The Endocrine System

Dr. Endeshaw Asaye ( MD, Assistant

Professor of Pathology)

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➢ The endocrine system consists of a highly integrated and widely
distributed group of organs that orchestrate a state of metabolic
equilibrium among the various organs of the body.
➢ Signaling by secreted molecules can be classified into three
types:-
▪ Autocrine
▪ Paracrine, or
▪ Endocrine on the basis of the distance over which the signal
acts.
➢ In endocrine signaling, the secreted molecules, also known as
hormones, act on target cells that are distant from their sites of
synthesis.

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▪ Endocrine diseases can be generally classified as:-
1) Diseases of underproduction or overproduction of hormones and
their resulting biochemical and clinical consequences and
2) Diseases associated with the development of mass lesions.
➢ Nonfunctional, or they might be associated with overproduction
or underproduction of hormones.

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PITUITARY GLAND

➢ The pituitary gland is composed of two morphologically and

functionally distinct components.
➢ The anterior lobe (adenohypophysis) and the posterior lobe
(neurohypophysis).
➢ The anterior pituitary constitutes about 80% of the gland.
➢ The production of most pituitary hormones is controlled in large
part by positively and negatively acting factors from the
hypothalamus, which are carried to the anterior pituitary by a
portal vascular system.

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➢ There are six terminally differentiated cell types in the anterior
pituitary, including:
▪ Somatotrophs, producing growth hormone (GH)
▪ Mammosomatotrophs, producing GH and prolactin (PRL)
▪ Lactotrophs, producing PRL

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▪ Corticotrophs, producing adrenocorticotropic hormone (ACTH)
and pro-opiomelanocortin (POMC), melanocyte stimulating
hormone (MSH).
▪ Thyrotrophs, producing thyroid-stimulating hormone (TSH), and
▪ Gonadotrophs, producing follicle-stimulating hormone (FSH)
and luteinizing hormone (LH).

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➢ The posterior pituitary consists of modified glial cells (termed
pituicytes) and axonal processes extending from the
hypothalamus through the pituitary stalk to the posterior lobe
(axon terminals).
➢ Two peptide hormones are secreted from the posterior pituitary:-
▪ Oxytocin and
▪ Antidiuretic hormone (ADH, also called vasopressin).

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➢ Dilation of the cervix in pregnancy results in massive oxytocin
release, leading to contraction of the uterine smooth muscle,
facilitating parturition (uterine labor).
➢ Similarly, oxytocin released upon nipple stimulation in the
postnatal period acts on the smooth muscles surrounding the
lactiferous ducts of the mammary glands and facilitates
lactation.

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➢ The most important function of ADH is to conserve water by
restricting diuresis during periods of dehydration and
hypovolemia.
▪ Decreased blood pressure, sensed by baroreceptors (pressure
sensing receptors) in the cardiac atria and carotids, stimulates
ADH release.
▪ An increase in plasma osmotic pressure detected by
osmoreceptors also triggers ADH secretion.
➢ In contrast, states of hypervolemia and increased atrial
distention result in inhibition of ADH secretion.

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Pituitary Adenomas and Hyperpituitarism
▪ The most common cause of hyperpituitarism is an adenoma
arising in the anterior lobe.
▪ Pituitary adenomas can be functional (i.e., associated with
hormone excess and clinical manifestations there of) or
nonfunctioning (i.e., without clinical symptoms of hormone
excess).
▪ Some pituitary adenomas can secrete two hormones (GH and
prolactin being the most common combination), and rarely,
pituitary adenomas are plurihormonal.

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➢ Pituitary adenomas are usually found in adults; the peak
incidence is from 35 to 60 years of age.
➢ They are designated, some what arbitrarily, microadenomas if
they are less than 1 cm in diameter and macroadenomas if they
exceed 1 cm in diameter.
➢ G-protein mutations are one of the most common alterations in
pituitary adenomas.
➢ The two distinctive morphologic features of most adenomas are
their cellular monomorphism and absence of a reticulin network.

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Classification of Pituitary Adenomas

Pituitary Cell Hormone Adenoma Associated

Type Subtypes Syndrome
Lactotroph Prolactin Lactotroph Galactorrhea and
adenoma amenorrhea (in
females), Sexual
dysfunction,
infertility

Somatotroph GH Somatotroph Gigantism

adenoma (Children)
Acromegaly
(Adults)

Mammosomatotr Prolactin,GH Mammosomatotr Combined

oph oph adenoma features of GH
and prolactin
excess

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Corticotroph ACTH and other Corticotroph - Cushing
POMC-derived adenoma syndrome
peptides - Nelson
syndrome

Thyrotroph TSH Thyrotroph Hyperthyroidism

adenomas
Gonadotroph FSH, LH Gonadotroph Hypogonadism,
adenomas mass effects,
and
hypopituitarism

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 Clinical Course
➢ The signs and symptoms of pituitary adenomas are related
to endocrine abnormalities and mass effects.
➢ Lactotroph adenomas secrete prolactin and can present with
amenorrhea, galactorrhea, loss of libido, and infertility.
✓ The mechanism appears to involve inhibition of luteinizing
hormone (LH), and perhaps follicle-stimulating hormone (FSH)
secretion, via inhibition of the release of gonadotropin-releasing
hormone (GnRH).
➢ Somatotroph adenomas secrete GH and present with gigantism
in children and acromegaly in adults, impaired glucose
tolerance, and diabetes mellitus.

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➢ Corticotroph adenomas secrete ACTH and present with Cushing
syndrome and hyperpigmentation.
➢ Local mass effects may be produced by any type of pituitary
tumor.
➢ Among the earliest changes referable to mass effect are
radiographic abnormalities of the sella turcica, including:-
✓ Sellar expansion, bony erosion, and disruption of the
diaphragma sella.

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➢ Because of the close proximity of the optic nerves and chiasm to
the sella, expanding pituitary lesions often compress
decussating fibers in the optic chiasm.
➢ This gives rise to visual field abnormalities, classically in the
form of defects in both lateral (temporal) visual fields, so-called
bitemporal hemianopsia.
▪ Like any expanding intracranial mass, pituitary adenomas can
produce signs and symptoms of elevated intracranial pressure,
including headache, nausea, and vomiting.

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➢ On occasion, acute hemorrhage into an adenoma is associated
with clinical evidence of rapid enlargement of the lesion, a
situation appropriately termed pituitary apoplexy.
➢ Acute pituitary apoplexy is a neurosurgical emergency, in that it
can cause sudden death.

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 Hypopituitarism
▪ Hypopituitarism refers to decreased secretion of pituitary
hormones, which can result from diseases of the hypothalamus
or of the pituitary.
➢ The causes include the following:-
▪ Tumors and other mass lesions
▪ Traumatic brain injury and subarachnoid hemorrhage
▪ Pituitary surgery or radiation
▪ Pituitary apoplexy
▪ Ischemic necrosis of the pituitary and Sheehan syndrome
➢ Sheehan syndrome, also known as postpartum necrosis of the
anterior pituitary, is the most common form of clinically
significant ischemic necrosis of the anterior pituitary.
▪ Hypothalamic lesions

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 Posterior Pituitary Syndromes
▪ The clinically relevant posterior pituitary syndromes involve ADH
and include diabetes insipidus and secretion of inappropriately
high levels of ADH.

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 Diabetes insipidus
▪ ADH deficiency causes diabetes insipidus, a condition
characterized by excessive urination (polyuria) due to an
inability of the kidney to resorb water properly from the urine.
▪ Diabetes insipidus can occur in a variety of conditions, including
head trauma, tumors, inflammatory disorders of the
hypothalamus and pituitary, and surgical complications.
▪ The condition can also arise spontaneously, in the absence of
an identifiable underlying disorder.

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▪ Diabetes insipidus from ADH deficiency is designated as central
to differentiate it from nephrogenic diabetes insipidus, which is a
result of renal tubular unresponsiveness to circulating ADH.
▪ Serum sodium and osmolality are increased by the excessive
renal loss of free water, resulting in thirst and polydipsia.

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 Syndrome of inappropriate ADH (SIADH) secretion

➢ ADH excess causes resorption of excessive amounts of free

water, resulting in hyponatremia.
➢ The most frequent causes of SIADH are the secretion of ectopic
ADH by malignant neoplasms (particularly small-cell carcinoma
of the lung), drugs that increase ADH secretion, and a variety of
central nervous system disorders, including infections and
trauma.

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➢ The clinical manifestations of SIADH are dominated by
hyponatremia, cerebral edema, and resultant neurologic
dysfunction.
➢ Although total body water is increased, blood volume remains
normal, and peripheral edema does not develop.

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 Hypothalamic Suprasellar Tumors
➢ Neoplasms in this location may induce hypofunction or
hyperfunction of the anterior pituitary, diabetes insipidus, or
combinations of these manifestations.
➢ The most commonly implicated tumors are gliomas and
craniopharyngiomas.
➢ The craniopharyngioma is thought to arise from vestigial
remnants of Rathke pouch.
❖ A diverticulum arising from the embryonic buccal cavity, from
which the anterior pitutary gland develops.

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 THYROID GLAND
➢ The thyroid gland, usually located below and anterior to the
larynx, consists of two bulky lateral lobes connected by a
relatively thin isthmus.
➢ The thyroid is divided by thin fibrous septae into lobules
composed of about 20 to 40 evenly dispersed follicles, lined by
a cuboidal to low columnar epithelium, and filled with PAS-
positive thyroglobulin.
➢ The binding of TSH to its receptor on the thyroid follicular
epithelium stimulates thyroid growth and thyroid hormone
synthesis and release via cAMP-dependent protein kinases.

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➢ Thyroid follicular epithelial cells convert thyroglobulin into
thyroxine (T4) and lesser amounts of triiodothyronine (T3).
➢ In the periphery, the majority of free T4 is deiodinated to T3; the
latter binds to thyroid hormone nuclear receptors in target cells
with tenfold greater affinity than does T4 and has proportionately
greater activity.
➢ Thyroid hormone has diverse cellular effects, including the
stimulation of carbohydrate and lipid catabolism and protein
synthesis in a wide range of cells.
➢ The net result is an increase in the basal metabolic rate.
➢ In addition, thyroid hormone has a critical role in brain
development in the fetus and neonate.

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➢ The thyroid gland follicles also contain a population of
parafollicular cells, or C cells, which synthesize and secrete the
hormone calcitonin.
➢ This hormone promotes the absorption of calcium by the
skeletal system and inhibits the resorption of bone by
osteoclasts.
➢ Diseases of the thyroid include conditions associated with:-
✓ Excessive release of thyroid hormones (hyperthyroidism)
✓ Thyroid hormone deficiency (hypothyroidism), and
✓ Mass lesions of the thyroid.

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 Hyperthyroidism
➢ Thyrotoxicosis is a hypermetabolic state caused by elevated
circulating levels of free T3 and T4.
➢ Because it is caused most commonly by hyperfunction of the
thyroid gland, it is often referred to as hyperthyroidism.
➢ The three most common causes of thyrotoxicosis are associated
with hyperfunction of the gland and include the following:-

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❖ Diffuse hyperplasia of the thyroid associated with Graves
disease (approximately 85% of cases)
❖ Hyperfunctional multinodular goiter
❖ Hyperfunctional thyroid adenoma

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 Clinical Course
➢ Include changes referable to the hypermetabolic state induced
by excess thyroid hormone and to overactivity of the
sympathetic nervous system (i.e., an increase in the β-
adrenergic “tone”).
➢ Excessive levels of thyroid hormone result in an increase in the
basal metabolic rate.

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➢ The skin of thyrotoxic patients tends to be soft, warm, and
flushed because of increased blood flow and peripheral
vasodilation, adaptations that serve to increase heat loss.
➢ Heat intolerance is common.
➢ Sweating is increased because of higher levels of calorigenesis.
➢ Heightened catabolic metabolism results in weight loss despite
increased appetite.

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➢ Cardiac manifestations are among the earliest and most
consistent features.
➢ Individuals with hyperthyroidism can have elevated cardiac
contractility and cardiac output, in response to increased
peripheral oxygen requirements.
➢ Tachycardia, palpitations, and cardiomegaly are common.
➢ Arrhythmias, particularly atrial fibrillation, occur frequently and
are more common in older patients.
➢ Congestive heart failure may develop, especially in older
patients with preexisting cardiac disease.

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➢ Overactivity of the sympathetic nervous system produces
tremor, hyperactivity, emotional lability, anxiety, inability to
concentrate, and insomnia.
➢ Proximal muscle weakness and decreased muscle mass are
common (thyroid myopathy).
➢ In the gastrointestinal system, sympathetic hyperstimulation of
the gut results in hypermotility, diarrhea, and malabsorption.

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➢ Ocular changes often call attention to hyperthyroidism.
➢ A wide, staring gaze and lid lag are present because of
sympathetic overstimulation of the superior tarsal muscle, which
functions along side the levator palpebrae superioris muscle to
raise the upper eyelid.
➢ However, true thyroid ophthalmopathy associated with proptosis
occurs only in Graves disease.

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➢ The skeletal system is also affected.
➢ Thyroid hormone stimulates bone resorption, increasing
porosity of cortical bone and reducing the volume of trabecular
bone.
➢ The net effect is osteoporosis and an increased risk of fractures
in patients with chronic hyperthyroidism.

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➢ Thyroid storm refers to the abrupt onset of severe
hyperthyroidism.
➢ This condition occurs most commonly in patients with underlying
Graves disease and probably results from an acute elevation in
catecholamine levels.

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➢ The measurement of serum TSH concentration is the most
useful single screening test for hyperthyroidism, because its
levels are decreased even at the earliest stages, when the
disease may still be subclinical.
➢ A low TSH value is usually confirmed with measurement of free
T4, which is predictably increased.

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➢ Once the diagnosis of thyrotoxicosis has been confirmed by a
combination of TSH assays and free thyroid hormone levels,
measurement of radioactive iodine uptake by the thyroid gland
can help to determine the etiology.
➢ For example, there may be diffusely increased uptake in the
whole gland (Graves disease), increased uptake in a solitary
nodule (toxic adenoma), or decreased uptake (thyroiditis).

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 Graves Disease
➢ Graves disease is the most common cause of endogenous
hyperthyroidism.
➢ The disease is characterized by a triad of clinical findings:-
✓ Hyperthyroidism associated with diffuse enlargement of the
gland
✓ Infiltrative ophthalmopathy with resultant exophthalmos
✓ Localized, infiltrative dermopathy, sometimes called pretibial
myxedema
➢ Is characterized by thickening of the dermis due to deposition of
glycosaminoglycans and lymphocyte infiltration.

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➢ Graves disease has a peak incidence between 20 and 40 years
of age.
➢ Women are affected as much as 10 times more frequently than
men.

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 Pathogenesis
➢ Graves disease is an autoimmune disorder characterized by the
production of autoantibodies against multiple thyroid proteins,
most importantly the TSH receptor.
➢ The most common antibody subtype, known as thyroid
stimulating immunoglobulin (TSI), is observed in approximately
90% of patients with Graves disease.
➢ TSI binds to the TSH receptor and mimics its actions,
stimulating adenyl cyclase and increasing the release of thyroid
hormones.

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➢ Autoimmunity also plays a role in the development of the
infiltrative ophthalmopathy that is characteristic of Graves
disease.
➢ In Graves ophthalmopathy, the protrusion of the eyeball
(exopthalmos) is associated with increased volume of the retro-
orbital connective tissues and extraocular muscles, for several
reasons.

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These include:-

(1) Marked infiltration of the retro-orbital space by mononuclear

cells, predominantly T cells
(2) Inflammation with edema and swelling of extraocular muscles
(3) Accumulation of extracellular matrix components, specifically
hydrophilic glycosaminoglycans such as hyaluronic acid and
chondroitin sulfate; and
(4) Increased numbers of adipocytes (fatty infiltration).
❖ These changes displace the eyeball forward and can interfere
with the function of the extraocular muscles.

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 MORPHOLOGY
➢ The thyroid gland is usually symmetrically enlarged due to
diffuse hypertrophy and hyperplasia of thyroid follicular epithelial
cells.
➢ Histologically, the follicular epithelial cells in untreated cases are
tall and more crowded than usual.
➢ This crowding often results in the formation of small papillae,
which project into the follicular lumen and encroach on the
colloid, sometimes filling the follicles.

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➢ The colloid within the follicular lumen is pale, with scalloped
margins.
➢ Lymphoid infiltrates, consisting predominantly of T cells, along
with scattered B cells and mature plasma cells, are present
throughout the interstitium.
➢ Germinal centers are common.

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➢ Laboratory findings in Graves disease include elevated free T4
and T3 levels and depressed TSH levels.
➢ Because of ongoing stimulation of the thyroid follicles by thyroid
stimulating immunoglobulins, radioiodine scans show a diffusely
increased uptake of iodine.

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 Diffuse and Multinodular Goiters
➢ Enlargement of the thyroid, or goiter is caused by impaired
synthesis of thyroid hormone, which is most often the result of
dietary iodine deficiency.
➢ Impairment of thyroid hormone synthesis leads to a
compensatory rise in the serum TSH level, which, in turn,
causes hypertrophy and hyperplasia of thyroid follicular cells
and, ultimately, gross enlargement of the thyroid gland.
➢ The degree of thyroid enlargement is proportional to the level
and duration of thyroid hormone deficiency.
➢ Goiters can broadly be divided into two types: diffuse nontoxic
and multinodular.

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➢ Diffuse nontoxic (simple) goiter causes enlargement of the
entire gland without producing nodularity.
➢ Because the enlarged follicles are filled with colloid, the term
colloid goiter has been applied to this condition.
➢ Endemic goiter occurs in geographic areas where the soil,water,
and food supply contain low levels of iodine.
➢ The term endemic is used when goiters are present in more
than 10% of the population in a given region.
➢ Such conditions are particularly common in mountainous areas
of the world.

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➢ With time, recurrent episodes of hyperplasia and involution
combine to produce a more irregular enlargement of the thyroid,
termed multinodular goiter.
➢ Virtually all longstanding simple goiters convert into multinodular
goiters.
➢ Multinodular goiters produce the most extreme thyroid
enlargements and are more frequently mistaken for neoplasms
than any other form of thyroid disease.

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 Clinical Course
▪ The dominant clinical features of multinodular goiter are those
caused by mass effects.
▪ In addition to the obvious cosmetic effects, goiters may cause
airway obstruction, dysphagia, and compression of large
vessels in the neck and upper thorax (superior vena cava
syndrome).

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➢ Most patients are euthyroid or have subclinical hyperthyroidism
(identified only by reduced TSH levels), but in a substantial
minority of patients an autonomous nodule may develop within a
long-standing goiter and produce hyperthyroidism (toxic
multinodular goiter).
➢ This condition is known as Plummer syndrome.

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 Hypothyroidism
➢ Hypothyroidism is a condition caused by a structural or
functional derangement that interferes with the production of
thyroid hormone.
➢ Primary hypothyroidism can be congenital, autoimmune, or
iatrogenic.
Congenital hypothyroidism
▪ Worldwide, congenital hypothyroidism is most often the result of
endemic iodine deficiency in the diet.

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 Autoimmune hypothyroidism
➢ Autoimmune hypothyroidism is the most common cause of
hypothyroidism in iodine-sufficient areas of the world.
➢ The vast majority of cases of autoimmune hypothyroidism are
due to Hashimoto thyroiditis.
➢ Circulating autoantibodies, including antimicrosomal, antithyroid
peroxidase, and antithyroglobulin antibodies, are found in this
disorder, and the thyroid is typically enlarged (goitrous).

Iatrogenic hypothyroidism
➢ This can be caused by either surgical or radiation-induced
ablation.

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➢ Cretinism refers to hypothyroidism that develops in infancy or
early childhood.
➢ Clinical features of cretinism include impaired development of
the skeletal system and central nervous system, manifested by
severe mental retardation, short stature,coarse facial features, a
protruding tongue, and umbilical hernia.
➢ The term myxedema is applied to hypothyroidism developing in
the older child or adult.
➢ Myxedema is marked by a slowing of physical and mental
activity.

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 Hashimoto Thyroiditis
➢ Hashimoto thyroiditis is an autoimmune disease that results in
destruction of the thyroid gland and gradual and progressive
thyroid failure.
➢ It is the most common cause of hypothyroidism in areas of the
world where iodine levels are sufficient.
➢ It is most prevalent between 45 and 65 years of age and is more
common in women than in men, with a female predominance of
10 : 1 to 20 : 1.
➢ It can also occur in children and is a major cause of non-
endemic goiter in the pediatric population.

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 Pathogenesis
➢ Hashimoto thyroiditis is caused by a breakdown in self-tolerance
to thyroid autoantigens.
➢ This is exemplified by the presence of circulating autoantibodies
against thyroglobulin and thyroid peroxidase in the vast majority
of Hashimoto patients.

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➢ Induction of thyroid autoimmunity is accompanied by a
progressive depletion of thyroid epithelial cells by apoptosis and
replacement of the thyroid parenchyma by mononuclear cell
infiltration and fibrosis.
➢ Multiple immunologic mechanisms may contribute to thyroid cell
death, including:-

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✓ CD8+ cytotoxic T cell-mediated cell death: CD8+ cytotoxic T
cells may destroy thyroid follicular cells.
✓ Cytokine-mediated cell death: Activation of CD4+ T cells leads
to the production of inflammatory cytokines such as interferon-γ
in the thyroid gland, with resultant recruitment and activation of
macrophages and damage to follicles.
✓ A less likely mechanism involves binding of antithyroid
antibodies (antithyroglobulin, and antithyroid peroxidase
antibodies) followed by antibody-dependent cell mediated
cytotoxicity.

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 MORPHOLOGY
➢ The thyroid is often diffusely enlarged, although more localized
enlargement may be seen in some cases.
➢ The capsule is intact, and the gland is well demarcated from
adjacent structures.

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➢ There is extensive infiltration of the parenchyma by a
mononuclear inflammatory infiltrate containing small
lymphocytes, plasma cells, and well-developed germinal
centers.
➢ The thyroid follicles are atrophic and are lined in many areas by
epithelial cells distinguished by the presence of abundant
eosinophilic, granular cytoplasm, termed Hürthle cells.

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 Clinical Course
➢ Hashimoto thyroiditis most often comes to clinical attention as
painless enlargement of the thyroid,usually associated with
some degree of hypothyroidism, in a middle-aged woman.
➢ The enlargement of the gland is usually symmetric and diffuse.

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 Granulomatous Thyroiditis
➢ Granulomatous thyroiditis (also called De Quervain thyroiditis)
occurs much less frequently than does Hashimoto disease.
➢ The disorder is most common between the ages of 40 and 50
and, like other forms of thyroiditis, affects women considerably
more often than men (4 : 1).
➢ Granulomatous thyroiditis is believed to be triggered by a viral
infection.
➢ Granulomatous thyroiditis is the most common cause of thyroid
pain.

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 Neoplasms of the Thyroid
Adenomas
➢ Adenomas of the thyroid are typically discrete, solitary masses,
derived from follicular epithelium, and hence they are also
known as follicular adenomas.
➢ Although the vast majority of adenomas are nonfunctional, a
small subset produces thyroid hormones and causes clinically
apparent thyrotoxicosis.
➢ Hormone production in functional adenomas (“toxic adenomas”)
is independent of TSH stimulation.

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 MORPHOLOGY
➢ The typical thyroid adenoma is a solitary, spherical, encapsulated
lesion that is demarcated from the surrounding thyroid parenchyma by
a well-defined, intact capsule.
➢ These features are important in making the distinction from
multinodular goiters.
➢ Microscopically, the constituent cells often form uniform appearing
follicles that contain colloid.
➢ The hallmark of all follicular adenomas is the presence of an intact,
well-formed capsule encircling the tumor.
➢ Careful evaluation of the integrity of the capsule is therefore critical in
distinguishing follicular adenomas from follicular carcinomas, which
demonstrate capsular and/or vascular invasion.

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 Carcinomas
➢ The major subtypes of thyroid carcinoma and their relative
frequencies are as follows:
❖ Papillary carcinoma (>85% of cases)
❖ Follicular carcinoma (5% to 15% of cases)
❖ Anaplastic (undifferentiated) carcinoma (<5% of cases)
❖ Medullary carcinoma (5% of cases)
➢ Most thyroid carcinomas (except medullary carcinomas) are
derived from the thyroid follicular epithelium, and of these, the
vast majority are well-differentiated lesions.

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 Papillary Carcinoma
➢ Papillary carcinomas are the most common form of thyroid
cancer, accounting for nearly 85% of primary thyroid
malignancies in the United States.
➢ They occur throughout life but most often between the ages of
25 and 50, and account for the majority of thyroid carcinomas
associated with previous exposure to ionizing radiation.
Pathogenesis
➢ Most papillary carcinomas have gain-of-function mutations
involving the genes encoding the RET or NTRK1 receptor
tyrosine kinases, or in the serine/threonine kinase BRAF.

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 MORPHOLOGY
➢ Papillary carcinomas may be solitary or multifocal.
➢ Some tumors are well circumscribed and even encapsulated;
others infiltrate the adjacent parenchyma and have ill-defined
margins.
➢ The tumors may contain areas of fibrosis and calcification and
are often cystic.
➢ The microscopic hallmarks of papillary neoplasms include the
following:-

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➢ Papillary carcinomas may contain branching papillae having a
fibrovascular stalk covered by a single to multiple layers of
cuboidal epithelial cells.
➢ The nuclei of papillary carcinoma cells contain finely dispersed
chromatin, which imparts an optically clear or empty
appearance, giving rise to the designation ground glass or
Orphan Annie eye nuclei.
➢ In addition, invaginations of the cytoplasm may give the
appearance of intranuclear inclusions (“pseudo-inclusions”) or
intranuclear grooves.

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➢ The diagnosis of papillary carcinoma can be made based on
these nuclear features, even in the absence of papillary
architecture.
➢ Concentrically calcified structures termed psammoma bodies
are often present, usually within the cores of papillae.
➢ These structures are almost never found in follicular and
medullary carcinomas, and so, when present in fine-needle
aspiration material, they are a strong indication that the lesion is
a papillary carcinoma.
➢ Foci of lymphatic invasion by tumor are often present, but
involvement of blood vessels is relatively uncommon,
particularly in smaller lesions.

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 Follicular Carcinoma
➢ Follicular carcinomas account for 5% to 15% of primary thyroid
cancers, but are more frequent in areas with dietary iodine
deficiency, where they constitute 25% to 40% of thyroid cancers.
➢ They are more common in women (3 : 1) and present more
often in older patients than do papillary carcinomas; the peak
incidence is between 40 and 60 years of age.
➢ In contrast to papillary carcinomas, follicular carcinomas are
associated with acquired mutations that activate RAS or the PI-
3K/AKT arm of the receptor tyrosine kinase signaling pathway.

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 MORPHOLOGY
➢ Follicular carcinomas are single nodules that may be well
circumscribed or widely infiltrative.
➢ Sharply demarcated lesions may be exceedingly difficult to
distinguish from follicular adenomas by gross examination.
➢ Larger lesions may penetrate the capsule and infiltrate well
beyond the thyroid capsule into the adjacent neck.

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➢ Microscopically, most follicular carcinomas are composed of
fairly uniform cells forming small follicles containing colloid, quite
reminiscent of normal thyroid.
➢ Occasional tumors are dominated by cells with abundant
granular, eosinophilic cytoplasm (Hürthle cell or oncocytic
variant of follicular carcinoma).

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➢ While nuclear features (optically clear nuclei, nuclear grooves)
are helpful in distinguishing papillary from follicular neoplasms,
there is no reliable cytologic difference between follicular
adenomas and minimally invasive follicular carcinomas.
➢ Making this distinction requires extensive histologic sampling of
the tumor-capsule-thyroid interface to exclude capsular and/or
vascular invasion.

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 Anaplastic (Undifferentiated) Carcinoma

➢ Anaplastic carcinomas are undifferentiated tumors of the thyroid

follicular epithelium, accounting for less than 5% of thyroid
tumors.
➢ They are aggressive, with a mortality rate approaching 100%.
➢ Patients with anaplastic carcinoma are older than those with
other types of thyroid cancer, with a mean age of 65 years.
➢ These highly aggressive and lethal tumors can arise de novo, or
more commonly, by “dedifferentiation” of a well-differentiated
papillary or follicular carcinoma.
➢ Molecular alterations present in anaplastic carcinomas include
those also seen in well-differentiated carcinomas (e.g., RAS or
PIK3CA mutations).

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 MORPHOLOGY

➢ Microscopically, these neoplasms are composed of highly

anaplastic cells, with variable morphology, including:-
❖ 1) Large, pleomorphic giant cells, including occasional
osteoclast-like multinucleate giant cells.
❖ 2) Spindle cells with a sarcomatous appearance; and
❖ 3) Mixed spindle and giant cells.
➢ Foci of papillary or follicular differentiation may be present in
some tumors, suggesting an origin from a better-differentiated
carcinoma.
➢ The neoplastic cells express epithelial markers like cytokeratin,
but are usually negative for markers of thyroid differentiation,
like thyroglobulin.

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 Clinical Course
➢ Anaplastic carcinomas usually present as a rapidly enlarging
bulky neck mass.
➢ In most cases, the disease has already spread beyond the
thyroid capsule into adjacent neck structures or has
metastasized to the lungs at the time of presentation.
➢ Symptoms related to compression and invasion, such as
dyspnea, dysphagia, hoarseness, and cough, are common.
➢ There are no effective therapies, and the disease is almost
uniformly fatal.

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 Medullary Carcinoma
➢ Medullary carcinomas of the thyroid are neuroendocrine
neoplasms derived from the parafollicular cells, or C cells, of the
thyroid, and account for approximately 5% of thyroid neoplasms.
➢ Medullary carcinomas, similar to normal C cells, secrete
calcitonin, the measurement of which plays an important role in
the diagnosis and postoperative follow-up of patients.

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➢ In some instances the tumor cells elaborate other polypeptide
hormones, such as serotonin, ACTH, and vasoactive intestinal
peptide (VIP).
➢ About 70% of tumors arise sporadically.
➢ The remainder occurs in the setting of MEN syndrome 2A or 2B
or as familial tumors without an associated MEN syndrome
(familial medullary thyroid carcinoma, or FMTC.)
➢ Activating point mutations in the RET proto-oncogene play an
important role in the development of both familial and sporadic
medullary carcinomas.

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 MORPHOLOGY
➢ Sporadic medullary thyroid carcinomas present as a solitary
nodule.
➢ In contrast, bilaterality and multicentricity are common in familial
cases.
➢ Larger lesions often contain areas of necrosis and hemorrhage
and may extend through the capsule of the thyroid.

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➢ Microscopically, medullary carcinomas are composed of
polygonal to spindle-shaped cells, which may form nests,
trabeculae,and even follicles.
➢ Small, more anaplastic cells are present in some tumors and
may be the predominant cell type.
➢ Acellular amyloid deposits derived from calcitonin polypeptides
are present in the stroma in many cases.

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➢ Calcitonin is readily demonstrable within the cytoplasm of the
tumor cells as well as in the stromal amyloid by
immunohistochemical methods.
➢ As with all neuroendocrine tumors, electron microscopy reveals
variable numbers of membrane-bound electron-dense granules
within the cytoplasm of the neoplastic Cells.
➢ One of the features of familial medullary cancers is the presence
of multicentric C-cell hyperplasia in the surrounding thyroid
parenchyma, a feature that is usually absent in sporadic lesions,
and that is believed to be a precursor lesion in familial cases.

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