commonly involve vascular spread with metastases throughout
the body, unlike follicular adenomas
o The more invasive the follicular carcinoma is, the worse the prognosis
o Most follicular carcinomas are cold nodules
o Most are treated with thyroidectomy
Anaplastic (undifferentiated) carcinoma – undifferentiated tumors of the thyroid follicular
epithelium
o They are extremely aggressive and almost always lethal
o Occur in older people
o The tumor will have large giant cells and spindle cells
o Anaplastic carcinomas usually present as a rapidly enlarging neck mass, that has spread
beyond the thyroid capsule into other parts of the neck
o Death usually results from the rapid compromise of vital structures in the neck
Medullary carcinoma- tumors of the parafollicular (C) cells of the thyroid
o Medullary carcinomas secrete calcitionin
o Cases can be sporadic, or familial
 Sporadic will show up as a single nodule, while familial can have multiple
nodules, and be part of multiple endocrine neoplasia syndromes (MEN)-p 1125
 MEN happens from RET mutations
o Medullary carcinomas can also secrete VIP (causing diarrhea) or ACTH (causing Cushign
syndrome)
o MEN’s often also include tumors in the adrenals and the parathyroids
Thyroglossal duct cysts are remnants from the development of the thyroid
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They can become infected and even cancerous
There are 4 parathyroid glands, made mostly of chief cells
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Chief cells have granules holding parathyroid hormone (PTH)
Often chief cells have a “water-clear” appearance from lakes of glycogen
The parathyroids also have larger oxyphil cells, which show eosinophilic cytoplasm and tons of
mitochondria, but few granules
In infancy, the parathyroids are made almost entirely of sheets of chief cells, but then the
stromal fat in the parathyroid increases as you age, peaking at a 1/3 the parathyroids at age 25
Parathyroid gland activity is controlled by the level of free (ionized) calcium in the blood
o Decreased free calcium stimulates making and release of PTH
Jobs of PTH – to increase the level of free calcium
o PTH increases reabsorption of calcium in the kidney tubules
o PTH increases conversion of vitamin D to its active form in the kidneys
o PTH increases excretion of phosphates in the urine
o PTH increases calcium absorption in the GI
Once free calcium in the blood is increased by PTH, the calcium inhibits any more PTH release
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So excessive PTH can cause hypercalcemia
Hypercalcemia is one of the most common complications of malignant tumors
o So if hypercalcemia is symptomatic, it’s more often from cancer, while if it’s
asymptomatic, it’s more often primary hyperparathyroidism
o Cancers that cause hypercalcemia are usually more advanced, and so have a worse
prognosis
o Hypercalcemia from malignancy is caused by increased bone resorption that releases
the calcium, by either a tumor that invaded the bone, or one that didn’t
 Many tumors secrete PTH-related protein, which promotes expression of
receptor activator of nuclear factor kB ligand (RANKL) on osteoblasts
 RANKL binds to RANK on osteoclast precursors to cause differentiation into
osteoclasts
 To inhibit RANKL to RANK binding, osteoblasts can release osteoprotegerin
(OPGN), which acts as a decoy receptor of RANKL
 PTH-related protein inhibits osteoprotegerin secretion, promoting osteoclasts
and bone resorption
Hyperparathyroidism can be primary, or secondary usually from kidney problems
Primary hyperparathyroidism is one of the most common endocrine problems, & causes hypercalcemia
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Most of the time (90%), primary hyperparathyroidism is from a single spontaneous adenoma
o Less often, it’s from primary hyperplasia (10%), or carcinoma (less than a %)
Primary hyperparathyroidism usually happens in adults, and more often in women after middle
age
Multiple endocrine neoplasia-1 (MEN-1) – inactivating mutation to the MEN1 tumor suppressor
gene that can cause parathyroid adenomas and hyperplasia
Multiple endocrine neoplasia-2 (MEN-2) – activating mutation to the tyrosine kinase receptor
RET, that can cause primary hyperparathyroidism
Familial hypocalciuric hypercalcemia – mutation to the parathyroid calcium-sensing receptor
gene (CASR) makes the parathyroids over function because the receptor isn’t as sensitive to
extracellular calcium
Common mutations seen in parathyroid adenomas are to cyclin D1 and MEN-1
o Cyclin D1 gene is often relocated to be next to the PTH gene, causing overexpression of
cyclin D1 protein, forcing cells to proliferate
o 1/3 of parathyroid tumors that aren’t part of MEN-1 still show MEN-1 mutations
Unlike in primary hyperplasia of the parathyroids, a parathyroid adenoma will have shrunken
glands outside the adenoma, due to feedback inhibition from high blood calcium
Parathyroid adenomas are usually made mostly of chief cells
When the parathyroids do hyperplasia, usually it’s the chief cells undergoing hyperplasia
o Hyperplasia usually shows all 4 parathryoids being hyperplastic, although maybe not
each as big as the other
Carcinoma of the parathyroids will show just one of the parathyroids being enlarged
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The only way to tell the difference between parathyroid carcinoma and parathyroid
adenoma, is if it metastasizes or invades local tissue
Hyperparathyroidism will also cause skeletal and kidney changes:
o The bones will have increased #’s of osteoclasts, which resorb the bone to increase
blood calcium
 Osteoblasts are increased to try and compensate
o Often the bone has widely spaced trabeculae like that seen in osteoporosis
 More severe cases have the cortex thinned, and the marrow has more fibrous
tissue, accompanied by hemorrhage and cysts, called osteitis fibrosa cystica
o Hyperparathyroidism can cause clusters of osteoclasts, giant cells, and hemorrhagic
debris, called brown tumor of hyperparathyroidism
o PTH-induced hypercalcemia favors formation of urinary tract stones (nephrolithiasis),
and calcification of the renal interstitium and tubules (nephrocalcinosis)
Primary hyperparathyroidism is the most common cause of asymptomatic hypercalcemia
The way you tell the difference between hypercalcemia from primary hyperparathyroidism, or
cancer elsewhere:
o In primary hyperparathryodiism, serum PTH is increased despite high blood calcium
o In tumors, PTH levels are low from the increased blood calcium
Symptomatic primary hyperparathyroidism shows “painful bones, renal stones, abdominal
groans, and psychic moans:”
o Bone – the hyperparathryroidism causes bone pain from fractures weakened by
osteoporosis or osteitis fibrosa cystica
o Kidney stones (nephrolithiasis) can show pain and obstructive uropathy, and chronic
renal insufficiency can cause polyuria and secondary polydipsia
o GI – constipation, nausea, peptic ulcers, pancreatitis, and gallstones
o CNS problems – depression, lethargy, and seizures
o Heart valve calcifications
Secondary hyperparathyroidism is caused by anything that causes chronic low calcium, which forces the
parathryoids to have to work
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The most common cause of secondary hyperparathyroidism is by far kidney failure
Chronic renal insufficiency decreases phosphate excretion, which increases blood phosphate,
which can decrease blood calcium and stimulate PTH release
Also, loss of functioning parts of the kidney decreases the amount of 1α-hydroxylase, so less
vitamin D is made active, and so less calcium is absorbed from the GI
o Vitamin D also normally suppresses the parathryoids and PTH release
The parathyroid glands in secondary hyperparathyroidism are hyperplastic
Symptoms of secondary hyperparathyroidism are mainly those of kidney failure, with less bone
or other changes usually seen from high PTH
Vitamin D supplements and phosphate binders can help treat secondary hyperparathyroidism
Hypoparathyroidism is way less common than hyperparathyroidism
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Acquired hypoparathyroidism is usually from surgery, like a thyroidectomy that accidentally
removed the parathyroids, or when you mistake them for lymph nodes
Autoimmune hypoparathyroidism happens in chronic mucocutaneous candidiasis and primary
adrenal insuffiency, together called autoimmune polyendocrine syndrome type 1 (APS1)
o APS1 is caused by mutation to the autoimmune regulator (AIRE) gene, and usually
starts in childhood when they first get candidiasis
 Then years later the hypoparathyroidism and adrenal insufficiency show up
Autosomal-dominant hypoparathyroidism – gain of function mutation to the CASR gene,
causing it to be too sensitive to calcium and suppress PTH
The hallmark of hypocalcemia is tetany, characterized by neuromuscular irritability, from
decreased serum free calcium
o Symptoms include numbness, paresthesias (tingling), and carpopedal spasm, lifethreatening laryngospasm, and generalized seizures
o Classically, hypocalcemic tetany shows Chvostek sign and Trousseau sign
 Chvostek is elicited by tapping the course of their facial nerve, which causes
contractions of the muscles of the eye, mouth, or nose
 Trousseau sign – carpal spasms caused by blocking circulation to the forearm
and hand with a blood pressure cuff for several minutes
Other symptoms of hypocalcemia include:
o Mental status changes – like emotional instability, anxiety and depression, confusion,
hallucinations, and psychosis
o Parkinsonian-like movements
o Increased intracranial pressure – causes papilledema
o Calcification of the lens of the eye – causing cataracts
o Prolonged QT intervals
o Tooth changes early in life – dental hypoplasia, failure of eruption, defective enamel and
root formation, and abraded carious teeth
Pseudohypoparathyroidism – end organs don’t listen to PTH, causing increased PTH, causing
hypocalcemia, hyperphosphatemia