Far Eastern University – Nicanor Reyes Medical Foundation
Pathology B – Endocrine Disorders (Part 1)
Aida Lat M.D.
 In endocrine system, secreted molecules called hormones act on
target cells that are distant from their sites of synthesis.
 Endocrine hormone is frequently carried by blood.
 In response, tissue factor often release factors that down-
regulate the activity of the gland known as feedback inhibition.
 Endocrine diseases can be generally classified as:
1. Disease of underproduction or overproduction
2. Development of mass lesions
Pituitary Gland
 Composed of two morphologically and functionally components:
 Anterior lobe (Adenohypophysis)
 Posterior lobe (Neurohypophysis)
 The anterior pituitary constitutes 80% of the gland.
 Production of most hormones is controlled in large part by
positively and negatively acting factors from the hypothalamus
carried by a portal vascular system.
 In histologic sections, the anterior lobe contain cells with:
 Eosinophilic cytoplasm (acidophil)
 Basophilic cytoplasm (basophil)
 Poorly stained (chromophobe)
 Six terminally differentiated cell types in the anterior pituitary:
 Somatotrophs – produce GH
 Mammosomatotrophs – produce GH and Prolactin
 Lactotrophs – produces prolactin
 Corticotrophs – produce ACTH, POMC, MSH
 Thyrotrophs – produce TSH
 Gonadotrophs – produce FSH and LH
 Posterior pituitary consist of modified glial cells termed
pituicytes, and axonal processes extending from the
hypothalamus to the pituitary stalk to the posterior lobe.
 Two peptide hormones secreted in the posterior lobe, but are
actually synthesized in the hypothalamus and stored in the axon
terminals:
 Antidiuretic hormone (vasopressin)
 Oxytocin
CLINICAL MANIFESTATIONS OF PITUITARY DISEASE
Hyperpituitarism
 Excess secretion of trophic hormones.
 Causes are:
 Pituitary adenoma, hyperplasia, carcinomas of anterior lobe
 Secretion of hormones by non-pituitary tumors
 Hypothalamic disorders
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Hypopituitarism
 Deficiency of trophic hormones.
 Caused by:
 Destructive processes (ischemic, surgical, radiation)
 Inflammatory reactions
 Non-functional pituitary adenomas
Local Mass Effects
 Abnormalities of the sella turcica, including sellar expansion,
bony erosions, and disruption of diaphragmatic sella.
 Expanding pituitary lesions compress decussating fibers in the
optic chiasm, giving rise to visual field abnormalities, classically
in the form of defects in both temporal (lateral) fields so-called
bitemporal hemianopsia.
 Also produces signs and symptoms associated with elevated
intracranial pressure including headache, nausea, and vomiting.
 Acute hemorrhage into an adenoma is associated with evidence
of enlargement of the lesion, termed pituitary apoplexy, a
neurosurgical emergency, may cause sudden death.
Diseases of the posterior pituitary often come to clinical attention
because of increased or decreased secretion of ADH.
PITUITARY ADENOMAS AND HYPERPITUITARISM
 Most common cause of hyperpituitarism is an adenoma arising
in the anterior lobe.
 Classified on the basis of hormones produced.
 Some adenomas can secrete 2 hormones; most common
combination is GH and Prolactin.
 Rarely plurihormonal.
 It can be:
 Functional – hormone excess and clinical manifestations
 Non-functioning – no symptoms of hormone excess
 Less common causes include pituitary carcinomas and
hypothalamic disorders.
 Non-functional adenomas come to clinical attention later than
those associated with endocrine abnormalities, therefore more
likely to be macroadenomas.
 Larger pituitary adenomas, specifically non-functioning ones,
may cause hypopituitarism by destroying adjacent parenchyma.
 Usually found in adults, incidence is 35-60 years.
 Microadenomas are less than 1 cm
 Macroadenomas if they exceed 1 cm
 Vast majority of these lesions are clinically silent microadenomas
(pituitary incidentaloma).
 Genetic anomalies associated with pituitary adenomas:
 G protein mutations
 Most common alterations
 G protein plays a critical role in signal transduction,
transmitting signals from surface receptors to intracellular
effectors then generate second messengers.
 40% of somatotroph cell adenomas bear GNAS mutations
that abrogate the GTPase activity of Gsα, leading to
constitutive activation of Gsα with persistent generation of
cAMP and unchecked cellular proliferation.
 GNAS mutations are also described in corticotroph
adenomas, absent in thyrotrophs, lactotrops, and
gonadotroph adenomas since they don’t activate cAMP.
Types of Pituitary Adenomas

 Majority of pituitary adenomas are sporadic Clinical Course

 5% arise from inherited genetic defects:  Related to endocrine abnormalities and mass effect.
 PRKAR1A – encodes for a negative regulator of PKA,  Local mass effects:
present in GH and Prolactin adenomas.  Radiographic abnormalities of sella turcica
 MEN1 – encodes for menin, a protein with protean roles in  Visual field anomalies
tumor suppression, present in GH, Prolactin, ACTH  Signs and symptoms of elevated intracranial pressure
adenomas.  Hypopituitarism
 CDKN1B – p27 protein is a negative regulator of the cell  Acute hemorrhage associated with pituitary apoplexy.
cycle, present in ACTH adenomas.
 AIP – receptor for aryl hydrocarbons and a ligand- Lactotroph Adenoma
activated transcription factor, present in GH adenomas,  Prolactin-secreting adenomas are the most common frequent
especially those younger than 35. type of hyperfunctioning pituitary adenomas (30% of cases).
 PRKAR1A is due to gain-of-function, the rest is loss-of-function
(Check Robbins 9th ed., page 1076, Table 24-2)
Morphology
 Molecular abnormalities associated with aggressive behavior
 Sparsely granulated lactotroph adenomas - comprised of
include aberrations in cell cycle check point proteins such as
chromophobic cells with juxtanuclear localization of transcription
overexpression of cyclin D1, TP53 mutations, silencing of RB.
factor PIT-1 known as
 Activation of HRAS oncogene is observed in pituitary CA.
 Densely granulated lactotroph adenomas – diffuse cytoplasmic
PIT-1 expression localization.
Morphology
 Prolactin can be demonstrated in the secretory granules by IHC.
 Typical Pituitary Adenoma
 May undergo dystrophic calcification ranging from isolated
 Soft, well-circumscribed
psammoma bodies to whole mass calcification (pituitary stone)
 Small adenomas may be confined to the sella turcica
 Even microadenomas can produce enough prolactin to have
 Larger lesions extend superiorly to the diaphragm sella into
hyperprolactinemia; serum prolactin correlates with its size.
the suprasellar region where they compress the optic chiasm
 30% are not encapsulated and infiltrate neighboring tissues
Clinical Course
termed invasive adenomas.
 Prolactenemia, increased serum prolactin, causes amenorrhea,
 Macroadenomas are more invasive, with more foci of
galactorrhea, loss of libido, and infertility.
hemorrhage and necrosis.
 Diagnosis is made more readily in women, 20-40 years old.
 Uniform, polygonal cells arrayed in sheets or cords.
 Lactotroph adenoma underlies ¼ of cases of amenorrhea.
 Supporting tissue or reticulin is sparse accounting for the
 Older women and men have subtle features which may allow
soft, gelatinous consistency.
progression of the tumor to macroadenomas before detection.
 Mitotic activity is sparse.
 May also occur in the following, aside from lactotroph adenoma:
 Cytoplasm depends on the type of secretory product but is
 Physiologic hyperprolactinemia in pregnancy, elevated nipple
generally uniform throughout the tumor.
stimulation, response to stress.
 Cellular Monomorphism and Absence of reticulin network
 Pathologic hyperprolactinemia can result from lactotroph
distinguish pituitary adenomas to non-neoplastic anterior
hyperplasia caused by loss of dopamine-mediated inhibition.
pituitary parenchyma.
 Can be due to damage of dopaminergic neurons
 Atypical Pituitary Adenoma
 Damage to the pituitary stalk
 Elevated mitotic activity and nuclear p53 expression (TP53).  Exposure to drugs that block dopamine
 Higher propensity for aggressive behavior (recurrence).

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  Any mass in the suprasellar area may disturb normal
inhibitory influences of the hypothalamus on prolactin.
 May also be caused by renal failure and hypothyroidism.
 Lactotroph adenoma can be treated by surgery or bromocriptine
Somatotroph Adenoma
 GH-secreting adenomas are the second most common type of
functioning pituitary adenomas.
 Causes gigantism in children and acromegaly in adults.
Morphology
 Also classified into densely or sparsely granulated.
 Densely granulated are composed of monomorphic, acidophilic
cells that have strong cytoplasmic GH reactivity on IHC.
 Sparsely granulated are composed of chromophobes with
considerable, weak staining for GH.
 Bihormonal mammosomatotroph synthesize both GH and
prolactin, most resemble densely granulated pure somtatrophs
but are distinguished by IHC reactive for both prolactin and GH.
Clinical Course
 Persistently elevated levels of GH stimulate the hepatic secretion
of insulin-like growth factor 1 (IGF-1) which causes:
 If it appears in children before epiphyses have closed, it
causes gigantism.
 Characterized by generalized increase in body size.
 Disproportionately long arms and legs.
 If it presents after closure of epiphyses, acromegaly develops
 Growth is most conspicuous in skin and soft tissue, viscera,
and bones of the face, hands, and feet.
 Increased bone density – hyperostosis in spine and hips
 Enlargement of jaw resulting in protrusion – prognathism
 Broadening of the lower face
 Feet and hands are enlarged, become sausage-like
 These may develop slowly which may make the adenoma
larger to reach substantial size.
 GH excess can be associated with other disturbances:
 Gonadal dysfunction  Arthritis
 Diabetes Mellitus  Congestive Heart Failure
 Generalized Weakness  Increased risk of GIT cancer
 Hypertension
 Diagnosis of pituitary GH excess relies on documentation of
elevated serum GH and IGF-1 levels.
 Failure to suppress GH production in response to an oral load of
glucose is one of the most sensitive tests for acromegaly.
 Can be surgically removed or pharmacologically treated using
somatostatin analogs or GH receptor antagonists.
Corticotroph Adenomas
 Excess production of ACTH lead to adrenal hypersecretion of
cortisol and development of hypercortisolism/Cushing syndrome
Morphology
 Usually microadenomas at the time of diagnosis.
 Most often basophilic densely granulated.
 Occasionally chromophobic sparsely granulated.
 Both positively stain with PAS because of the carbohydrate in
proopiomelanocortin (POMC), the ACTH precursor molecule.
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 Demonstrate variable immunoreactivity for POMC and its
derivatives, including ACTH and β-endorphins.
Clinical Course
 When hypercortisolism is due to excessive production of ACTH
by the pituitary is designated as Cushing Syndrome.
 Large destructive pituitary adenomas can develop in patients
after surgical removal of the adrenal glands for Cushing
syndrome, known as Nelson Syndrome.
 Occurs most often due to loss of inhibitory effects of adrenal
corticosteroids on a pre-existing microadenoma.
 Since adrenals are absent, hypercortisolism does not develop
and patients present with mass effects of the tumor.
 There can be hyperpigmentation due to effects on melanocyte
OTHER ANTERIOR PITUITARY ADENOMAS
Gonadotrophs
 LH-producing and FSH-producing adenomas
 Difficult to recognize because they can secrete hormone
inefficiently and variably and usually do not cause syndromes.
 Most frequently found in middle aged women and men when
they become large enough to cause neurologic symptoms.
 Impaired vision, headaches, diplopia, or pituitary apoplexy
 Deficiencies can also be found, most commonly impaired
secretion of LH, results to decreased energy and libido in men,
and amenorrhea in premenopausal women.
 The cells demonstrate immunoreactivity to gonadotropin α-
subunit and the specific β-FSH and β-LH subunits.
 FSH is usually the predominant hormone secreted.
 Usually express steroidogenic factor-1 (SF-1) and GATA-2.
Thyrotrophs
 TSH-producing adenomas are uncommon.
 Accounts for 1% of all pituitary adenomas.
 Rare cause of hyperthyroidism.
Non-functioning Pituitary Adenomas
 Constitutes 25% to 30% of all pituitary tumors.
 The lineage can be distinguished by IHC of hormones or
transcription factors.
 Many have been called silent variants or null cell adenomas.
 Typically present with symptoms stemming from mass effects.
 May also compress the residual anterior pituitary sufficient
enough to cause hypopituitarism.
 Nay appear slow due to gradual enlargement.
 May appear abruptly due to pituitary apoplexy (acute
intratumoral hemorrhage).
Pituitary Carcinoma
 Rare, accounts for less than 1% of tumors.
 Presence of craniospinal or systemic metastasis is a sine qua non
of a pituitary carcinoma.
 Most are functional with prolactin & ACTH being most common.
 Metastases appear late, following multiple local recurrences.
HYPOPITUITARISM
 It refers to decreased secretion of the pituitary hormones.
 Result from disease of hypothalamus or pituitary.
 Hypofunction of the anterior pituitary occurs when
approximately 75% of the parenchyma is lost or absent.
 Maybe congenital or acquired.
 Hypopituitarism with evidence of posterior pituitary dysfunction
is almost always of hypothalamic origin.
Most cases are destructive processes directly involving the anterior
pituitary, causes include the following:
 Tumors and other mass lesions – any mass lesion in the sella can
cause damage by exerting pressure on adjacent cells.
 Traumatic brain injury and subarachnoid hemorrhage
 Most common causes of pituitary hypofunction.
 Pituitary apoplexy
 Sudden hemorrhage occurring into a pituitary adenoma.
 Sudden onset of headache, diplopia, and hypopituitarism.
 Ischemic necrosis and Sheehan Syndrome
 Sheehan syndrome – also known as postpartum necrosis is
the most common form of clinically significant ischemic
necrosis. During pregnancy, the anterior pituitary doubles its
size and this expansion is NOT accompanied by increase in
blood supply causing hypoxia.
 Posterior pituitary receives most of its supply from the
arteries and therefore not affected as much as the anterior
 Necrosis may also be encountered in DIC, Sickle cells,
elevated ICP, trauma, or shock.
 Ischemic area is resorbed and replaced by nubbin of fibrous
tissue attached to the wall of an empty sella.
 Rathke Cleft Cyst
 Lined by ciliated cuboidal epithelium with occasional goblet
cells can accumulate proteinaceous fluid and expand.
 Empty Sella Syndrome
 Any condition or treatment that destroys part or all of the
pituitary gland such as by surgery or radiation.
 Primary Empty Sella
 A defect in the diaphragma sella which allows arachnoid
mater and CSF to herniate and compress the glands
 Occurs in obese women with history of multiple pregnancy
presents with visual disturbances and hyperprolactinemia.
 Secondary Empty Sella
 A mass enlarges the sella and is then either surgically
removed or undergoes infarction, leading to loss of
pituitary function.
 Hypothalamic lesions
 Interference with the delivery of pituitary hormone-releasing
factors from the hypothalamus.
 Diminished ADH secretion leading to diabetes insipidus.
 May be caused by tumors which may be benign or malignant,
most of which are metastases from tumors from lungs and
breast.
 Hypothalamic insufficiency may also appear on irradiation.
 Inflammatory Disorders and Infections
 Sarcoidosis, Tuberculous Meningitis
 Genetic Defects
 PIT-1 mutations result in combined pituitary hormone
deficiencies of GH, TSH, and prolactin.
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Clinical Manifestations
 Depends on the specific hormones that are lacking.
 GH deficiency – can develop growth failure (pituitary dwarfism).
 LH and FSH deficiency – leads to amenorrhea and infertility in
women and decreased libido, impotence, loss of pubic and
axillary hair in men.
 TSH and ACTH deficiency – hypothyroidism and hypoadrenalism
 Prolactin deficiency – failure of postpartum lactation
 MSH (melanocyte stimulating hormone) deficiency – pallor due
to loss of stimulation of MSH on melanocytes
POSTERIOR PITUITARY SYNDROMES
Diabetes Insipidus
 ADH deficiency is characterized by excessive urination (polyuria)
due to an inability of the kidney to resorb water properly from
the urine.
 Designated as central or nephrogenic.
 Central DI – loss of circulating ADH
 Nephrogenic DI – renal tubular unresponsiveness to ADH
 Clinical manifestations include excretion of large volumes of
dilute urine with lower than normal specific gravity.
 Serum sodium and osmolality are increased by excessive renal
loss of free water resulting in thirst and polydipsia.
Syndrome of Inappropriate ADH secretion (SIADH)
 ADH excess causes resorption of excessive amounts of water
resulting in hyponatremia.
 Most frequent causes are secretion of ectopic ADH by malignant
neoplasms, particularly small-cell carcinoma of the lungs, drugs
that increase ADH secretion, and CNS disorders.
 Clinical manifestations include cerebral edema and resultant
neurologic dysfunction.
 Edema does not develop, blood volume remains normal
HYPOTHALAMIC SUPRASELLAR TUMORS
 May induce hypofunction or hyperfunction of the anterior
pituitary, diabetes insipidus, or combination of both.
 Most common are gliomas (sometimes arising from the chiasm)
and craniopharyngioma (arise from remnants of Rathke pouch).
 Slow growing tumors, accounts for 1-5% of intracranial tumors.
 Most are suprasellar.
 Bimodal age of distribution (5-15 years, and 65 years older).
 Come to attention due to visual disturbance and headache.
 In children, may present with growth retardation.
Morphology
 Crainiopharyngiomas average 3-4cm in diameter.
 May be encapsulated and solid.
 More commonly cystic and sometimes multiloculated.
 Often encroach the optic chiasm or cranial nerves.
rd
 Infrequently bulge into the floor of 3 ventricle and base
 Two distinct variants:
 Adamantinomatous
 Most often in children
 Frequently demonstrate radiologic calcifications
 With nests or cords of stratified squamous epithelium
embedded in a spongy reticulum in the internal layers
 Palisading squamous epithelium at periphery
 Compact, lamellar keratin formation (wet keratin) is a
diagnostic feature of this tumor.
 Cyst formation, fibrosis, chronic inflammation.
 Often contain cholesterol-rich, thick brownish fluid
compared to machine oil.
 Extend fingerlets of epithelium adjacent to the brain,
where they elicit a brisk glial reaction.
 Papillary
 Most often in adults
 Contain both solid sheets and papilla.
 Usually lack keratin, calcifications, and cysts.
 Squamous cells of solid sections lack palisading.
 Do not generate spongy reticulum.
 Crangiopharyngiomas less than 5 cm have excellent overall
survival without recurrence.
 Larger lesions are more invasive but do not impact prognosis.
 Malignant transformation to squamous carcinomas are rare
only happens after irradiation.
Thyroid Gland
 Usually located below and anterior to the larynx, consists of 2
bulky lateral lobe connected by a relatively thin isthmus.
 15-25g, evagination of pharyngeal epithelium that descends
from foramen cecuma as part of the thyroglossal duct.
 Excessive descent results to sub-sternal thyroid.
 Divided by thin fibrous septa into lobules with about 20-40
evenly dispersed follicles lined by a cuboidal to low columnar.
 Filled with PAS-positive thyroglobulin.
 Binding of TSH to its receptor on the thyroid epithelium, it
results in activation of the receptor, allowing it to associate with
a Gs protein.
 Stimulates downstream events that result in an increase in
intracellular cAMP levels which stimulate thyroid growth and
thyroid hormone synthesis.
 Thyroxine (T4) and Triiodothyronine (T3) are released into
systemic circulation where most are reversibly bound to
Thyroxine-binding globulin and thransthyretin.
 The binding proteins act as buffer that maintain the serum
unbound or free T3 and T4.
 Majority of free T4 is deiodinated to T3 which binds to nuclear
receptors in target cells.
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 Binding results in assembly of multiprotein hormone-receptor
complex on thyroid hormone response elements (TRE) in the
target genes, upregulating their transcription.
 Functions of the thyroid gland:
 Stimulation of carbohydrate and lipid catabolism
 Protein synthesis
 Increase in basal metabolic rate
 Critical role in brain development in fetus and neonates
 The function of the gland can be inhibited by goitrogens which
decreases synthesis of T3 and T4 resulting to elevated TSH and
hyperplastic enlargement of the gland (goiter) follows.
 Propylthiouracil inhibits oxidation of iodide blocking the
production of T3 and T4, it also inhibits peripheral deiodination,
relieving symptoms of hyperthyroidism.
 Iodides when given large doses to hyperthyroid patients block
the release by inhibiting proteolysis of the thyroglobulin.
 There are also Parafollicular cells or C cells that synthesize and
secrete calcitonin, promote absorption of calcium and inhibit
resorption of bone by osteoclasts.
HYPERTHYROIDISM
 Thyrotoxicosis is a hypermetabolic state caused by elevated
levels of circulating free T3 and T4.
 Can be related to:
 Excessive release or preformed hormones in thyroiditis
 Extrathyroidal source of hyperfunctioning gland.
 Primary hyperthyroidism – intrinsic thyroid abnormality
 Secondary hyperthyroidism – extrinsic thyroid abnormality
 Three most common causes:
 Diffuse hyperplasia associated with Graves’ disease – 85%
 Hyperfunctional multinodular goiter
 Hyperfunctional thyroid adenoma
Clinical Course
 Hypermetabolic state induced by excess thyroid hormone to
overactivity of the sympathetic nervous system.
 Increase in metabolic rate.
 Skin tends to be soft, warm, and flushed due to increased
peripheral blood flow and vasodilation.
 Heat intolerance, sweating is increased (↑ calorigenesis).
 Weight loss despite increased appetite – catabolic
 Cardiac manifestations are among the earliest and most
consistent features – elevated contractility and cardiac
output in response to increased peripheral O2 req’t.
  Tachycardia, palpitations, cardiomegaly HYPOTHYROIDISM
 Arrhythmia – atrial fibrillation more common in elderly
 Congestive heart failure may develop
 Myocardial change - local lymphocytic and eosinophilic
infiltrates, mild fibrosis, myofibril fatty change
 Increase in number of mitochondria
 Develop reversible left ventricular dysfunction and
low-output heart failure so called thyrotoxic or
hyperthyroid cardiomyopathy
 Overactivity of the sympathetic nervous system
 Tremor, hyperactivity, emotional lability, anxiety
 Inability to concentrate, insomnia.
 Thyroid myopathy – proximal muscle weakness
 Hypermotility, diarrhea, and malabsorption
 Ocular changes
 Wide, staring gaze and lid lag are present because of
sympathetic overstimulation of superior tarsal muscle.  A condition caused by a structural or functional derangement
 True thyroid ophthalmopathy associated w/ proptosis that interferes with the production of thyroid hormone.
 Thyroid hormone stimulates bone resorption, increasing  Common, prevalence increases with age, more in women.
porosity of cortical bone and reducing volume of trabecular  Can also be divided into primary and secondary.
bone, net effect is osteoporosis.  Primary accounts for most of the cases and may be
 Thyroid storm refers to abrupt onset of severe accompanied by an enlargement in the size of the thyroid due to
hyperthyroidism, results from acute elevation of TSH.
catecholamine levels.
 Apathetic hyperthyroidism occurs in adult whom advance
age and co-morbid conditions blunt features of thyroid
hormone excess.

 Diagnosis is made both using clinical and laboratory finding.
 Serum TSH concentration is the most useful
 Its levels are decreased even at the earliest stages.
 Low TSH value is confirmed with free T4 measurement (↑)
 Predominantly from increased circulating levels of T3, the
free T4 may be decreased in these cases.
 In pituitary-associated, TSH levels may be normal or raised,
TSH levels are determined after injection of TRH normal rise
exclude secondary hyperthyroidism
 Diagnosis is confirmed by TSH assays and free thyroid
hormone levels by radioactive iodine uptake.
 Diffusely increased uptake – Graves’ disease
 Increased uptake in a solitary nodule – Toxic adenoma
 Decreased uptake - Thyroiditis
 Management include beta blockers, thionamide, iodine solution.
Congenital Hypothyroidism
 Most often result in endemic iodine deficiency in the diet.
 Inborn errors of thyroid metabolism (dyshormogenic goiter)
 Rarely, there may be complete absence of thyroid parenchyma
or thyroid agenesis or the gland is greatly reduced or thyroid
hypoplasia due to germline mutations.
Autoimmune Hypothyroidism
 Most common cause in iodine sufficient areas.
 Vast majority are caused by Hashimoto Thyroiditis.
 Circulating autoantibodies are:
 Anti-thyroid peroxidase
 Anti-microsomal
 Anti-thyroglobulin
 Thyroid is typically enlarged (goitrous).
 Occur in isolation or in conjunction with autoimmune
polyendocrine syndrome (APS), types 1 and 2.

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Iatrogenic Hypothyroidism Hashimoto Thyroiditis
 Can be caused by surgical or radiation induced ablation.
 Large resection or total thyroidectomay for hyperthyroidism or
neoplasm can lead to hypothyroidism.
 Drugs – Methimazole, PTU can cause acquired hypothyroidism
 Lithium and P-aminosalicylic acid can also cause hypothyroid
 Secondary or central hypothyroidism is caused by deficiencies of
TSH or far uncommonly TRH.

Cretinism
 Hypothyroidism that develops in infancy or early childhood.
 The term cretin was derived from French chretien meaning
Christian or Christ-like, and was applied to this unfortunates
because they were considered to be so mentally retarded as to
be incapable of sinning.
 Occurred in regions with iodine deficient supply.
 Cretinism may also result from genetic defects that interfere
with thyroid hormone biosynthesis - dyshormonogenetic goiter
 Clinical features include:  Autoimmune disease results in destruction of thyroid gland and
gradual and progressive thyroid failure.
 Impaired development of skeletal system and CNS
 Most common cause of hypothyroidism in iodine sufficient areas
 Severe mental retardation, umbilical hernia.
 Derived from Hashimoto describing patients w/ goiter & intense
 Short stature, coarse facial features, protruding tongue
lymphocytic infiltration of the thyroid (struma lymphomatosa).
 Severity of the mental impairment seems to be related to
 Most prevalent between 45-65 years old, women (10:1 – 20:1).
the time at which thyroid deficiency occurs in utero.
 Major cause of non-endemic goiter in pediatric population.
 If there is maternal deficiency of T3 and T4, mental
retardation is severe.
Pathogenesis
 Maternal thyroid hormone deficiency later in pregnancy,
 Caused by a breakdown in self-tolerance to thyroid autoantigens
after the fetal thyroid is functional, does not affect normal
brain development.  Presence of anti-thyroglobulin and anti-thyroid peroxidase
 Abnormalities in regulatory T cells.
Myxedema (Gull Disease)  Associated with polymorphisms in immune regulation
 Applied to hypothyroidism developing in the older child or adult. association gens CTLA4 and PTPN22, coding for regulators of T
 Cretinoid state in adult – William Gull cell responses, also seen in Diabetes Mellitus Type 1.
 Marked by a slowing of physical and mental activity.  Progressive depletion of thyroid epithelial cells by apoptosis and
replacement by mononuclear infiltrates and fibrosis.
 Generalized fatigue, apathy, and mental sluggishness.
 Contributors to thyroid cell death:
 Speech and intellectual functions are slowed.
 CD8+ cytotoxic T-cell mediated death.
 Listless, cold intolerant, and frequently overweight.
 Cytokine-mediated cell death
 Decreased sympathetic activity – constipation, decreased sweat
 Binding of auto-antibodies followed by antibody-dependent
 Reduced cardiac output contributes to shortness of breath and
cell-mediated cytotoxicity
decreased exercise capacity – two frequent complains.
 Decreased blood flow leads to cool, pale skin.
Morphology
 Accumulation of matrix substances in skin, subcutaneous tissue,
 Often diffusely enlarged, capsule is intact, well-demarcated.
and visceral sites resulting to non-pitting edema, broadening
 Cut surface is pale, yellow-tan, firm, and somewhat nodular.
and coarsening of face, enlargement of tongue and deep voice.
 Extensive mononuclear inflammatory infiltrate with small
 Diagnosis:
lymphocytes, plasma cells, and well-developed germinal centers.
 Patients with unexplained increases in body weight or
 Thyroid follicles are atrophic, lined by Hürthle cells, epithelial
hypercholesterolemia should be assessed for hypothyroid.
cells with abundant eosinophilic, granular cytoplasm.
 Serum TSH is the most sensitive.
 This is a metaplastic response to ongoing injury.
 TSH is increased in primary hypothyroidism.
 Interstitial connective tissue is increased and may be abundant.
 TSH is not increased in primary hypothalamic/pituitary dse
 Fibrosis does not extend beyond the capsule.
 T4 is decreased in hypothyroidism of any origin
 Hurthle cell + heterogeneous lymphocytes = Hashimoto
THYROIDITIS
Clinical Course
 Inflammation of the thyroid gland.
 Most often comes to attention as painless enlargement of the
 Three most common subtypes:
thyroid associated with some degree of hypothyroidism in a
1. Hashimoto Thyroiditis
middle-aged woman.
2. Granulomatous (de Quervain) Thyroiditis
 Enlargement is usually symmetric and diffuse.
3. Subacute lymphocytic thyroiditis

Page 7 of 14
 Develops gradually, may be preceded by transient thyrotoxicosis
caused by disruption of follicles leading to release of T3 and T4
(hashitoxicosis).
 During this phase, free T3 and T4 are elevated.
 TSH is diminished, radioactive iodine uptake is decreased.
 As hypothyroidism supervenes, T3, T4 decreases & TSH increase
 Increased risk of developing DM1, autoimmune adrenalitis, SLE,
myasthenia gravis, Sjogren syndrome, extranodal marginal B-cell
lymphomas within the gland.
Subacute Lymphocytic (Painless) Thyroiditis
 Come to clinical attention due to mild hyperthyroidism, goitrous
enlargement of the gland, or both.
 Most often in middle-aged adult women.
 Can occur in postpartum period in 5% of women.
 Most have circulating anti-thyroid peroxidase or family history
of other autoimmune disease.
Clinical Course
 Most common cause of thyroid pain.
 Variable enlargement.
 Transient inflammation and hyperthyroidism, usually diminishing
in 2-6 weeks, high serum T4 and T3, low serum TSH in this phase.
 Radioactive iodine uptake is decreased.
 After recovery, 6-8 weeks, normal thyroid function returns.
Riedel Thyroiditis
 Less common form of thyroiditis.
 Extensive fibrosis involving the thyroid and neck structures.
 Hard, fixed thyroid mass, simulating thyroid carcinoma.
GRAVES DISEASE

Morphology
 Mild symmetric enlargement, grossly appears normal.
 Lymphocytic infiltration with germinal centers.
 Patchy disruption and collapse of thyroid follicles.
 Fibrosis, Hurthle cells are not prominent compared to Hashimoto

Clinical Course
 Painless goiter, transient overt hyperthyroidism, or both.
 Some patients transition from hyperthyroidism to hypothyroid
before recovery.
 1/3 of affected individual progress to hypothyroid over 10 years.

Granulomatous Thyroiditis (De Quevain Thyroiditis)

 Less frequent than Hashimoto, most common in 40-50 years
affecting more women than men.
 A common cause of endogenous hyperthyroidism.
Pathogenesis  Violent and long continued palpitations in females (1835).
 Believed to be triggered by viral infection.  Triad:
 Majority have history or URTI just before the onset. 1. Hyperthyroidism – diffuse enlargement
 Seasonal incidence – peaks in summer. 2. Infiltrative Ophthalmopathy – exophthalmos
3. Localized, infiltrative Dermopathy – pre-tibial myxedema
 Clusters of cases in association with coxsackievirus, mumps,
measles, adenovirus, etc.  Peak incidence of 20-40 years old, women are 10x more affected
 Pathogenesis is unclear.
Pathogenesis
 One model suggest that it results from viral infection that leads
 An autoimmune disorder characterized by production of
to exposure to a viral or thyroid antigen secondary to virus-
autoantibodies against multiple thyroid proteins, most
induced host tissue damage.
importantly the TSH receptors.
 The antigen stimulates CD8 lymphocytes that damage follicles.
 Most common: Thyroid stimulating immunoglobulin (TSI)
Morphology  TSI binds to TSH receptor and mimics its actions, stimulating
adenylyl cyclase and increasing the release of thyroid hormones.
 May be unilateral or bilaterally enlarged and firm.
 Some have TSH receptor blocking antibodies, may lead to
 Intact capsule, may adhere to surrounding structures.
hypothyroidism.
 Firm, yellow-white on cut sections.
 Exophthalmos is associated with increased volume of the
 Histologic changes are patchy and depend on the stage.
retroorbital connective tissue and extraocular muscles.
 Early active inflammatory phase have disrupted scattered
 Marked infiltration of the spaces by T cells.
follicles replaced by neutrophils forming microabscesses.
 Inflammation with edema and swelling of extraocular muscle
 Later, more characteristic feature appear in form of lymphocytic
 Accumulation of ECM components (GAGs)
aggregates, activated macrophages and plasma cells in collapsed
and damaged thyroid follicles.  Increased number of adipocytes (Fatty infiltration)
 Multinulceate giant cells enclose naked pools / colloid fragment  Activated CD4+ helper T cells secrete cytokines that stimulate
fibroblast proliferation and synthesis of ECM.
 Chronic inflammatory infiltrate and fibrosis.

Page 8 of 14
Morphology
 Usually symmetrically enlarged due to diffuse hypertrophy and
hyperplasia of the follicular cells.
 Increases in weight to over 80 grams.
 Parenchyma has a soft meaty appearance resembling muscles
 Follicular cells are tall and more crowded resulting to formation
of small papilla that projects into the lumen and encroach the
colloid, sometimes filling the follicles.
 Lacks fibrovascular cores.
 Colloid is pale, with scalloped margins.
 Lymphoid infiltrates predominantly T cells.
 Germinal centers are common.
 Iodine administration causes involution of the epithelium and
accumulation of colloid by blocking thyroglobulin secretion.
 PTU exaggerates the hypertrophy and hyperplasia by stimulating
TSH secretion.
 Heart may be hypertrophied and ischemic changes present.
 Tissue of the orbit with edema, lymphocytic infiltrates, fibrosis
Clinical Course
 Changes associated with thyrotoxicosis.
 Thyroid enlargement – increased flow of blood through the
hyperactive gland producing bruit.
 Sympathetic overactivity – wide staring gaze, lid lag.
 Ophthalmopathy – abnormal protrusion of the eyeball, may lead
to corneal injury.
 Pre-tibial myxedema – Most common in the skin overlying the
shins, presents as scaly thickening and induration.
 Sometimes may spontaneously develop hypothyroidism.
 At risk of other autoimmune disease – SLE, DM, Addison
 Laboratory findings:
 Elevated T3 and T4
 Depressed TSH
 Elevated TRH
 Increased uptake of radioactive iodine
 Treated with beta blockers to address increased adrenergic tone
 Thionamides – decrease thyroid hormone synthesis
 Surgery used in patients who have large goiters.
DIFFUSE AND MULTINODULAR GOITERS
 Enlargement of the thyroid (goiter) caused by impaired synthesis
of thyroid hormone, most often result as iodine deficiency.
 Leads to compensatory increase in serum TSH.
 Causes hypertrophy and hyperplasia of the follicular cells leading
to gross enlargement of the thyroid gland.
 Compensatory increase in functional mass overcomes the
hormone deficiency ensuring a euthyroid metabolic state.
 Compensatory response may be inadequate in congenital
biosynthetic defect – goitrous hypothyroidism
 The degree of enlargement is proportional to the level and
duration of thyroid hormone deficiency.
 Can be broadly classified to: non-toxic and multinodular.
Diffuse Non-toxic (Simple) Goiter
 Enlargement without nodularity.
 Enlarged follicles are filled with colloid – colloid goiter
 Occurs in both endemic and sporadic distribution.
Page 9 of 14
 Endemic Goiter
 Occur in areas where supply of iodine is low.
 Endemic is used when goiters are present in more than 10%
 Common in mountainous areas of the world.
 Lack of iodine leads to decreased synthesis of hormones
leading to a compensatory increase in TSH results to follicular
hypertrophy and hyperplasia and enlargement.
 Goitrogens interfere thyroid hormone synthesis, present in
vegetables of Brassicacaea family (cabbage, cauliflower,
turnips, cassava, Brussels sprouts).
 Cassava contains a thiocyanate that inhibits iodide tranposrt
within the thyroid.
 Sporadic Goiter
 Occurs less frequently.
 Female predominance, peaks in puberty or young adults.
 Caused by several conditions.
 Ingestion of substances that interfere hormone synthesis
 Hereditary enzymatic defects (autosomal recessive)
Morphology
 Two phases:
 Hyperplastic phase – diffusely and symmetrically enlarged,
gland rarely exceeds 100-150g, crowded columnar cells may
pile up to form projections, accumulation is not uniform.
 Colloid involution phase
 If iodine increases or hormone demand decreases, the
epithelium involutes to form an enlarged, colloid-rich gland
(colloid goiter).
 Cut surface is brown, glassy, and translucent.
 Epithelium is flattened and cuboidal, colloid is abundant.
Clinical Course
 Clinically euthyroid.
 Manifestations are related to mass effects.
 Serum TSH is usually elevated or upper range of normal.
 Dyshormogenetic goiter in children may induce cretinism.
Multinodular Goiter
 Recurrent episodes of hyperplasia and involution combine to
produce a more irregular enlargement (multinodular goiter).
 All long-standing simple goiters covert to multinodular goiters.
 Produce the most extreme thyroid enlargements and mistaken
for neoplasms.
 Arise because of variations among the follicular cells in their
response to external stimuli.
 Uneven follicular hyperplasia, generation of new follicles, and
accumulation of colloid produces physical stress that may lead to
rupture followed by hemorrhage, scarring and calcifications.
Morphology
 Multilobulated, asymmetrically enlarged, weighs > 2000g.
 Pattern of enlargement is unpredicatable, may involve one lobe
far more than the other producing lateral pressure.
 Goiter may grow behind the sternum or clavicles and produce
intra-thoracic or plunging goiter.
 Cut sections show irregular nodules w/ brown gelatinous colloid
 Older lesions have hemorrhage, fibrosis, calcification, cysts.
 Colloid rich follicles lined by flattened, inactive epithelium and
areas of follicular hyperplasia with degenerative changes.
 Capsule between the nodule and parenchyma is NOT present.
Clinical Course
 Dominant feature is due to the mass effects.
 May cause airway obstruction, dysphagia, and large vessel
compression (SVC syndrome).
 Most are euthyroid or subclinical hyperthyroid (reduced TSH).
 Plummer syndrome – hyperthyroidism not accompanied by
infiltrative ophthalmopathy and dermopathy.
 Incidence of malignancy is low (<5%) but not zero.
 Solitary thyroid nodule mimics neoplasms.
 Uneven iodine uptake, hot autonomous nodule consistent with
diffuse parenchymal involvement and admixture of hyperplastic
and involuting nodules.
NEOPLASMS OF THE THYROID
 Solitary nodules are more likely to be neoplastic than multiple
 Nodules in younger patients are more likely neoplastic than
adult patients.
 Nodules in males are more likely neoplastic than in females.
 History of radiation to the head and neck is associated with an
increased incidence of thyroid malignancy.
 Functional nodules (hot nodules) are more likely to be benign.
Thyroid Adenomas
 Typically discrete, solitary masses derived from follicular
epithelium, hence are also known as follicular adenomas.
 NOT forerunners to carcinomas.
 Vast majority are non-functional, a small subset produces
thyrotoxicosis.
 Hormone production is independent of TSH stimulation.
Pathogenesis
 Somatic mutations of the TSH receptor signaling pathway are
found in toxic adenomas as well as toxic nodular goiters.
 Gain-of-function mutations in one of two components:
 Gene encoding for the TSH receptor – most common
 α-subunit of Gs (GNAS)
 Causes follicular cells to secrete thyroid hormones independent
of the TSH stimulation (thyroid autonomy).
 Leads to symptom of hyperthyroidism and produces hot nodule.
 Minority (<20%) of non-functioning follicular adenomas have
mutations of RAS or PIK3CA encoding for PI-3 kinase or bear
PAX8-PPARG fusion gene.
Page 10 of 14
Morphology
 Solitary, spherical, encapsulated lesion demarcated from the
surrounding thyroid parenchyma by a well-defined intact capsule
 Adenoma bulges from the surface and compress the adjacent
thyroid, color ranges from gray-white to red-brown.
 Areas of hemorrhage, fibrosis, calcification, and cystic changes.
 Uniform-appearing follicles with colloid.
 Neoplastic cells show little variation.
 Hürthle cells – or oxyphils may be present, these are cells with
brightly eosinophilic granular cytoplasm.
 Hallmark of all follicular adenomas is the presence of an intact,
well-formed capsule encircling the tumor.
Clinical Features
 Unilateral painless masses discovered on routine PE.
 Larger masses may produce local symptoms (dysphagia).
 Non-functioning adenomas take up less iodine, appears as cold
nodule on radionuclide scanning.
 Other diagnostics: Ultrasound, FNAB.
 Because of the need for evaluating capsular integrity, the
definitive diagnosis can be made only after careful histologic
examination of the resected specimen.
 Do not recur or metastasize
Carcinomas
 Accounts for 1.5% of all cancers.
 Female predominance, early and middle adult years.
 Cases in childhood or late adult have no gender predilection.
 Major subtypes
 Papillary carcinoma - > 85% of the cases
 Follicular carcinoma – 5-15% of cases
 Anaplastic carcinoma - < 5% of cases
 Medullary carcinoma – 5% of cases
 Most (except medullary CA) are derived from the thyroid
follicular epithelium, and majority are well-differentiated.
Pathogenesis
Genetic Factors
 Genetic alterations in the 3 follicular cell derived malignancies
are in growth factor receptor signaling pathways.
 Papillary carcinomas
 Most have gain-of-function mutations in RET or NTRK1
receptor tyrosine kinases, or serine/threonine kinase BRAF.
 RET gene (10q11) – the receptor tyrosine kinase this gene
encodes is normally not expressed. RET/PTC fusion gene is
present in 20-40% of papillary thyroid cancers, produces
gene that encode fusion proteins with constitutive tyrosine
kinase activity.
 BRAF encodes intermediate signaling component in MAP
kinase pathway, commonly a valine-to-glutamine change in
codon 600 in 1/3-1/2 of papillary thyroid CA.
 BRAF mutations correlate with adverse prognostic factors
such as metastatic disease and extrathyroidal extension.
 Follicular carcinomas
 Associated with acquired mutations that activate RAS or the
PI-3K/AKT arm of RTK signaling pathway.
 Harbor gain-of-function point mutations of RAS or PIK3CA,
PIK3CA amplifications, loss-of-function of PTEn are almost
always mutually exclusive of follicular carcinomas.
 PAX8-PPARG fusion genes in 1/3-1/2 of follicular CA.
 Anaplastic Carcinomas
 Highly aggressive, lethal can arise de novo or more
commonly by dedifferentiation of a well-differentiated CA.
 RAS, PIK3CA.
 Hits such as TP53 inactivation or activation mutations of
beta-catenin are restricted to anaplastic CA.
 Medullary Carcinomas
 Familial medullary CA occur in multiple endocrine neoplasia
type 2 (MEN2) and associated with germline RET mutations
 Chromosomal rearrangements of RET (such as in papillary
CA) is NOT seen in medullary.
Environmental Factors
 Major risk factor is exposure to ionizing radiation particularly
during the first 2 decades of life.
 Deficiency of dietary iodine is more linked with higher frequency
of follicular carcinomas.
Papillary Carcinoma
 Most common form of thyroid cancer (85%).
 Most often occurs between 25-50 years old.
 Previous exposure to ionizing radiation.
Morphology
 May be solitary or multifocal.
 May be well circumscribed or may invade adjacent parenchyma.
 May contain areas of fibrosis and calcification, often cystic.
 May contain branching papillae having a fibrovascular stalk
covered by a single to multiple layers of cuboidal epithelial cells.
 Nuclei contain finely dispersed chromatin which imparts
optically clear or empty appearance giving rise to ground-glass
or Orphan Annie eye nuclei.
 Invaginations of cytoplasm may give rise to pseudo-inclusions.
 Diagnosis can be made based on these features.
 Concentrically calcified psammoma bodies are often present.
Page 11 of 14
 When present, it is a strong indication of papillary carcinoma.
 Foci lymphatic invasion are often present, blood vessel
involvement is uncommon.
 Most common variant, most liable to misdiagnosis, is follicular
variant, which has nuclear features of papillary carcinoma and
almost totally follicular architecture.
 Tall cell variant has tall columnar cells with intensely
eosinophilic cytoplasm, occur in older individuals, and higher
frequencies of vascular invasion, extrathyroid extension and
metastases, harbors BRAF mutations and RET/PTC translocation,
 Diffuse Sclerosing variant occurs in younger individuals with
prominent papillary pattern with solid areas of nests of
squamous metaplasia, often with lymphocytic infiltrate,
simulating Hashimoto. Lacks BRAF, but RET/PTC are common.
 Papillary Microcarcinoma conventional papillary CA < 1 cm
Clinical Course
 Most present as asymptomatic thyroid nodules.
 First manifestation may be a mass in the cervical lymph node.
 Most are single nodules that move freely with the thyroid.
 Hoarseness, dysphagia, cough, dyspnea suggest advanced dse.
 Cold masse on scintiscans.
 Excellent prognosis, 10 yr survival rate in excess of 95%.
 5-20% have recurrences, 10-15% have distant metastases.
 Prognosis is dependent on age (less favorable > 40), presence of
extrathyroidal extension, and distant metastases.
Follicular Carcinoma
 Account for 5-15%, more frequent in dietary iodine deficiency
 More common in women and older patients.
 Peak incidence in 40-60 years of age.
Morphology
 Single nodules, may be well-circumscribed or infiltrative.
 Gray to tan to pink, may be translucent due to presence of large,
colloid filled follicles.
 Central fibrosis and calcifications may be present.
 Composed of fairly uniform cells containing colloid like normal
thyroid follicles.
 There may be nests or sheets of cells without colloid.
 Occasionally dominated by Hurthle cells.
 Nuclei lack features typical of papillary carcinoma and
psammoma bodies are absent.
 No reliable cytologic difference between adenoma and
carcinoma arising from the follicles.
 Making this distinction requires extensive histologic
sampling of the tumor-capsule-thyroid interface to exclude
invasion.
 Widely invasive follicular carcinoma infiltrate the thyroid
parenchyma and the extra thyoidal tissues.
 Tends to have greater proportion of solid or trabecular growth
pattern, less differentiation, increased mitotic activity.
Clinical Course
 Slowly enlarging painless nodules.
 Cold nodules.
 Rarely may become hyperfunctional (hot nodule).
 Little propensity for invading lymphatics and regional LN.
 Hematgenous dissemination is common, with metastasis to
lungs, liver, and elsewhere.
 Prognosis depends on the extent of invasion and stage at
presentation.
 Minimally invasive, 10 year survival rate of >90%.
 Treated by total thyroidectomy.
 Treated with thyroid hormone post-op to suppress endogenous
TSH levels. Serum thyroglobulin levels are used for monitoring.
Anaplastic Carcinoma
 Undifferentiated tumors of the follicular epithelium accounting
for less than 5% of primary thyroid tumors.
 Aggressive, mortality rate of approaching 100%.
 Older patients, mean age of 65.
 ¼ have past history of well-differentiated thyroid CA.
Morphology
 Composed of highly anaplastic cells with variable morphology:
1. Large pleomorphic giant cells, occasional osteoclast-like
multinucleate giant cells.
2. Spindle cells with a sarcomatous appearance.
3. Mixed spindle and giant cells.
4. Small cells
 Express epithelial markers like cytokeratin, but negative for
thyroid differentiation markers, like thyroglobulin.
Clinical Course
 Present as rapidly enlarging bulky neck mass.
 Most cases, disease has already spread beyond the capsule or
has metastasized at the time of presentation.
 Symptoms of compression and invasion.
 Uniformly fatal, death in < 1 year of diagnosis.
Medullary Carcinoma
 Neuroendocrine neoplasms derived from the parafollicular cells.
 Account for approximately 5% of thyroid neoplasms.
 Secretes calcitonin which can be measured for diagnosis and
post-op follow up.
 Can elaborate other polypeptide hormones (5HT, ACTH, VIP).
 80% are sporadic, 20% part of MEN syndrome 2A or 2B as
familial medullary thyroid CA.
 Mutation of RET protooncogene.
 MEN-2 in younger patients.
 Sporadic in adults, ages 40-50 years old.
Morphology
 Sporadic medullary CA present as solitary nodule.
 Bilaterality and multicentricity are common in familial.
 Tumor is firm, pale, gray to tan and infiltrative.
 Composed of polygonal to spindle shaped cells.
 May form nests, trabeculae or even follicles.
 Acellular amyloid deposits from calcitonin are present.
 Calcitonin is demonstrable by IHC.
 C-cell hyperplasia in the surrounding parenchyma is absent in
sporadic lesions, precursor lesion of familial cases.
Page 12 of 14
Clinical Course
Sporadic:
 Come to clinical attention most often as mas in the neck
associated with dysphagia or hoarsness.
 Paraneoplastic syndrome due to secretion of hormones (e.g
Diarrhea due to VIP, Cushing due to ACTH).
 Hypocalcemia is NOT prominent despite elevated calcitonin.
 Secretoin of CEA is a useful biomarker.
Familial
 Symptoms localized to the thyroid.
 MEN2B are generally more aggressive and metastasize more.
 Asymptomatic MEN2 with RET mutation are offered prophylactic
thyroidectomy to prevent development of medullary CA.
 Presence of C-cell hyperplasia or micromedullary (<1cm)
carcinomas are present in asymptomatic patients.
CONGENITAL ANOMALIES
Thyroglossal Duct Cyst
 Most common clinically significant anomaly.
 Vestigial remnant of tubular development.
 Sinus tract may persist or may obliterate leaving small segments
to form cysts.
 Occur at any age, do not become evident until adult life.
 Mucinous, clear secretions may collect within the cysts.
 Present in the midline of the neck anterior to the trachea.
 Lined by stratified squamous epithelium resembling the
posterior portion of the tongue in the region of foramen cecum.
 Anomalies in the lower more proximal to the thyroid are lined by
epithelium resembling the thyroidal acinar epithelium.
 There is intense lymphocytic infiltrate.
 Infection may convert these to abscess, rarely they become CA.
Parathyroid Glands
 Chief cells
 Predominant
 Water-clear appearance due to presence of large amount of
cytoplasmic glycogen
 Secretory granules contain parathyroid hormone
 Oxyphil cells
 Found throughout the whole gland, singly or in clusters
 Larger than chief cells
 Acidophilic cytoplasm and packed with mitochondria
 Glycogen granules are present with sparse or absent
secretory granules
 In infancy and early childhood, the glands are composed almost
entirely of chief cells
 Function is to regulate calcium homeostasis and is controlled by
level of free (ionized) calcium in the bloodstream
 Decreased levels of free Ca stimulate synthesis and
secretion of PTH
 Metabolic functions of PTH that regulate serum calcium levels:
 Increases renal tubular reabsorption of calcium
 Increases conversion of Vit D to its active form in kidneys
 Increases urinary phosphate excretion
 Augments GI calcium absorption
HYPERPARATHYROIDISM
 Caused by elevated PTH, classified into three categories.
 Primary hyperparathyroidism – autonomous overproduction of
PTH, resulting from an adenoma or hyperplasia of the PT tissue
 Secondary hyperparathyroidism – compensatory hypersecretion
of PTH in response to prolonged hypocalcemia from chronic renal
failure
 Tertiary hyperparathyroidism – persistent hypersecretion of PTH
even after prolonged hypocalcemia is corrected
Primary Hyperparathyroidism
 One of the most common endocrine disorders and an importance
cause of hypercalcemia
 Frequency of lesions are due to:
 Adenoma (85-95%)
 Primary hyperplasia (diffuse or nodular) [5-10%]
 Parathyroid CA (1%)
 Common in adults (50s or later) and in women than in men
 Most common cause is adenoma arising sporadically
 Molecular defects that have an established role in the
development of sporadic adenomas:
 Cyclin D1 gene inversions leading to overexpression of
cyclin D1 – 10-20% of adenomas have this rearrangement,
40% of adenomas have overexpression of cyclin D1
 MEN1 mutations - 20-30% of tumors have mutations on
both copes of the gene and are also found on familial
parathyroid adenomas
 Familial syndromes are a distant second to sporadic adenomas as
causes of primary hyperparathyroidism
 Multiple Endocrine Neoplasia, Types 1 and 2 – germline
mutations of MEN1 and RET, respectively
 Familial hypocalciuric hypercalcemia – AD disorder, due to
loss of function mutations on CASR gene, decreasing
sensitivity to calcium
Morphology
 Changes are seen in the PT glands and those organs affected by
elevated levels of PTH and Ca.
 Parathyroid adenomas are almost always solitary and lie in close
proximity of the thyroid or in an ectopic site
 0.5 to 5gm, well circumscribed, soft, tan to reddish-brown
nodule invested by a delicate capsule
 Composed of uniform, polyglonal chief cells with small,
centrally placed nuclei
 Few nests of oxyphil cells are present, and if primarily
composed of this cell type it is called oxyphil adenomas
 Resemble Hurthle cell tumors in the thyroid
 Rim of compressed, non-neoplastic PT tissue, separated by
a fibrous capsule is visible at the edge of the lesion
 Mitotic figures are rare
 Endocrine atypia - bizarre and pleomorphic nuclei within
adenomas, not a criterion for malignancy
 Primary hyperplasia - sporadic or a part of MEN syndrome
Page 13 of 14
 Classically, all four glands are involved, but sparing of one or
two glands can occur
 Most common pattern: chief cell hyperplasia, involving the
glands in a diffuse or multinodular pattern
 Less commonly, constituent cells contain abundant water-
clear cells: water-clear cell hyperplasia
 Islands of oxyphils are present
 Poorly developed fibrous strands envelope the nodules
 Parathyroid Carcinomas – may be circumscribed or clearly
invasive neoplasms
 Enlarge one PT gland, consist of gray-white, irregular mass
 Uniform and resemble normal PT cells, and arrayed in
nodular or trabecular patterns
 Enclosed by a dense, fibrous capsule
 Diagnosis is based on invasion and metastasis
Skeletal Abnormalities
 Osteoporosis – decreased bone mass, involving the phalanges,
vertebrae and femur
 Osteoclastic activity: cortical> medullary bone
 Dissecting osteitis – rail-road track appearance
 Marrow spaces are replaced by fibrovascular tissue
 Radiographic findings: decrease bone density or
osteoporosis
 Brown tumor – mass of reactive tissue due to influx of
macrophages and ingrowths of fibrous tissue secondary to
microfractures and hemorrhages
 Brown color is due to vascularity, hemorrhage and
hemosiderin deposition
 Undergo cystic degeneration
 Generalized Osteitis Fibrosa Cystica – von Recklinghausen disease
of the bone
 Combination of increased osteoclast activity, peritrabecular
fibrosis, cystic brown tumors
 Hallmark of severe hyperparathyroidism
Urinary Tract Abnormalities
 Formation of urinary tract stones (nephrolithiasis)
 Calcification of the renal interstitium and tubules
(nephrocalcinosis)
 Metastatic calcifications are also seen in the stomach, lungs,
myocardium and blood vessels
Clinical Course
Asymptomatic Hyperparathyroidism
 Most common cause of asymptomatic hypercalcemia
 Malignancy is the most common cause of symptomatic
hypercalcemia in adults
 Identified incidentally through routine blood chemistry profile
 The most common mechanism through which osteolytic tumors
induce hypercalcemia is by secretion of PTH-related peptide
(PTHrP) [80%]
 Metastasis to the bone and subsequent cytokine-induced
bone resorption (20%)
 In primary hyperparathyroidism, PTH levels are elevated
compared to serum Ca
 In hypercalcemia secondary to non-parathyroid diseases, PTH
levels are low to undetectable
Symptomatic Primary Hyperparathyroidism
 Reflects the effects of increased PTH secretion and hypercalcemia
 “Painful bones, renal stones, abdominal groans and psychic moans”
 Bone disease and bone pain secondary to fractures of bones
(osteoporosis or osteitis fibrosa cystica)
 Nephrolithiasis with attendant pain and obstructive
uropathy, may lead to polyuria and secondary polydipsia
 GI disturbances (e.g. constipation, nausea, peptic ulcers,
pancreatitis and gall stones)
 CNS alterations (e.g. depression, lethargy, seizures)
 Neuromuscular abnormalities (e.g. weakness and fatigue)
 Cardiac manifestations (e.g. aortic or mitral valve
calcifications, or both)
 Most directly related are nephrolithiasis and bone disease
 Attributable to hypercalcemia are fatigue, weakness,
pancreatitis, metastatic calcifications and constipation
Secondary Hyperparathyroidism
 Caused by any condition that gives rise to chronic hypocalcemia,
leading to compensatory overactivity of the PT gland
 Renal failure is the most common cause of secondary
hyperparathyroidism
 Inadequate intake of calcium, steatorrhea, and Vit. D deficiency
Morphology
 Glands are hyperplastic
 Degree of glandular enlargement is not necessarily symmetric
 Increased in number of chief cells or water-clear cells in a diffuse
or multinodular distribution
 Fat cells are decreased in number
 Metastatic calcifications in the lungs, heart, stomach & vessels
Clinical Course
 Not as severe or as prolonged as primary hyperparathyroidism
 Renal osteodystrophy is milder
 Calciphylaxis – vascular calcification, ischemic damage to skin
 Vitamin D supplementation and phosphate binders are often
given to patients with secondary hyperparathyroidism
 Parathyroidectomy is performed in tertiary hyperparathyroidism
Page 14 of 14
HYPOPARATHYROIDISM
 Acquired Hypoparathyroidism is almost always an inadvertent
consequence of surgery
Causes of Hypoparathyroidism
1) Surgically induced hypoparathyroidism – inadvertent removal of
all the PT glands during thyroidectomy
2) Autoimmune hypoparathyroidism – associated with chronic
mucocutaneous candidiasis & primary adrenal insufficiency
 Autoimmune polyendocrine syndrome type 1 (APS1) –
mutations in the autoimmune regulator gene (AIRE)
 Presents in childhood with onset of candidiasis,
hypoparathyroidism and adrenal insufficiency during
adolescence
3) Autosomal-dominant hypoparathyroidism – gain of function
mutations in the calcium-sensing receptor (CASR) gene leading to
hypocalcemia and hypercalciuria
4) Familial isolated hypoparathyroidism (FIH) – rare condition,
either AR or AD
 Autosomal Dominant FIH – mutation in the gene encoding
PTH precursor peptide, impairs mature hormone process
 Autosomal Recessive FIH – loss of function mutations in the
glial cells missing-2 (GCM2), essential for development.
5) Congenital absence of parathyroid – occur in conjunction with
other malformations (e.g. thymic aplasia [DiGeorge syndrome]
and cardiovascular defects) or part of 22q11 deletion syndrome
Clinical Features
 Hallmark of hypocalcemia is tetany.
 Classic findings on PE: Chvostek sign (induces contraction of
muscles of eye, mouth and nose by tapping the facial nerve)
and Trousseau sign (carpal spasms produced by occlusion
of the circulation to the forearm and hand with a BP cuff)
 Mental status changes -emotional instability, anxiety, depression,
confusion, hallucinations and psychosis
 Intracranial manifestations - calcifications of basal ganglia,
parkinsonian-like disorders and increased ICP with papilledema
 Ocular disease – calcifications of the lens and cataract formation
 Cardiovascular manifestations – conduction defect, prolonged QT
 Dental abnormalities – present during early development (e.g.
dental hypoplasia, failure of eruption, defective enamel and root
formation, abraded carious teeth)
Pseudohypoparathyroidism
 Hypoparathyroidism occurs due to end-organ resistance to PTH
 PTH levels are normal or elevated
 TSH, FSH/LH resistance is also present
 These hormones signal via G-protein-coupled receptors and the
disorder from genetic defects in the components of the pathway
are shared across endocrine tissues
 PTH resistance is the most obvious manifestation
 Hypocalcemia, hyperphosphatemia, and elevated circulating PTH
 TSH resistance is mild, LH/FSG resistance manifest as
hypergonadotrophic hypogonadism in females