THYROID GLAND

Elizabeth H., MD.

Pathologist
 Outline
• Introduction
• Synthesis and function of thyroid hormones
• Thyroid function test
• Congenital anomalies
• Thyroid hormone excess
• Hypothyrodism
• Thyroditis
• Neoplasm
reserved
•reserved
 Introduction
• Embryologically
– From an evagination of the developing pharyngeal
epithelium that descends from the foramen cecum
at the base of the tongue to its normal position in
the anterior neck.
Consists of
Divided into lobules, each
composed of about 20 to 40
evenly dispersed follicles.
• The follicles range from
uniform to variable in
size and are lined by
cuboidal to low
columnar epithelium,
which is filled with
thyroglobulin, the
iodinated precursor
protein of active thyroid
hormone.
Steps in thyroid hormone synthesis
 Monoiodotyrosine (MIT) and Diiodotyrosine (DIT)
• TSH: mediates trapping, organification, and proteolysis
• Thyroid hormone: iodide attached to tyrosine
• FT4: prohormone; rendered metabolically active by outer ring
deiodinase to give FT3
• In the periphery the majority of free T4 is deiodinated to
T3(with 10-fold greater affinity and has proportionately
greater activity).
• FT4/FT3: negative feedback with TSH/TRH
• The binding proteins serve to maintain the serum unbound
( free) T3 and T4 concentrations within narrow limits
• The interaction of thyroid hormone with its nuclear thyroid
hormone receptor (TR) results in the formation of a hormone-
receptor complex that binds to thyroid hormone response
elements (TREs) in target genes, regulating their transcription.
 Functions of thyroid hormone
• Controls basal metabolic rate
• Growth and maturation of tissue (e.g., brain)
• Turnover of hormones and vitamins
• Cell regeneration
• Synthesis of low-density lipoprotein (LDL)
receptors for LDL (main vehicle for transporting
cholesterol)
• Synthesis of β-adrenergic receptors for
catecholamines
 Thyroid function tests
• Total serum T4
– T4 bound to TBG + free (unbound) T4 (FT4)
– Increase in TBG synthesis by the liver
automatically increases total serum T4
– Estrogen increases the synthesis of TBG. (↑total
serum T4 but not FT4 )
• Clinical situations where thyroid-binding
globulin(TBG) is altered
TBG FT4/FT3 Possible causes
Normal Increase Graves disease
Thyroiditis

Normal Decrease Hypothyroidism

Decrease Normal Anabolic Steroids
Nephrotic Syndrome

Increase Normal Taking estrogen

Pregnancy
• Serum thyroid-stimulating hormone (TSH)
– Excellent screening test for thyroid dysfunction
– ↑Serum TSH: primary hypothyroidism
– ↓Serum TSH: thyrotoxicosis, hypopituitarism,
hypothalamic dysfunction
• 123I (radioactive) uptake
– Used to measure synthetic activity of the thyroid
gland.
– ↑123I uptake: ↑synthesis of thyroid hormone;
Graves disease
– ↓123I uptake: thyroiditis; patient taking excess
thyroid hormone
• Thyroglobulin
Evaluates functional status of thyroid nodules
Decreased 123I uptake in a nodule
“Cold” nodule—cyst, adenoma, cancer
Increased 123I uptake in a nodule
“Hot” nodule—toxic nodular goiter
 Lingual thyroid
• Failed descent of thyroid anlage from the base
of the tongue
– Persistence of thyroid tissue at the base of tongue
• Clinical findings
– Presents as a base of tongue mass
– Dysphagia for solids
– Mass lesion
• 123I scan locates the lesion
A, The broken blue line shows
the course of the thyroglossal duct.
Blue circles indicate possible sites of
ectopic thyroid tissue and
thyroglossal duct remnants. The
arrow shows
the direction of thyroid migration.
B, Lingual thyroid. Note the mass
lesion at the base of the tongue
(white arrow).

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 THYROGLOSSAL DUCT CYST

• Cystic dilation of thyroglossal duct

remnant
• Thyroid develops at the base of tongue and then
travels along the thyroglossal duct to the anterior
neck.
• Thyroglossal duct normally involutes; a persistent
duct, however, may undergo cystic dilation.
• Presents as an cystic midline anterior neck mass
 Thyroid hormone excess
• Thyrotoxicosis
– Definition—Describes hormone excess regardless
of cause (e.g., Graves disease, thyroiditis,
increased intake of thyroid hormone)
• Hyperthyroidism
– Definition— Thyrotoxicosis due to excess thyroid
hormone synthesis (E.g., Graves disease, toxic
nodular goiter)
• Increased level of circulating thyroid hormone
– Increases basal metabolic rate (due to increased
synthesis of Na+ -K+ ATPase)
• Overactivity of the sympathetic nervous system
– Increases sympathetic nervous system activity
(due to increased expression of beta 1- adrenergic
receptors)
Clinical findings in all causes of thyrotoxicosis

Constitutional signs
• Weight loss (good appetite)
• Fine tremor of the hands
• Heat intolerance, diarrhea,
anxiety
• Menstrual irregularities
(oligomenorrhea)
• Lid stare
– Due to increased sympathetic
stimulation of eyelid muscles
(e.g., levator palpebrae
superioris)
 GRAVES DISEASE
• Most common cause of hyperthyroidism and
thyrotoxicosis
• Female dominant
• Autoimmune disease
• Childbearing age (20- 40 years)
• HLA-B8 and HLA-Dr3 association with Graves
disease in whites.
 Pathogenesis
• Graves disease is characterized by a breakdown in self-
tolerance to thyroid autoantigens, of which the most
important is the TSH receptor.
• T cells induce specific B cells to produce IgG antibodies
against the TSH receptor
– Stimulating type of antibody as opposed to a blocking antibody
– Type II HSR
• Antimicrosomal and antithyroglobulin antibodies are
present.
• Inciting events that may initiate onset of the disease
– Infection, withdrawal of steroids, iodide excess, postpartum
state
 Clinical Features
• Uniquely with Graves disease:
– Diffuse hyperplasia of the thyroid
• Constant TSH stimulation leads to thyroid hyperplasia and hypertrophy
– Ophthalmopathy (40%)
• The volume of the retroorbital connective tissues and extraocular
muscles is increased, due to
– Inflammatory edema (cytokines induced)
– T – cell and fatty infiltration
– mucopolysaccharide and water accumulation
– Dermopathy.
• pretibial myxedema
• ↑hyaluronic acid
A, Graves disease. The patient
has exophthalmos and a diffuse
enlargement of the thyroid gland
(goiter). B, Severe exophthalmos in
Graves disease. Note the proptosis of
the eye, increased vascularity of the
conjunctiva, and the enlarged lacrimal
gland. C, Pretibial myxedema in
Graves disease. Note the thickened
area of erythema involving the pretibial
area and dorsum of the foot.
 MORPHOLOGY
• The thyroid gland
– enlarged (usually
symmetrically) due to
diffuse hypertrophy and
hyperplasia of thyroid
follicular epithelial cells.
– smooth and soft, and its
capsule is intact.
 DIFFUSE AND MULTINODULAR
GOITER
• Enlargement of the thyroid, or goiter, is the
most common manifestation of thyroid
disease.
• Diffuse and multinodular goiters
• The degree of thyroid enlargement is
proportional to the level and duration of
thyroid hormone deficiency.
 Dietary iodine deficiency

Impairment of thyroid hormone

synthesis

Compensatory rise in the serum TSH

e re
Hypertrophy and hyperplasia of s ev
thyroid follicular cells ntly
cie
ffi
su

Gross enlargement of the thyroid gland

Goitrous hypothyroidism

Ensuring a euthyroid metabolic state

 Goiters can be endemic or sporadic
Endemic goiter
• absolute/relative thyroid
hormone deficiency due to
iodide deficiency
• Endemic – when goiters are
present in more than 10% of
the population in a given
region.
• In mountainous areas of the
world
Sporadic goiter
• Occurs less commonly
• More common in females
than in males
• Puberty or young
adulthood, (physiologic
demand for T4.)
• Causes include- Ingestion of
substances that interfere
with thyroid hormone
synthesis at some level Eg.
Goitrogens (e.g., cabbage),
enzyme deficiency
(dyshormonogenetic goiter),
puberty, pregnancy
Clinical Features and Complications
• Mass effects of the enlarged gland.
– airway obstruction,
– dysphagia, and
– Compression of large vessels in the neck and upper thorax
(so-called superior vena cava syndrome).
• A hyperfunctioning (toxic) nodule may develop within
a long-standing goiter, resulting in hyperthyroidism.
• The incidence of malignancy in long-standing
multinodular goiters is low (less than 5%) but not zero.
• Hemorrhage into cysts, Primary hypothyroidism
• Colloid goiter
– If dietary iodine subsequently increases, or if the
demands for thyroid hormone decrease, the
stimulated follicular epithelium involutes to form an
enlarged, colloid-rich gland.
– The cut surface of the thyroid in such cases usually is
brown, somewhat glassy-appearing, and translucent.
• Multinodular goiter
• Colloid is abundant during the latter periods.
• With time, recurrent episodes of hyperplasia and
involution combine to produce a more irregular
enlargement of the thyroid.
• Hormonally silent
• Thyrotoxicosis secondary to the development of
autonomous nodules that produce thyroid hormone
independent of TSH stimulation.
– Approximately 10% over 10 years
– Toxic multinodular goiter or Plummer syndrome
MORPHOLOGY
Hyperplastic nodule, with compressed residual thyroid
parenchyma on the periphery. The hyperplastic follicles contain
abundant pink “colloid” within their lumina. Note the absence of
a prominent capsule, a feature distinguishing such lesions from
neoplasms of the thyroid.
 Thyroid storm
– Abrupt onset of Causes
severe • Inadequately treated patients
with Graves disease undergo
hyperthyroidism. surgery.
– Untreated patients • Infection, trauma
die of cardiac • Iodine, pregnancy
arrhythmias. Clinical findings
• Tachyarrhythmias
• Hyperpyrexia
• Shock - Volume depletion from
vomiting
• Coma
Apathetic hyperthyroidism refers to
thyrotoxicosis occurring in elderly persons, in
whom the typical features of thyroid hormone
excess seen in younger patients are blunted.
– Cardiac abnormalities (Atrial fibrillation, CHF)
– Muscle weakness, apathy
– Thyromegaly
• Graves disease in the elderly
 Laboratory findings
• Increased serum T4, decreased serum TSH
• Increased/ Decreased123I uptake
• Hyperglycemia
• Hypocholesterolemia
• Hypercalcemia
• Absolute lymphocytosis
 Hypothyroidism
• Definition—reduced secretion of thyroid
hormone
– Basal metabolic rate (BMR) is decreased.
– β-Receptor/LDL receptor synthesis is decreased.
• The clinical manifestations of hypothyroidism
include cretinism and myxedema.
 Cretinism
• Hypothyroidism in neonates and infants
• Characterized by
– mental retardation,
– short stature with skeletal abnormalities,
– coarse facial features,
– enlarged tongue, and
– umbilical hernia
• Causes include
– maternal hypothyroidism during early pregnancy,
– thyroid agenesis,
– iodine deficiency.
– Dyshormonogenetic goiter - is due to a congenital defect in thyroid
hormone production; most commonly involves thyroid peroxidase
 MYXEDEMA
• Hypothyroidism in older children or adults
• Most common causes are iodine deficiency
and Hashimoto thyroiditis; other causes
include drugs (e.g., lithium) and surgical
removal or radioablation of the thyroid.
• Clinical features are based on decreased basal
metabolic rate and decreased sympathetic
nervous system activity.
 Clinical feature
• Myxedema- accumulation • Cold intolerance with
of glycosaminoglycans in decreased sweating
the skin and soft tissue;
• Bradycardia with
results in a deepening of
voice and large tongue decreased cardiac
• Weight gain despite normal output, leading to
appetite shortness of breath and
• Slowing of mental activity fatigue
• Muscle weakness • Oligomenorrhea
• Hypercholesterolemia
• Constipation
 Laboratory findings
• Decreased serum T4, increased serum TSH
• Increased antimicrosomal, antiperoxidase, and
antithyroglobulin antibodies
– Hashimoto thyroiditis, subacute painless
lymphocytic thyroiditis
• Hypercholesterolemia
– Due to decreased synthesis of low-density
lipoprotein (LDL) receptors (type II
hyperlipoproteinemia
 Thyroiditis
• Acute thyroiditis
• Subacute Granulomatous (de Quervain)
thyroiditis
• Hashimoto thyroiditis (or chronic lymphocytic
thyroiditis);
• Subacute lymphocytic thyroiditis
• Riedel thyroiditis
 Acute thyroiditis
• Bacterial infection (e.g., Staphylococcus aureus)
• Clinical findings
– Fever
– Tender gland with painful cervical adenopathy
– Initial thyrotoxicosis from gland destruction
• Increased serum T4, decreased serum TSH
– Decreased 123I uptake
• Permanent hypothyroidism is uncommon.
• Mic – Neutrophilic infiltration and tissue
necrosis
 Subacute granulomatous thyroiditis
• Viral infection (e.g., coxsackievirus, mumps)
• Occurs most often in women 40 to 50 years old
• Clinical findings
– Most common cause of a painful thyroid gland
– Often preceded by an upper respiratory infection
– Cervical adenopathy is not prominent.
– Initial thyrotoxicosis from gland destruction
• Permanent hypothyroidism is uncommon.
• Decreased 123I uptake
 Chronic Lymphocytic (Hashimoto) Thyroiditis
• Epidemiology
– Hashimoto thyroiditis is the most common cause of
hypothyroidism in areas of the world where iodine
levels are sufficient.
– Autoimmune thyroiditis
– Incidence increases with age
– More common in women than men
– Human leukocyte antigen (HLA)-Dr3 and HLA-Dr5
associations
– Increased incidence of other autoimmune diseases
(e.g., pernicious anemia)
 Pathogenesis
• Type IV (mainly)
• Type II hypersensitivity
• Antimicrosomal and Antithyroglobulin antibodies

• Increased susceptibility is associated with

polymorphisms in multiple immune regulation–
associated genes, like cytotoxic T lymphocyte–
associated antigen-4 gene (CTLA4), which codes
for a negative regulator of T cell function
Pathogenesis
MORPHOLOGY
A, Microscopic section of Hashimoto thyroiditis. Note the
prominent germinal follicle and heavy infiltrate of
lymphocytes throughout the gland with destruction of the
thyroid follicles.
 Clinical Features
• Initial thyrotoxicosis from gland destruction
– Known as hashitoxicosis
• Signs of hypothyroidism
• Risk factor for primary B-cell malignant
lymphoma of the thyroid
Primary hypothyroidism
in a patient with Hashimoto thyroiditis.
The patient has a puffy face, particularly
around the eyes (localized myxedema),
and coarse hair
 Subacute Lymphocytic Thyroiditis
• Autoimmune disease that develops postpartum
• Gland lacks germinal follicles.
• Clinical findings
– Abrupt onset of thyrotoxicosis due to gland
destruction
– Slightly enlarged and painless gland
– Progresses to primary hypothyroidism in 40% to
50% of cases
– Antimicrosomal antibodies (50%–80% of cases)
 Riedel thyroiditis
• Fibrous tissue replacement of the gland
• Extension of fibrosis into surrounding tissue
– Can obstruct the trachea
• Associated with other sclerosing conditions
– Example— sclerosing mediastinitis
• Hypothyroidism may occur.
 NEOPLASMS OF THE THYROID
• Usually presents as a distinct, solitary nodule
• Thyroid nodules are more likely to be benign than malignant.
• Several clinical criteria provide a clue to the nature of a given
thyroid nodule:
– Solitary nodules, in general, are more likely to be neoplastic than are
multiple nodules.
– Nodules in younger patients are more likely to be neoplastic than are
those in older patients.
– Nodules in males are more likely to be neoplastic than are those in
females.
– A history of radiation treatment to the head and neck region is
associated with an increased incidence of thyroid malignancy.
– Nodules that take up radioactive iodine in imaging studies (hot
nodules) are more likely to be benign than malignant, reflecting well-
differentiated cells.
 Adenomas
• Most common benign tumor
• Benign proliferation of follicles surrounded by
a complete capsule
• Presents as a solitary “cold” nodule
• Approximately 10% progress into a follicular
carcinoma.
• Unilateral painless mass, cold nodules relative
to the adjacent thyroid tissue
Follicular adenoma of the thyroid. A, A solitary, well
circumscribed nodule is visible in this gross specimen. B, The
photomicrograph shows well-differentiated follicles resembling
those of normal thyroid parenchyma.
• Careful evaluation of the
integrity of the capsule is
therefore critical in
distinguishing follicular
adenomas from follicular
carcinomas, which
demonstrate capsular
and/or vascular invasion
• well-defined, intact
capsule are important in
making the distinction
from multinodular goiters
 Pathogenesis
• The TSH receptor signaling pathway plays an
important role in the pathogenesis of toxic adenomas.
• Activating ("gain of function") somatic mutations in
one of two components of this signaling system-most
often the TSH receptor itself or the α-subunit of Gs-
cause chronic overproduction of cAMP, generating
cells that acquire a growth advantage
• This results in clonal expansion of follicular epithelial
cells that can autonomously produce thyroid hormone
and cause symptoms of thyroid excess
OTHER BENIGN TUMORS
• Dermoid cysts,
• Lipomas,
• Hemangiomas, and
• Teratomas (seen mainly in infants).
 Carcinomas
• The major subtypes of thyroid carcinoma and
their relative frequencies are
– Papillary carcinoma (accounting for more than
85% of cases)
– Follicular carcinoma (5% to 15% of cases)
– Anaplastic (undifferentiated) carcinoma (less than
5% of cases)
– Medullary carcinoma (5% of cases)
 PATHOGENESIS
• Both genetic and environmental factors are
implicated in the pathogenesis of thyroid
cancers.
 Papillary carcinoma
• Epidemiology
– Most common endocrine cancer and thyroid
cancer
– More common in women than men (3 : 1) in the
second and third decades
– Associated with radiation exposure
• Lymphatic invasion
– Metastasize to cervical nodes, lung
• Prognosis is excellent (10-year survival> 95%)
Gross and microscopic findings
 Follicular carcinoma
• Most common thyroid cancer presenting as a solitary cold
nodule
• Female dominant cancer
• Malignant proliferation of follicles surrounded by a fibrous
capsule with invasion through the capsule
– Invasion through the capsule helps distinguish follicular carcinoma
from follicular adenoma.
• FNA only examines cells and not the capsule; hence, a
distinction between follicular adenoma and follicular
carcinoma cannot be made by FNA.
• Metastasis generally occurs hematogenously
– lung and bone
 Medullary carcinoma
• Types • MEN IIa syndrome includes:
– Sporadic (80% of cases) – Medullary carcinoma,
– Familial (20% of cases) – primary hyperparathyroidism
(HPTH), and
• Familial type – pheochromocytoma
– Associated with autosomal • MEN IIb (III) syndrome
dominant MEN IIa/Iib includes:
– Associated with mutations – Medullary carcinoma,
in the RET oncogene – mucosal neuromas
– Better prognosis (lips/tongue),
– pheochromocytoma,
• Ectopic hormones – Marfan like habitus
– ACTH, which can produce
Cushing syndrome
 Pathogenesis
• Tumors derive from parafollicular C cells,
neuroendocrine cells
• C cells synthesize calcitonin.
– Tumor marker
– May produce hypocalcemia (uncommon)
• by increasing renal calcium excretion but is inactive at normal
physiologic levels.
– Converted into amyloid
• C-cell hyperplasia is a precursor lesion for medullary
carcinoma.
 ANAPLASTIC CARCINOMA
• Undifferentiated malignant tumor of the
thyroid
• Usually seen in elderly
• Often invades local structures, leading to
dysphagia or respiratory compromise
• Poor prognosis
• Primary B-cell malignant lymphoma
– Most often develop from Hashimoto thyroiditis
Thank you !!