6.

2 Endocrine Pathology: Pituitary and Thyroid Glands PATHOLOGY

Dr. Bailon | February 11, 2014 2nd 2013-2014

OUTLINE THE CELLS OF THE ANTERIOR PITUITARY

I. Normal Pituitary Gland
A. The Cells of the Anterior Pituitary 1. Somatotrophs
B. Control of Endocrine Function o Growth Hormone
II. Pituitary Adenomas 2. Corticotrophs
III. Genetic Alterations in Pituitary Tumors o Synthesize Pro-opiomelanocortin (POMC), which splits into:
IV. Genetic Abnormalities Associated with Pituitary Adenomas
 Corticotropin (ACTH) – controls adrenal glucocorticoid (mainly
V. Anterior Pituitary Gland
A. Diseases of the Anterior Lobe cortisol) and androgen secretion
B. Anterior Pituitary Hyperfunction  β lipotropin – B-melanocyte-stimulating hormone (B-MSH)
C. Anterior Pituitary Hypofunction (may be responsible for certain skin discoloration or darkening
VI. Posterior Pituitary Gland in certain situations), endorphins (gives feeling of
A. Diseases of the Posterior Pituitary
wellness/elation) and encephalin
B. Posterior Pituitary Syndromes
C. Hypothalamic Suprasellar Tumors 3. Thyrotrophs
VII. Thyroid Gland o Thyrotropin/Thyroid-Stimulating Hormone (TSH)
A. Thyroid Pathology  Growth of follicular cells
B. Tumors of the Thyroid  Secretion of thyroid hormone
4. Gonadotrophs
References:
Dra. Bailon’s PPT and recording o FSH (Follicle-stimulating hormone)
Robbins and Cotran’s Pathologic Basis of Disease, 8th edition  Stimulates production and maturation of ovarian Graafian
follicles
Legend: o LH (Luteinizing hormone)
Italicized – from recording
 Ovulation and corpus luteum formation and function
Bold – for emphasis
 – from Robbins (secretes progesterone, which is important for the
maintenance of pregnancy)
 Stimulates production of testosterone by testicular interstitial
I. NORMAL PITUITARY GLAND cells of Leydig
 Divided into posterior (neurophysis) and anterior 5. Lactotrophs
(adenohypophysis) lobes. o Prolactin
 Anterior pituitary constitutes about 80% of the gland  Milk production and secretion
 The production of most pituitary hormones is controlled 6. Nonsecretory cells
predominantly by releasing factors from the hypothalamus.
CONTROL OF ENDOCRINE FUNCTION

Figure 1: Normal Pituitary Gland (gross)

Figure 3: Control of endocrine function; (+) = stimulates secretion, (-) = inhibits

secretion; TRH = thyroid releasing hormone, TSH = thyroid stimulating hormone,
PIF = prolactin inhibiting factor, PRL = prolactin, CRH = corticotropin releasing
hormone, ACTH = adrenocorticotropic hormone, GHRH = growth hormone
releasing hormone, GH = growth hormone, GIH = growth hormone inhibiting
hormone, GnRH = gonadotropin releasing hormone, FSH = follicle stimulating
hormone, LH = luteinizing hormone

 Note: The control of endocrine function is both central and

Figure 2: Normal Anterior Pituitary Gland (histo); Cells were previously named
after their staining characteristics. Acidophils - GH and Prolactin. Basophils -
ACTH, TSH and Gonadotropins (FSH and LH). Chromophobes - may have
secretory activities.
peripheral. The central control starts from the hypothalamus,
which secretes stimulatory and inhibitory hormones. The
hormones secreted will then stimulate or inhibit specific organs to
secrete specific hormones.

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Group 28: Geronimo, A., Geronimo, AD, Geronimo, K., Gilera, Goco (09178926392), Gonzalez

II. PITUITARY ADENOMAS
Table 1: Classification of Pituitary Adenomas
III. GENETIC ALTERATIONS IN PITUITARY TUMORS
Table 2: Genetic Alterations in Pituitary Tumors
IV. GENETIC ABNORMALITIES ASSOCIATED WITH
PITUITARY ADENOMAS
 G-protein mutations
o Normally, activation of Gs alpha with resultant generation of
cAMP are transient due to intrinsic GTPase activity in the alpha
subunit which hydrolyzes GTP into GDP
o Mutation in the alpha subunit interferes with this intrinsic
ATPase activity  constitutive activation of Gs alpha, persistent
generation of cAMP and unchecked cellular proliferation
resulting in the formation of the tumor
o GNAS mutations - 40% somatotroph adenomas & few
corticotroph adenomas; absent in thyrotroph, lactotroph &
gonadotroph adenomas
 Pituitary adenomas mostly sporadic; 5% of cases -inherited
predisposition:
o 4 genes causing familial pituitary adenomas:
1. MEN1
2. CDL1B
3. PRKAR1A
4. AIP (aryl hydrocarbon receptor interacting protein)
 Molecular abnormalities associated with aggressive behavior of
pituitary tumors – aberration in cell cycle checkpoint genes:
o Overexpression of cyclin D1
o Mutations of p53
o Epigenetic silencing of RB gene (RB1)
o Activating mutations of HRAS oncogene – Pituitary CA
PATHOLOGY 6.2
Figure 4: Illustration of G-protein mutation
Figure 5: Pituitary Tumor (gross); an expanding mass occupying the area of
sella turcica. Growing mass may expand the sella turcica or destroy it.
V. ANTERIOR PITUITARY GLAND
Figure 6: Histology of Anterior Pituitary Tumor; Monotonous small round cells,
absent reticulin network (helpful in distinguishing pituitary adenomas from
non-pituitary adenomas; reticulin stain used)
DISEASES OF THE ANTERIOR LOBE
A. Hyperpituitarism
 Increase in pituitary hormones
 Causes:
o Anterior Lobe Adenoma – most common cause; 35 - 60 y/o
 Functional or Non-functional
- Functional – associated with hormone excess and clinical
manifestations thereof
- Non-functional – immunohistochemical and/or
ultrastructural demonstration of hormone production at
the tissue level, without clinical symptoms of hormone
excess. Nonfunctional adenomas may cause
hypopituitarism due to destruction of normal pituitary
parenchyma (common with gonadotroph adenomas).
 Microadenoma (<1cm) or Macroadenoma
o Hypothalamic disorder
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 PATHOLOGY 6.2
o Pituitary CA/hyperplasia develop ACROMEGALY (enlargement of head, hands, feet, jaw,
o Non-pituitary tumors tongue and soft tissues)

B. Hypopituitarism
 Decreased pituitary hormones
 75% of anterior lobe is destroyed
 Causes:
o Non-functioning pituitary adenomas (most common cause)
o Inflammation (infections)
o Ischemic injury, surgery, radiation
o Rarely hypothalamic in origin

C. Local mass effects

 Enlarged sella turcica on CT scan, X-ray, MRI
 Visual field defects (bitemporal hemianopsia)
 Increased intracranial pressure: manifested by headache, nausea
and vomiting; pituitary apoplexy
 Typified by nonfunctional pituitary adenomas with Figure 7. Signs of Acromegaly
hypopituitarism due to destruction of the normal pituitary
parenchyma (usually seen in gonadotroph adenomas) C. Corticotroph Adenoma
 Hypersecretion of ACTH (hypercortisolism)
ANTERIOR PITUITARY HYPERFUNCTION 1. Cushing Disease
Table 3. Anterior pituitary hormones and their corresponding lesions and
o Due to a pituitary corticotroph adenoma
manifestations
2. Cushing Syndrome
Hormone Lesion Classic Staining Manifestations
o Hypercortisolism regardless of cause
of Tumor cells
o Often pituitary origin and less often adrenal origin
Prolactin Prolactin cell Chromophobic Amenorrhea &
o May be due to ectopic ACTH production by tumors (especially
(lactotroph) (EM - sparsely galactorrhea;
small cell CA of the lung)
adenoma gran.) impotence &
o Clinical effects and manifestations of Cushing’s syndrome
infertility (males)
 Central obesity with "moon facies" and “buffalo hump"
Somatotropin Somatotroph Acidophilic Gigantism
 Increased gluconeogenesis  protein (muscle) wasting 
(growth adenoma (EM - densely (children),
thin extremities and growth retardation in children
hormone) gran.) Acromegaly
 Skin atrophy with easy bruising and purplish striae
(adults)
especially over abdomen
Corticotropin Corticotroph Basophilic Pituitary
 Slow wound healing
(ACTH) adenoma Cushing’s
 Increased susceptibility to infection
syndrome,
 HPN, sodium retention, potassium loss due to
Nelson syndrome
mineralocorticoid effect of cortisol
 D.M. due to cortisol effect on glucose metabolism
A. Lactotroph Adenoma (Prolactinoma)  Osteoporosis
 Most common hyperfunctioning pituitary adenoma (30% of cases)  Mental disturbances: steroid encephalopathy
 Other pathologic causes of prolactin excess:  Associated androgen excess leading to hirsutism, acne, and
o lactotroph hyperplasia menstrual disturbances
o hypothalamic lesions o Diagnosis of PRESENCE of Cushing’s syndrome
o medications (methyldopa, reserpine) that interfere with  Elevated plasma cortisol
dopamine secretion;  Loss of diurnal rhythm of cortisol secretion
o estrogen treatment  Failure to suppress cortisol secretion with low dose
o renal failure dexamethasone test
o hypothyroidism o Diagnosis of the CAUSE of Cushing’s syndrome
 Physiologic causes: nipple manipulation/stimulation & stress  Check for plasma ACTH level
 ¼ cases of amenorrhea  High dose dexamethasone test
 Dystrophic calcification - If there is suppression of cortisol secretion - pituitary
ACTH excess
B. Somatotroph Adenoma - If there is no suppression - indicates adrenal neoplasm or
ectopic ACTH syndrome
 Second most common pituitary tumor
3. Nelson Syndrome
 Gigantism BEFORE epiphyseal closure & acromegaly AFTER o Large destructive adenomas following postsurgical removal of
epiphyseal closure adrenals for Cushing syndrome mass effect but no
If somatotroph adenomas appear before epiphyseal
hypercortisolism due to absent adrenals
closure, elevated GH results in GIGANTISM (generalized increase o Hyperpigmentation secondary to stimulation of by products
in body size and disproportionately long arms and legs) of ACTH precursor molecules on melanocytes
if increased GH appears after epiphseal closure, patients

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 PATHOLOGY 6.2
o Normal blood volume

B. Diabetes Insipidus (Central type of ADH Deficiency)

 Polyuria ( dehydration)
 Excessive thirst
 Polydipsia due to increased serum osmolarity
 Hypernatremia
 Low urine specific gravity
 Most common causes: tumors (craniopharyngioma), trauma,
inflammation(involving the posterior pituitary or hypothalamus)
 Central type of ADH deficiency should be differentiated with the
nephrogenic diabetes insipidus, wherein the renal tubules are
unresponsive to the circulating ADH.
Figure 8. Major clinical manifestations of Cushing’s Syndrome
HYPOTHALAMIC SUPRASELLAR TUMORS
ANTERIOR PITUITARY HYPOFUNCTION  May present as anterior pituitary hypo- or hyperfunction, diabetes
A. Hypopituitarism insipidus or both
 Decreased secretion of pituitary hormones  Tumors above the sella turcica
 Causes  Two most implicated lesions
1. Pituitary tumors & cysts 1. Craniopharyngiomas
2. Traumatic brain injury & subarachnoid hemorrhage surgery or  Diagnostic feature = “WET KERATIN”
radiation  Seen as calcifications on X-ray
3. Apoplexy 2 variants are recognized
 Sudden hemorrhage into the pituitary gland Adamantinomatous craniopharyngiomas
4. Sheehan Syndrome More common in childrens
 Postpartum anterioir pituitary necrosis Commonly calcify
5. Rathke Cleft Cyst  “Spongy” reticulum w/ peripheral
 Can accumulate proteinaceous fluid and expand thus palisading of the epithelium and compact, lamellar
compromising the space of the normal gland keratin (wet keratin)
6. Empty Sella Syndrome Cysts in this tumor contains
 Presence of an enlarged and empty sella turcica cholesterol-rich fluid likened to “machinery oil”
7. Genetic defects Papillary craniopharyngiomas
8. Hypothalamic lesions Rarely calcify
9. Inflammatory disorders and infections such as TB, meningitis, lacks keratin or cysts
and sarcoidosis 2. Gliomas
 Manifestations
1. Pituitary Dwarfism
 Deficiency if growth hormone in children leads to growth
retardation

VI. POSTERIOR PITUITARY GLAND

 Oxytocin (functions):
o Uterine contraction during labor
o Milk ejection
 Antidiuretic hormone (ADH/Vasopressin)
o Water retention via action of renal collecting ducts Figure 9. (Left) Craniopharyngiomas average 3-4cm; they may be encapsulated
and solid but more commonly they are cystic and sometimes multiloculated.
DISEASES OF THE POSTERIOR PITUITARY Cysts contains “machine oil”. They are often encroached on the optic chiasm or
 Presents as an increase or decrease in ADH secretion cranial nerves. They may also bulge into the floor of the 3rd ventricle and base
of the brain. (Right) Craniopharnygioma with compact lamellar wet keratin and
cords of squamous epithelium with peripheral pallisading.
POSTERIOR PITUITARY SYNDROMES
A. Syndrome of Inappropriate ADH Secretion (SIADH)
 Most common cause: ectopic ADH secretion by malignant tumors
(small cell CA of the lung, thymoma, pancreatic CA, lymphoma),
drugs, infections, injury to hypothalamus and/or posterior
pituitary
 Water retention  dilutional hyponatremia & inability to dilute
the urine  decreased serum osmolarity
 Manifestations:
o Cerebral edema
o Neurologic dysfunction

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 PATHOLOGY 6.2

VII.THYROID GLAND THYROID PATHOLOGY

 Requires medical or surgical treatment
 May present as hyperthyroidism, hypothyroidism, or goiter (focal
or diffuse enlargement of thyroid gland)

A. Congenital Anomalies of Thyroid Gland

1. Thyroglossal duct cyst
o Remnants of the thyroglossal duct
o Most common thyroid anomaly
2. Lingual/heterotropic/lateral aberrant thyroid tissue

B. Goiter
Figure 10. Normal thyroid gland which consists of left and right lobe connected  Types
by isthmus
1. Diffuse Non-toxic (Simple) Goiter
Figure 11. Normal histology of thyroid gland which consists of follicles which are
lined by follicular cells of the cuboidal type and they are filled with pinkish
homogenous material known as colloid. In between is the instertitial tissue and
beside these follicular cells are parafollicular or C cells.
2. Multinodular Goiter
Figure 12. Homeostasis in the hypothalamus-pituitary-thyroid axis and
mechanism of action of thyroid hormones. Secretion of thyroid hormones (T3
and T4) is controlled by trophic factors secreted by both the hypothalamus and
the anterior pituitary. Decreased levels of T3 and T4 stimulate the release of
thyrotropin-releasing hormone (TRH) from the hypothalamus and thyroid-
stimulating hormone (TSH) from the anterior pituitary, causing T3 and T4 levels
to rise. Elevated T3 and T4 levels, in turn, feed back to suppress the secretion of
both TRH and TSH. TSH binds to the TSH receptor on the thyroid follicular
epithelium, which causes activation of G proteins, and cAMP-mediated
synthesis and release of thyroid hormones (T3 and T4). In the periphery, T3 and
T4 interact with the thyroid hormone receptor (TR) to form a hormone-receptor
complex that translocates to the nucleus and binds to so-called thyroid
response elements (TREs) on target genes to initiate transcription.
o Toxic
o Non-toxic – no associated functional, inflammatory or
neoplastic changes
o Diffuse enlargement of thyroid without nodularity
o Endemic and sporadic form
 Endemic ( >10% of pop. in a region); dietary iodine
deficiency;
 Lack of iodine decrease in TH synthesis compensatory
increase in TSH follicular cell hypertrophy & hyperplasia 
goiter
o Goitrogens – food or drugs that interfere with TH synthesis
 Cabbage, excessive calcium intake, Brassicaceae (Cruciferae)
 Cassava contains thiocyanate which inhibits iodide transport
within TG
 Medications such as thiourea, mercaptoimidazole
o Morphology (2 Phases)
a. Hyperplastic phase
- Thyroid gland is enlarged although the increase is
usually modest
- The follicles become hypoplastic and produce
papillary projections
b. Colloid involution phase
- Follows increased dietary iodine or decreased TH
demand  colloid goiter
 Gross feature: cut surface is brown, glassy, translucent
 Histologic feature: flattened and cuboidal follicular epithelium
and abundant colloid during the involution phase
o Clinical course
 Euthyroid
- Normal T3 and T4
- Increased or upper normal TSH
 In children, CRETINISM (physical stunting) caused by
dyshormogenic goiter
o Can be toxic (Plummer syndrome) or non-toxic
o Can be endemic and sporadic
o Females > Males
o Clonal proliferation of cells with different proliferative potential
 autonomous nodule (some with identified TSH-signaling
pathway mutations)
o Both poly- & monoclonal nodules coexist within the same
multinodular goiter
o Uneven follicular hyperplasia, new follicles, uneven colloid
accumulation  tension  rupture of follicles and blood
vessels  hemorrhages, scarring, calcifications  nodularity
o Microscopic feature
 Islands of hyperplastic follicles filled with colloid
 Random, irregular scarring/fibrosis
 Focal hemorrhages and hemosiderin deposition
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 PATHOLOGY 6.2
 Focal calcifications in scarred areas
 Microcysts
o Clinical course
 Most patients are euthyroid or have clinical or have
subclinical hyperthyroidism
 Signs and symptoms due to size and location of mass:
- Dysphagia/choking sensation, inspiratory stridor
- Superior vena caval syndrome (compression of large
vessels in the neck and upper thorax)
- Hemorrhage into the goiter  sudden, painful
Figure 16. Histologic picture of a multinodular goiter. This consists of several
enlargement and obstruction
follicles of varying sizes in which some are dilated and filled with colloid whie
- Hyperthyroidism secondary to development of autonomous others are very small and atrophic. The absence of a prominent capsule is its
nodule (toxic multinodular goiter) – should be differentiated distinguishing feature from follicular neoplasm.
with a neoplasm, usually papillary or follicular (a fine needle
biopsy may be done)

Figure 13. Mulitnodular goiter. Multilobulated, asymmetrically enlarged glands.
May weigh more than 2000 grams. The capsule is intact but there are nodules
that appear dark brown to black.
Figure 17. Higher magnification of a follicle distended with colloid. The follicular
cellsare already flattened because of distention. You can also see small follicles
surrounding the very large follicle.
C. Hyperthyroidism
 Increase in the thyroid hormones
 Thyrotoxicosis: hypermetabolic state caused by the elevated
circulating levels of free T3 and T4
 Hyperthyroidism: hyperfunctioning of the thyroid gland

Table 4. Diseases Associated with Thyrotoxicosis

ASSOCIATED WITH HYPERTHYROIDISM
Primary
Diffuse toxic hyperplasia (Graves disease)*
Hyperfunctioning (“toxic”) multinodular goiter*
Hyperfunctioning (“toxic”) adenoma*
Iodine-induced hyperthyroidism
Neonatal thyrotoxicosis associated with maternal Graves’ disease
Secondary
TSH-secreting pituitary adenoma (rare)
NOT ASSOCIATED WITH HYPERTHYROIDISM
Subacute granulomatous thyroiditis (painful)
Figure 14. A person with multinodular goiter. The patient will present with an Subacute lymphocytic thyroiditis (painless)
anterior neck mass that moves with deglutition or swallowing. Struma ovarii (ovarian teratoma with ectopic thyroid tissue)
Factitious thyrotoxicosis (due to exogenous thyroxine intake)
*three most common causes of thyrotoxicosis

Manifestations related to
hyperthyroidism are due
to:
1. Hypermetabolic state
induced by excess
thyroid hormones  
BMR
2. Overactivity of the SNS

Figure 15. Gross picture of multinodular goiter. Demonstrates a coarsely

nodular gland containing areas of fibrosis and cystic changes. The cysts are
lined by whitish materials which probably represent calcifications.

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 PATHOLOGY 6.2
 Cardiac manifestations
o Earliest and most consistent features of hyperthyroidism:
1.  CO due to  cardiac contractility &  peripheral O2
requirements
2. Tachycardia due to  β-adrenergic tone
3. Palpitation tone
4. Cardiomegaly
o Thyrotoxic cardiomyopathy
 Reversible LV dysfunction & low output heart failure
 Microscopically:
- Foci of lymphocytic and eosinophilic infiltration
- Mild interstitial fibrosis
- Fatty changes in myofibers
Figure 18. Whatever is the cause of hyperthyroidism (be it from Grave’s disease,
- Increased size and number of mitochondria multinodular goiter, or from a toxic adenoma), the microscopic appearance of
o Arrhythmias – mostly atrial fibrillation the thyroid will be the same; there is hyperplasia of the thyroid follicles leading
o CHF – especially if with pre-existing cardiac disease to the formation of papillae; adjacent to these papillae are white areas known
 Skin as the moth-eaten colloid or scalloping of the colloid – this is typically seen in
o Warm, moist, flushed skin hyperthyroidism; take note of the appearance of the nuclei: they tend to be
 Due to  blood flow and peripheral vasodilatation arranged in single layer; to distinguish this from papillary carcinoma (which also
forms papillae), you have to look at the nuclei.
increased heat loss
o Excessive sweating – due to  calorigenesis
GRAVE’S DISEASE
 Neuromuscular – due to sympathetic overactivity
 Most common cause of hyperthyroidism (endogenous)
o Tremors
 Clinical triad:
o Emotional lability
1. Hyperthyroidism
o Anxiety
2. Infiltrative ophthalmopathy.
o Inability to concentrate
3. Infiltrative dermopathy (localized or pretibial myxedema)
o Insomnia
o Proximal muscle weakness with ↓ muscle mass  Peak incidence: 20 to 40 yrs of age
 GIT  F>M = 10:1
o  motility – due to sympathetic overactivity  Polymorphism in immune function genes (CTLA 4, PTPN22,& HLA-
DR3 allele)
o  appetite but with weight loss secondary to  BMR & bowel
motility  30 to 40% concordance rate in monozygotic twins
o Malabsorption, diarrhea  Pathogenesis of Grave’s disease:
 Skeletal system o Autoimmune disease initiated by auto-antibodies (IgG Abs)
o Thyroid hormone stimulates bone resorption  osteoporosis  against specific domains of TSH receptors (located at the
surface of the follicles)
 risk of fracture
o B cells are activated to produce anti-TSH receptor Abs:
 Menstrual abnormalities
1. Thyroid-stimulating immunoglobulin (TSI)
o Amenorrhea or oligomenorrhea
- An IgG antibody that mimics the action of TSH and reacts
with thyroid follicle TSH receptors and stimulate adenylyl
THYROID STORM
cyclase activity 
 Medical emergency
a. ↑ release of thyroid hormones  ↑ FT4 & FT3 levels,
 Results from acute elevation of catecholamines encountered
leading to:
during infection, surgery, sudden discontinuity of antithyroid
 Hypermetabolic state
medication or excessive stress
 Suppress TRH & TSH thru negative feedback  ↓
 Presents with achycardia out of proportion to fever serum TSH
 Can lead to cardiac arrythmias  death b. ↑ RAI uptake and diffuse uptake of iodine on radioiodine
scan secondary to stimulation of thyroid follicles
APATHETIC HYPERTHYROIDISM 2. Thyroid growth-stimulating Ig (TGI)
 Masked signs and symptoms due to old age and co-morbidities - Directed against TSH receptors
 Unexplained weight loss & worsening cardiovascular disease - Stimulates hyperplasia and hypertrophy of thyroid follicular
epithelium  symmetrically & diffusely enlarged thyroid
gland
3. TSH-binding inhibitor Ig
- Prevent TSH from binding normally to its receptors on the
thyroid epithelial cells. Some forms mimic TSH 
stimulation of thyroid epithelial cell activity
Other forms inhibit thyroid cell function – explains
episodes of hypothyroidism in Graves disease

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 PATHOLOGY 6.2

Figure 21. Thyroid gland in Graves disease. There is diffuse, symmetric

enlargement of the gland and a soft, beefy deep red parenchyma.

Figure 19. Triggering Factors of Grave’s Disease

CLINICAL COURSE
 Ophthalmopathy
1. Exophthalmos
2. Upper lid lag
3. Diplopia
o All of these occur due to:
 Retroorbital accumulation of mononuclear cells such as T
lymphocytes
 Inflammation, edema, and swelling of EOM
 Fatty infiltration Fig 22. Diffusely hyperplastic thyroid in a case of Graves’ disease. Hyperplasia
Orbital preadipocyte fibroblasts express TSH leads to papillary formation. The follicles are lined by tall, columnar epithelium.
receptors  targeted by autoimmune attack  activated The crowded, enlarged epithelial cells project into the lumens of the follicles.
T-cells secrete cytokines  proliferation of extracellular These cells actively resorb the colloid in the centers of the follicles, resulting in
matrix and increase surface TSH receptor expression the scalloped appearance or moth-eaten appearance of the edges of the
 Accumulation of hydrophilic glycosaminoglycans colloid. Be it Grave’s disease, toxic multinodular goiter or adenoma, the
microscopic appearance will be the same: (1) there is diffuse proliferation of the
(hyaluronic acid & chondroitin sulfate) follicular epithelial cells, hence enlargement of the gland; (2) there is moth-
eaten appearance of the colloid or scalloping of the colloid. All these features
signify that the patient has a hyperfunctioning thyroid. They differ in the classic
appearance of a person with Graves disease.

D. Hypothyroidism
 Decrease in the thyroid hormones
 Myxedema in adults and cretinism in children

Table 5. Causes of Hypothyroidism

ASSOCIATED WITH HYPOTHYROIDISM
PRIMARY
Developmental (thyroid dysgenesis: PAX-8, FOXE1, TTF-2, TSH-receptor
mutations)
Thyroid hormone resistance syndrome (THRB mutations)
Post-ablative (surgery, radioiodine therapy, or external irradiation)
Figure 20. Appearance of a person with Grave’s disease Autoimmune hypothyroidism (Hashimoto thyroiditis*)
Iodine deficiency*
 Infiltrative dermopathy (pretibial myxedema) Drugs (Lithium, iodides, p-aminosalicylic acid)*
o Scaly thickening & induration of skin or as papules/nodules with Congenital biosynthetic defect (dyshormonogenetic goiter)*
SECONDARY
orange-peel texture
Pituitary failure
o Due to the infiltration of the dermis by lymphocytes Hypothalamic failure
*Associated with enlargement of the thyroid (“goitrous hypothyroidism”).
Hashimoto thyroiditis and postablative hypothyroidism account for the majority
of cases of hypothyroidism in developed countries.

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 PATHOLOGY 6.2
Clinical Manifestations of
Hyperthyroidism
1. Muscle weakness
2. Coarse, dry, brittle hair
3. Loss of lateral eyebrows
4. “Myxedema” madness
5. Periorbital edema &
puffy face
6. Large tongue
7. Hoarseness
8. “Myxedema” heart
(cardiomegaly)
9. Gastric atrophy
10. Constipation
11. Menorrhagia
(anovulatory cycles) Figure 23. Pathogenesis of Hashimoto thyroiditis. Breakdown of peripheral
12. Peripheral edema tolerance to thyroid auto-antigens results in progressive autoimmune
(hands, feet) destruction of thyrocytes by infiltrating cytotoxic T cells, locally released
cytokines or by antibody-dependent cytotoxicity.

o Pathogenesis: (from recording)

LABORATORY CONFIRMATION OF DIAGNOSIS
Table 6. Comparison of Hormone Levels in Hyper and Hypothyroidism
 Other laboratory abnormalities in hypothyroidism:
o Increased serum cholesterol
o Decreased resin T3 uptake
E. Thyroiditis
Caused by diseases that result in:
Acute illness with severe thyroid pain
Disorders with little inflammation
Infectious thyroiditis – acute, reach thyroid by hematogenous
spread or direct seeding
Pneumocystis infections – chronic, immunocompromised
patients
1. Hashimoto Thyroiditis
o F > M (10:1 to 20:1)
45 -65 y/o
Gradual thyroid failure due to autoimmune destruction of
Gland
Strongly genetic: 40% concordance of monozaygotic
twins, 50% of asymptomatic siblings have presence of
circulating antibodies
Linked to polymorphisms in multiple immune regulation
associated genes such as cytotoxic T lymphocyte-associated
antigen-4 (CTLA4)
Also associated with protein tyrosine phosphatese-22
(PTPN22) gene polymorphisms
o Importance:
 Most common cause of hypothyroidism in regions with
sufficient iodine
 Major cause of non-endemic goiter in children
 Archetype of organ-specific autoimmune disease
 Hashimoto thyroiditis involves Helper T cell sensitization to
the thyroid antigens. This will eventually lead to different
pathways:
1. T cell mediated cytotoxicity
2. With the production of the interferon gamma, it will
activate macrophages releasing certain types of chemical
mediators of inflammation resulting to thyrocyte injury
Apoptosis
Replacement of thyroid parenchyma by
mononuclear cell infiltration
Fibrosis
3. B cells will produce the plasma cells which will cause the
production of anti-thryoid antibodies resulting to antibody
dependent cell mediated cytotoxicity
CD8+ cytotoxic T cell-mediated cell death
Cytokine-mediated cell death – recruitment
of macrophages and damage to follicles
Binding of anti-thyroid antibodies
o Clinical characteristics of Hashimoto thyroiditis:
 Majority initially euthyroid
 Gradual thyroid gland enlargement, non-tender, in middle-
aged women, assosciated with hypothyroidism
 Increased incidence of other autoimmune diseases (Type I
DM, SLE, Myasthenia gravis, Sjogren’s syndrome, B-cell non-
Hodgkin’s lymphoma)
 Diagnosis: Detection of circulating antithyroid antibodies
(immunoflourescence tests fro antimicrosomal &
antithyrogloblin antibodies) & increase in TSH
Figure 24. The appearance of the thyroid gland in Hashimoto thyroiditis
depends on the duration of the disease. In the early stages, the thyroid will not
look too small but with nodularities in the surface. Microscopically, the thyroid
follicles are replaced by lymphoid tissue with enlarged germinal centers
(presence of mantle of lymphocytes and the germinal centers contain
immunoblasts). Residual thyroid follicles are lined by deeply eosinophilic
Hurthle cells.

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 PATHOLOGY 6.2

Figure 25. Higher magnification. Lymphoid tissue with struma lymphomatosa –

Figure 28. Subacute granulomatous (de Quervain’s) thyroiditis. This is
this contains lymphocytes (dark and small cells) and immunoblasts (large cells;
characterized by the presence of epithelioid cells. The small dark cells
these are usually seen in the germinal center).
surrounding the epithelioid cells are lymphocytes. There are foreign body giant
cells (nuclei are haphazardly arranged as compared to the horseshoe
arrangement of the nuclei in TB).

3. Riedel’s Thyroiditis
o Thyroid gland replacement by fibrous tissue; unknown origin;
rare
o Important because it can clinically mimic carcinoma

TUMORS OF THE THYROID

Figure 26. In the late stages, there would already be atrophy and fibrosis of the  Benign and malignant (10:1)
thyroid follicles causing the decrease in thyroid hormone levels and  90% are thyroid adenomas
consequently an increase in TSH levels.
 Thyroid nodule(s) is/are likely neoplastic if:
o Solitary
o Occur in younger patients (<40)
o Males
 Functional nodules that take up radioactive iodine in imaging
studies (hot nodules) are significantly more likely to be benign
than malignant.
 History of radiation treatment to the head and neck region
increases the risk/incidence of thyroid malignancy
Figure 27. (Left) Immunoflourescence test for anti-microsomal antibody. (Right)
Immunofluorescence test for anti-thyroglobulin antibody. A. Benign Tumors of the Thyroid
1. Follicular Adenomas
2. Subacute Granulomatous (de Quervain’s) Thyroiditis
o Often solitary, appears usually as a cold nodule; sometimes as
40-50 years old
hot nodules
F > M, 4:1
o Most common in young females; excellent prognosis
o Focal destruction of thyroid tissue  granulomatous
May cause clinically apparent thyrotoxicosis
inflammation; infrequent
Caused by:
o Follows certain viral infections such as mumps or coxsackie
Mutations of RAS or PIK3CA
virus
PAX8-PPARG fusion gene
Pathogenesis
Somatic mutation of TSH receptor signalling pathway
Viral infections such as mumps, coxsackie virus,
adenovirus, etc.
Occurs after URTI
Infection causes exposure of immune system to
thyroid antigen, which is releasead secondary to virus-induced
host damage
T lymphocytes damage thyroid follicular cells
Caused by virus, so not self-perpetuating (limited)

Figure 29. Follicular adenoma of the thyroid. Cut surface of thyroid mass
appears to be encapsulated and single/solitary. It is pinkish brown with areas
of brownish discoloration. It may be soft or firm but often times it is firm.
Microscopically, this tumor contains closely packed follicles with colloid
formation of varying sizes. It is delineated from the normal areas by a thin
fibrous capsule (arrow). The entire mass is encapsulated and compressing the
adjacent normal thyroid parenchyma. Follicular adenoma is difficult to
differentiate from a follicular carcinoma by just looking at the gross specimen
unless there is already a break in the capsule with infiltration into the adjacent
normal thyroid parenchyma. You need to see vascular invasion in the
microscopic picture for you to be able to say that it is follicular carcinoma.

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Hurthle cell adenoma – clinical presentation and
behaviour of follicular adenoma with Hurthle cell adenoma
Characteristic of cut surface, color, and demarcation of
adjacent parenchyma is important in distinguishing follicular
adenoma from multinodular goiter
B. Malignant Tumors of the Thyroid
 Uncommon; slow-growing; M:F= 1:3 , middle-aged patients
 90-95% are well differentiated; most well differentiated thyroid
CA have estrogen receptors
 Major subtypes of thyroid carcinoma and their relative
frequencies:
o Papillary CA  >85%
o Follicular CA  5-15%
o Medullary CA  5%
o Anaplastic CA  <5%
 Pathogenesis of thyroid malignancies:
o Genetic Factors
 Two oncogenic pathways of genetic alterations in follicular
cell-derived malignancies of the TG:
1. Mitogen-activated protein (MAP) kinase pathway
2. Phosphatidylinositol-3-kinase (PI-3K)/AKT pathway
 In thyroid carcinomas, gain-of-function mutations along
components of these pathway lead to constitutive activation
even in the absence of ligand  carcinogenesis
Figure 30. Genetic alterations in follicular cell-derived malignancies of the
thyroid gland.
 Papillary CA
- Activation of MAP kinase pathway (a feature of most
papillary CA) is via 2 major mechaniss:
a. Translocation or inversion of RET or NTRK1
(neurotrophic tyrosine kinase receptor 1) gene 
RET/PTC (RET/papillary thyroid carcinoma) fusion
proteins (present in 20-40% of papillary thyroid CA) 
constitutive expression of tyrosine kinase in the follicular
cells  activation of MAP kinase pathway & other
oncogenic signaling pathways
b. Activating point mutations in BRAF
 35-50% of papillary thyroid CAs have gain-of-function
mutation in the BRAF gene. Presence of BRAF
mutations correlates with an adverse prognosis
(metastasis & extrathyroidal extension).
 Since chromosomal rearrangement of the RET or
NTRK1 genes & mutation of BRAF both result in
activation of the MAP kinase signaling pathway,
PATHOLOGY 6.2
papillary CA demonstrate or the other molecular abn.
but not both. Such rearrangements and mutation are
not seen in follicular adenomas or carcinomas.
 Follicular CA - RAS (NRAS, HRAS, KRAS) oncogene mutation or
PAX8-PPAR gamma1 fusion
 Papillary CA – rearrangement of the tyrosine kinase receptors
RET or NTRKI; activating mutations in the BRAF oncogene;
RAS mutations
 Medullary CA – familial type occur in MEN type II ; RET
protooncogene mutations
 Anaplastic CA – de novo or dediff. of wd papill./foll.CA
o Environmental Factor
 Exposure to ionizing radiation especially head & neck of
infants and children  papillary CA.
1. Papillary Carcinoma
25-50 years old, M<F 1:3
Mostly associated with ionizing radiation
o Most common thyroid cancer
o Clinical Progression:
rd th
 Very slow growth; seen during 3 -5 decades of life
 Lymphatic spread to cervical lymph nodes; rarely does it
metastasize hematogenously via the bloodstream into the
lungs
 Best prognosis among other forms of thyroid cancer
o Prognosis: excellent 10-year survival rate: >95%
Figure 31. Gross picture of papillary carcinoma. May range from microscopic
size to >10 cm infiltrative nodule. Rarely encapsulated and frequently
multifocal. There is no clear delineation between the nodule and the
surrounding whitish areas, which means there is already infiltration into the
surrounding thyroid parenchyma coming from the nodule. Gray-white in color
and has a firm consistency. Calcification and cystic changes may or may not be
present. You can see 2 lesions in the figure: the larger one is cystic with
excrescences while the smaller one looks like a satellite nodule and is more
solid. The rest of the brown areas are already the normal thyroid parenchyma.
Figure 32. (Left) There is marked proliferation of the papillary structures.
Papillary carcinoma is lined by cells with characteristic empty-appearing nuclei
sometimes called “Orphan Annie eye” nuclei or ground-glass nuclei.
Intranuclear inclusions (“pseudo-inclusions”) or intranuclear grooves also
visible. (Right) Concentrically calcified structures termed psammoma bodies,
which are only seen in papillary carcinomas.
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 PATHOLOGY 6.2
2. Follicular Carcinoma c. 20-25% of cases associated with multiple endocrine neoplasia
o F>M (3:1) (MEN) syndrome types IIa and IIb
o Peak incidence between 40-60 yrs o Also secretes somatostatin, prostaglandin, serotonin, ACTH,
Majority caused by mutations in PI-3K/AKT signaling neuron-specific enolase, histamine
pathway Related to point mutations in RET proto-oncogene
Gain-of-function point mutations of RAS and PIK3CA o On electron microscopy, there are neurosecretory dense-core
Amplification of PIK3CA granules
Loss-of-function mutation of PTEN
o Clinical Progression:
 Slow-growing but more rapid than papillary CA; painless
thyroid gland enlargement
 Early hematogenous spread to bone and lungs is common,
also to the liver (unlike follicular adenoma, which is mostly
lymphatic spread)
 Lymphatic spread to cervical lymph nodes is uncommon
 To distinguish follicular carcinoma from an adenoma:
presence of capsular invasion and/or vascular invasion
o Prognosis:
 Poorer prognosis than papillary carcinoma
 Prognosis depends on the size of the primary tumor, presence
or absence of capsular and vascular invasion, and the level of Figure 35. Medullary Carcinoma. Show a solid yellow or brown or red pattern
anaplasia of growth and do not have connective tissue capsules.
 10-year survival rate: 50% to 90%

Figure 36. Normal thyroid tissue. (Right) Medullary Carcinoma. Abundant

deposition of amyloid in the stroma (positive for Congo red), which is
derived from calcitonin molecules secreted by the neoplastic cells.
Figure 33. Gross: resembles follicular adenoma; firm, pale gray, tan or
pink cut surface

Figure 34. Vascular Invasion. Follicular carcinomas demonstrate capsular

invasion with infiltration into the adjacent thyroid parenchyma that may be
minimal or widespread. Another feature of follicular carcinomas is the presence
of vascular invasion (follicular adenoma doesn’t have this).

3. Medullary Carcinoma
40-50 years old Figure 37. (Top) Positive Congo red stain. Presence of pinkish,
o Neuroendocrine origin arising from the parafollicular C cells eosinophilic materials in the stroma. (Bottom) Under polarized light, it
(which secrete calcitonin) produces a pale greenish appearance.
o Three distinctive features:
a. Produces calcitonin, a calcium-lowering hormone  diarrhea
b. Sheets of tumor cells in an amyloid stroma

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 PATHOLOGY 6.2
4. Anaplastic Carcinoma
o Rare; tends to occur in older patients (65 years old)
o Aggressive; very poor prognosis
Related to concurrent or past history of well-
differentiated thyroid carcinoma
Mortality rate approaching 100%

Figure 38. Anaplastic Carcinoma

Figure 39. The cells are pleomorphic but most of them are predominantly
spindle in shape with varying size nuclei. Microscopically, these neoplasms
present with highly anaplastic cells, with variable morphology including: (1)
Large, pleomorphic, giant cells including occasional osteoclast-like
multinucleated giant cells; (2) with spindle cells.

Edited by: James Barte

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