TEAM BASED LEARNING: THYROID DISORDERS

Learning objectives :

1. Describe the causes and clinical features of hyperthyroidism and hypothyroidism

Topic highlights : Grave’s disease, Hashimoto thyroiditis, Multinodular goiter, Neoplasms : Papillary
carcinoma, follicular carcinoma, medullary carcinoma

ANATOMY OF THE THYROID

The normal adult thyroid consists of two lobes connected by an isthmus. The normal gland weight ranges from 14 to 18 g and depends on
sex, size, and nutritional status of the individual, as well as appropriate laryngeal nerves lie behind the gland. The superior and inferior thyroidal
arteries supply the gland. The intraglandular and subcapsular lymphatics drain into the internal jugular lymph nodes. Thyroid tissue is light
brown in colour and firm in consistency. Nodules are not uncommon in the euthyroid adult population. Microscopically, the thyroid is
composed of follicles lined by epithelial cells that surround the central colloid; 20 to 40 follicles make up a lobule. Birefringent
crystalline material (shown by chemical analysis and x-ray diffraction analysis to be calcium oxalate) is commonly found in the colloid of normal
or diseased thyroids. Small collections of C cells are situated within the confines of the basement membrane of the thyroid follicles. Difficult to
identify by ordinary histologic stains, the normal C cells can be identified by immunostaining for calcitonin.

Thyroid hormone synthesis and metabolism (Key concepts)

The thyroid gland straddles the trachea in the front of the neck and consists of multiple acini (follicles). Each follicle is surrounded by a single
layer of epithelial cells and is filled with colloid, consisting predominantly of thyroglobulin. When the gland is active, areas where the
colloid is being reabsorbed are visible (reabsorption lacunae). The gland transports and fixes iodide to amino acids present in
thyroglobulin to generate the thyroid hormones thyroxine (T4) and triiodothyronine (T3). Iodide is transported into the follicle epithelial
cells via the Na+/I– symporter (NIS) and from there to the colloid via the chloride/iodide exchanger, pendrin. Thyroid peroxidase converts iodide
to iodine then incorporates this into the carbon 3 position of Thyroid hormones circulate in the plasma predominantly in protein-bound forms.
Only the free hormones are biologically active, and both feedback to reduce secretion of TSH. The primary hormone secreted by the thyroid
is thyroxine (T4), along with much lesser amounts of triiodothyronine (T3). T3 has much greater biologic activity than T4 and is also specifically
generated at its site of action in peripheral tissues by deiodination of T4. The relationship of thyroid function to iodide is unique. Iodide is
essential for normal thyroid function, but iodide deficiency and iodide excess both inhibit thyroid function . The normal total plasma T4
level in adults is approximately 8 µg/dL (103 nmol/L), and the plasma T3 level is approximately 0.15 µg/dL (2.3 nmol/L). T4 and T3 are
relatively lipophilic; thus, their free forms in plasma are in equilibrium with a much larger pool of protein-bound thyroid hormones in plasma
and in tissues.
Synthesis and secretion of thyroid hormones is stimulated by thyroid-stimulating hormone (TSH) from the pituitary, which in turn is
released in response to thyrotropin-releasing hormone (TRH) from the hypothalamus. These releasing factors are controlled by changes
in whole body status (eg, exposure to cold or stress). Thyroid hormones exert their effects by entering cells and binding to thyroid receptors.
The liganded forms of thyroid receptors are nuclear transcription factors that alter gene expression. Thyroid hormones stimulate metabolic rate,
calorigenesis, cardiac function, and normal mentation, and interact synergistically with catecholamines. Thyroid hormones also play critical roles
in development, particularly of the nervous system, and growth. Disease results with both underactivity and overactivity of the thyroid gland.
Hypothyroidism is accompanied by mental and physical slowing in adults, and by mental retardation and dwarfism if it occurs in neonatal life.
Overactivity of the thyroid gland, which most commonly is caused by autoantibodies that trigger secretion (Graves disease), results in body
wasting, nervousness, and tachycardia.

Hyperthyroidism
Definition: a hypermetabolic statecaused by elevatedlevels of thyroid hormone.

Categories

Primary hyperthyroidism: the thyroid is over-functioning because of some intrinsic thyroid gland pathologies (e.g., Graves
disease).
Secondary hyperthyroidism: the thyroid is over-functioning because there is too much TSH around (causing over-stimulation
of the thyroid). Main problem here is in the pituitary (e.g., pituitary adenoma that secretes TSH). As such, quite rare.
Tertiary hyperthyroidism: the thyroid is over-functioning because there is too much TRH around (causing release of too
much TSH, resulting in over-stimulation of the thyroid). Main problem here is in the hypothalamus (e.g., TRH-producing
adenoma).

Signs and symptoms

Cardiac manifestations (increased oxygen demand = increased contractility)

□ rapid pulse
□ cardiomegaly
□ arrhythmias (especially atrial fibrillation)

Neuromuscular manifestations (overactivity of sympathetic nervous system)

□ nervousness
□ tremor (see this best by placing a sheet of paper on the patient’s outstretched hands)
□ emotional lability (can lead to a psychiatric misdiagnosis)
 Eye manifestations (overstimulation of the muscle opening the upper eyelid)

□ lid lag
□ wide, staring gaze

Skin manifestations (the body is trying to lose heat)

□ warm, moist, flushed skin

Gastrointestinal manifestations (overstimulation of gut = increased motility)

□ diarrhea
□ weight loss

Skeletal manifestations (thyroid hormone causes increased bone resorption)

□ osteoporosis.

Thyroid storm
□ The most dreaded complication of hyperthyroidism.
□ Occurs when a hyperthyroid patient undergoes some other major physiologic stress. Lots and lots of thyroid hormone
is released.
□ The patient suddenly develops extreme hypermetabolism, which can lead to coma and death.

Thyrotoxicosis is a hypermetabolic state caused by elevated circulating levels of free T3 and T4. Because it is caused most commonly
by hyperfunction of the thyroid gland, thyrotoxicosis often is referred to as hyperthyroidism. In certain conditions, however, the oversupply either
is related to excessive release of preformed thyroid hormone (e.g., in thyroiditis) or comes from an extrathyroidal source, rather than a
hyperfunctioning gland. Thus, strictly speaking, hyperthyroidism is only one (albeit the most common) category of thyrotoxicosis. Despite this
clear distinction, the following discussion adheres to the common practice of using the terms thyrotoxicosis and hyperthyroidism
interchangeably.

Thyroid storm designates the abrupt onset of severe hyperthyroidism. It occurs most often in patients with Graves disease and
probably results from an acute elevation in catecholamine levels, as might be encountered during infection, surgery, cessation of
anti-thyroid medication, or any form of stress. Thyroid storm is a medical emergency, as a significant number of untreated patients
die of cardiac arrhythmias.

• Apathetic hyperthyroidism refers to thyrotoxicosis occurring in older adults, in whom the typical features of thyroid hormone
excess often are blunted. The underlying thyroid disease is usually detected during laboratory workup for unexplained weight loss or
worsening cardiovascular disease. The diagnosis of hyperthyroidism is based on clinical features and laboratory data. The measurement of
serum TSH is the most useful single screening test for hyperthyroidism, because TSH levels are decreased even at the earliest
stages, when the disease may still be subclinical. In rare cases of pituitary-or hypothalamus-associated (secondary) hyperthyroidism, TSH
levels are either normal or raised. A low TSH value usually is associated with increased levels of free T4. In the occasional patient,
hyperthyroidism results predominantly from increased circulating levels of T3 (T3 toxicosis). In such cases, free T4 levels may be decreased,
and direct measurement of serum T3 may be useful. Once the diagnosis of thyrotoxicosis has been confirmed by a combination of TSH and
free thyroid hormone assays, measurement of radioactive iodine uptake by the thyroid gland can be valuable in determining the etiology. For
example, such scans may show diffusely increased uptake in Graves disease, increased uptake in a solitary nodule in toxic adenoma, or
decreased uptake in thyroiditis.

Hypothyroidism

Hypothyroidism results from deficient production of Thyroid Hormone (TH) by the thyroid gland. Hypothyroidism is the most
common disorder of thyroid function, affecting approximately 3.7% of the population, and occurs more commonly in women.

It may be primary or central. Primary hypothyroidism accounts for the majority of all cases. Central (secondary) hypothyroidism is
much less common and is related to either pituitary or hypothalamic failure. Subclinical hypothyroidism is a mild thyroid failure
estimated to occur in 4% to 8% of adults.It is defined as an elevation in TSH levels with normal levels of circulating TH.

Pathophysiology
 In primary hypothyroidism, loss of thyroid function leads to decreased production of TH and increased secretion of TSH and TRH. The most
common causes of primary hypothyroidism in adults include autoimmune thyroiditis (Hashimoto disease), iatrogenic loss of thyroid tissue after
surgical or radioactive treatment for hyperthyroidism or after head and neck radiation therapy, medications (e.g., lithium and amiodarone), and
endemic iodine deficiency. Infants and children may present with hypothyroidism because of congenital defects. Central (secondary)
hypothyroidism is caused by the pituitary's failure to synthesize adequate amounts of most common causes of primary hypothyroidism in adults
include autoimmune thyroiditis (Hashimoto disease), iatrogenic loss of thyroid tissue after surgical or radioactive treatment for hyperthyroidism
or after head and neck radiation therapy, medications (e.g., lithium and amiodarone), and endemic iodine deficiency. Infants and children may
present with hypothyroidism because of congenital defects. Central (secondary) hypothyroidism is caused by the pituitary's failure to synthesize
adequate amounts of TSH or a lack of TRH. Pituitary tumors that compress surrounding pituitary cells or the consequences of their treatment
are the most common causes of central hypothyroidism. Other causes include traumatic brain injury, subarachnoid haemorrhage, or pituitary
infarction. Hypothalamic dysfunction results in low levels of TH, TSH, and TRH.

Summarily, hypothyroidism is caused by structural or functional derangements that interfere with thyroid hormone production. This disorder may
be divided into primary and secondary categories, depending on whether it arises from an intrinsic abnormality in the thyroid or from
hypothalamic or pituitary disease.

Primary hypothyroidism can be secondary to congenital, autoimmune, or iatrogenic causes.

• Genetic defects that perturb thyroid development (thyroid dysgenesis) or the synthesis of thyroid hormone (dyshormonogenetic goiter) are rare
overall.

• Endemic deficiency of dietary iodine is typically manifested by hyothryoidism early in childhood and has been also called congenital but is not
caused by genetic defects. It is a common cause of hypothyroidism in infants and children worldwide.

• Autoimmune thyroid disease is a common cause of hypothyroidism in regions of the world where iodine is supplemented in dietary salt
products. The vast majority of cases of autoimmune hypothyroidism are due to Hashimoto thyroiditis. • Iatrogenic hypothyroidism can be caused
by either surgical or radiation-induced ablation of thyroid parenchyma, or as an unintended adverse effect of certain drugs.

Hypothyroidism generally affects all body systems and occurs insidiously over months or years. Decreased Thyroid Hormone (TH)
levels lower energy metabolism and heat production. The individual develops a low basal metabolic rate, cold intolerance, lethargy, and
slightly lowered basal body temperature. The decrease in the level of TH leads to excessive TSH production, which stimulates thyroid tissue
and causes goiter. The characteristic sign of severe or long-standing hypothyroidism is myxedema , which results from the altered composition
of the dermis and other tissues. The connective tissue fibers are separated by large amounts of protein and mucopolysaccharide. These
complex binds water, producing nonpitting, boggy edema, especially around the eyes, hands, and feet and in the supraclavicular fossae. The
tongue and laryngeal and pharyngeal mucous membranes thicken, producing thick, slurred speech and hoarseness. Myxoedema coma ,
a medical emergency, is a diminished level of consciousness associated with severe hypothyroidism. Signs and symptoms include hypothermia
without shivering, hypoventilation, hypotension, hypoglycaemia, and lactic acidosis. Older individuals with comorbid conditions, such as
pulmonary or urinary infections, congestive heart failure, or cerebrovascular accident, and with moderate or untreated hypothyroidism are
particularly at risk for developing myxedema coma. It also may occur after overuse of narcotics or sedatives or after an acute illness in
hypothyroid individuals. Symptoms of hypothyroidism in older adults should not be attributed to normal aging changes.

Cretinism Versus myxedema

. • Cretinism refers to hypothyroidism developing in infancy or early childhood. This disorder formerly was fairly common in areas of the world
where dietary iodine deficiency is endemic, including mountainous areas such as the Himalayas and the Andes (endemic cretinism). It is now
much less frequent because of the widespread supplementation of salt with iodine. By contrast, enzyme defects that interfere with thyroid
hormone synthesis are a cause of sporadic cretinism. Clinical features of cretinism include impaired development of the skeletal system and
central nervous system, severe mental retardation, short stature, coarse facial features, a protruding tongue, and umbilical hernia. The severity
of the mental impairment in cretinism seems to be influenced by the time of onset of the deficient state in utero. Normally, maternal hormones
that are critical to fetal brain development, including T3 and T4, cross the placenta. If maternal thyroid deficiency is present before the
development of the fetal thyroid gland, mental retardation is severe. By contrast, reduction in maternal thyroid hormones later in pregnancy,
after the fetal thyroid has developed, allows normal brain development.

• Hypothyroidism in older children and adults results in a condition known as myxedema. The initial symptoms include generalized fatigue,
apathy, and mental sluggishness, which may mimic depression. Decreased sympathetic activity results in constipation and decreased sweating.
The skin is cool and pale because of decreased blood flow. Reduced cardiac output contributes to shortness of breath and decreased exercise
capacity, two frequent complaints. Thyroid hormones regulate the transcription of several sarcolemmal genes, such as calcium ATPases,
whose encoded products are critical in maintaining efficient cardiac output. In addition, hypothyroidism promotes an atherogenic lipid profile—
an increase in total cholesterol and low-density lipoprotein (LDL) levels—that may contribute to the adverse cardiovascular mortality rates in this
disease. Histologically, there is an accumulation of matrix substances, such as glycosaminoglycans and hyaluronic acid, in skin, subcutaneous
tissue, and viscera. This results in nonpitting edema, broadening and coarsening of facial features, enlargement of the tongue, and deepening
of the voice. The diagnosis of hypothyroidism is based on laboratory evaluation. As in the case of hyperthyroidism, measurement of serum
TSH is the most sensitive screening test. The serum TSH concentration is increased in primary hypothyroidism because of a loss of
feedback inhibition of thyrotropin-releasing hormone (TRH) and TSH production by the hypothalamus and pituitary, respectively. The TSH
concentration is not increased in individuals with hypothyroidism caused by primary hypothalamic or pituitary disease. Serum T4 is decreased in
patients with hypothyroidism of any origin.

Autoimmune Thyroid Diseases

Autoimmunity is the underlying cause of a variety of thyroid diseases, which are collectively referred to as autoimmune thyroid disease (AITD).
These disorders include thyroiditis, and antibody-mediated disturbances in thyroid function that are not necessarily associated with inflammation
(exemplified by Graves disease). We discuss first the various forms of thyroiditis.

Thyroiditis encompasses a diverse group of disorders characterized by some form of thyroid inflammation. This discussion focuses on the three
most common and clinically significant subtypes: (1) Hashimoto thyroiditis, (2) granulomatous (de Quervain) thyroiditis, and (3) subacute
lymphocytic thyroiditis

Hashimoto thyroiditis

Hashimoto thyroiditis , originally described in 1912 by Hakaru Hashimoto as struma lymphomatosa, is characterized by extensive damage to
the thyroid parenchyma. It is predominantly a disease of women over 40 years of age. It presents as diffuse firm thyroid enlargement,
sometimes accompanied by signs of tracheal or esophageal compression. Initially the disease may be accompanied by mild hyperthyroidism
and later by hypothyroidism. At surgery, the thyroid gland is easily separated from other structures. The fascial attachment between the thyroid
gland and the tracheal wall is, at times, slightly thickened, but there is no strong fixation (unlike Riedel thyroiditis). Because of the firm character
of the lesion, it may be confused with carcinoma, but the diffuse involvement without adherence to the surrounding structures should be strong
evidence against it.
Grossly, the typical case shows diffuse and symmetrical enlargement of the gland. However, in some instances, one lobe is more enlarged
than the other, and in others the disease has a distinctly multinodular quality. The consistency is firm but not stony hard as in Riedel thyroiditis.
There is no extension of the process outside the gland. The cut surface is friable, vaguely or distinctly nodular or micronodular, yellowish gray,
and greatly resembles a hyperplastic lymph node. Colloid is not clearly discernible. Necrosis and calcification are absent. The texture of the
parenchyma infiltrated by lymphoid cells results in a distinctive pattern on ultrasound examination characterized by reduced echogenicity.

Hashimoto thyroiditis may initially cause thyroid enlargement, but later there may be atrophy and fibrosis. The gland appears firm, fleshy and
pale. Histologically, the gland is densely infiltrated by lymphocytes and plasma cells, with lymphoid follicle formation. Colloid content is reduced,
and the thyroid epithelial cells show a characteristic change in which they enlarge and develop eosinophilic granular cytoplasm due to
proliferation of mitochondria; they are then termed Askanazy cells, Hürthle cells or oncocytes. In advanced cases, there may be fibrosis.
Paradoxically, in the early stages of Hashimoto thyroiditis, the damage to the thyroid follicles may lead to release of thyroglobulin into the
circulation, causing a transient phase of thyrotoxicosis.

Hashimoto thyroiditis is the most common cause of hypothyroidism in areas of the world where iodine levels are sufficient . It is
characterized by gradual thyroid failure secondary to autoimmune destruction of the thyroid gland. It is most prevalent between 45
and 65 years of age and is more common in women with a female to male ratio of 10: 1 to 20: 1. Although it is primarily a disease of older
women, it can occur at any age, including childhood.
Pathogenesis

Hashimoto thyroiditis is an autoimmune disease caused by an immune response to thyroid autoantigens . Circulating autoantibodies against
thyroid antigens are present in the vast majority of patients. The immune response leads to progressive depletion of thyroid epithelial cells
associated with lymphocytic infiltrates and fibrosis.

The inciting events leading to the autoimmune response have not been fully elucidated, but multiple immunologic mechanisms that may
contribute to thyroid cell damage have been identified, including the following:

• CD8 + cytotoxic T-cell–mediated killing of thyroid epithelial cells.

• Cytokine-mediated cell death. T-cell activation leads to the production of inflammatory cytokines such as interferon-γ in the thyroid
gland, with resultant recruitment and activation of macrophages and damage to follicles.

• Binding of anti-thyroid antibodies (anti-thyroglobulin, and anti-thyroid peroxidase antibodies), followed by antibody-dependent
cell–mediated cytotoxicity.

Breakdown of immune tolerance to thyroid autoantigens results in progressive autoimmune destruction of thyrocytes by infiltrating cytotoxic T
cells, locally released cytokines, or antibody-dependent cytotoxicity. The disease appears to have a significant genetic component, based on a
concordance rate of about 40% in monozygotic twins and the presence of anti-thyroid antibodies in approximately 50% of asymptomatic siblings
of affected patients. Increased susceptibility to Hashimoto thyroiditis is associated with polymorphisms in immune regulation–associated genes,
the most significant of which is the cytotoxic T lymphocyte–associated antigen-4 gene (CTLA4), which codes for a negative regulator of T-cell
responses.

Morphology

The thyroid usually is diffusely and symmetrically enlarged. Microscopic examination reveals widespread infiltration of the parenchyma by
a mononuclear inflammatory infiltrate containing small lymphocytes, plasma cells, and well-developed germinal centres.

The thyroid follicles are atrophic and are lined in many areas by epithelial cells distinguished by the presence of abundant eosinophilic, granular
cytoplasm, termed Hürthle, or oxyphil, cells. This is a metaplastic response of the normal low cuboidal follicular epithelium to ongoing injury; on
ultrastructural examination, the Hürthle cells are characterized by numerous prominent mitochondria. Interstitial connective tissue is increased
and may be abundant. Less commonly, the thyroid is small and atrophic as a result of more extensive fibrosis (fibrosing variant). The thyroid
parenchyma contains a dense lymphocytic infiltrate with germinal centers. Residual thyroid follicles lined by deeply eosinophilic
Hürthle cells also are seen.

Clinical Features Hashimoto thyroiditis comes to clinical attention as painless enlargement of the thyroid, usually associated with some
degree of hypothyroidism, often in a middle-age woman. The enlargement of the gland usually is symmetric and diffuse, but in some
cases, it may be sufficiently localized to raise suspicion for neoplasm. In the usual clinical course, hypothyroidism develops gradually. In some
cases, however, it may be preceded by transient thyrotoxicosis caused by disruption of thyroid follicles, with secondary release of thyroid
hormones (hashitoxicosis). During this phase, free T4 and T3 concentrations are elevated, TSH is diminished, and radioactive iodine uptake is
decreased.

As hypothyroidism supervenes, T4 and T3 levels progressively fall, accompanied by a compensatory increase in TSH. Patients with
Hashimoto thyroiditis often have other autoimmune diseases and are at increased risk for the development of B-cell non-Hodgkin
lymphomas, which typically arise within the thyroid gland. The relationship between Hashimoto disease and thyroid epithelial cancers
remains controversial, with some morphologic and molecular studies suggesting a predisposition to papillary carcinomas.

Subacute Granulomatous (de Quervain) Thyroiditis

Subacute granulomatous thyroiditis, also known as de Quervain thyroiditis, is much less common than Hashimoto disease .

De Quervain thyroiditis is most common between 30 and 50 years of age and, like other forms of thyroiditis, occurs more frequently in women
than in men. Subacute thyroiditis is believed to be caused by a viral infection or an inflammatory process triggered by viral infections, and not by
an autoimmune process. A majority of patients have a history of an upper-respiratory infection shortly before the onset of thyroiditis. Unlike in
autoimmune thyroid disease, the immune response in subacute granulomatous thyroiditis is not self-perpetuating, so the process
spontaneously remits.

Morphology

The gland is firm, with an intact capsule, and may be unilaterally or bilaterally enlarged. Histologic examination reveals disruption of thyroid
follicles, extravasation of colloid, and infiltrating neutrophils, which are replaced over time by lymphocytes, plasma cells, and macrophages. The
extravasated colloid provokes an exuberant granulomatous reaction with giant cells, some containing fragments of colloid. Healing occurs by
resolution of inflammation and fibrosis.

Clinical Features The onset of this form of thyroiditis often is acute. It is characterized by neck pain (particularly with swallowing), fever,
malaise, and variable enlargement of the thyroid. Transient hyperthyroidism may occur, as in other cases of thyroiditis, as a result of
disruption of thyroid follicles and release of excessive thyroid hormone. The leukocyte count and erythrocyte sedimentation rates are
increased. With progression of the gland destruction, a transient hypothyroid phase may ensue. The condition typically is self-limited, with
most patients returning to a euthyroid state within 6 to 8 weeks.

Subacute Lymphocytic Thyroiditis

Subacute lymphocytic thyroiditis also is known as silent or painless thyroiditis; in a subset of patients, the onset follows pregnancy (postpartum
thyroiditis). This disease is most likely autoimmune in aetiology, as circulating anti-thyroid antibodies are found in a majority of patients. It mostly
affects middle-aged women, who present with a painless neck mass or features of thyroid hormone excess. The initial phase of thyrotoxicosis
(which is likely to be secondary to thyroid tissue damage) is followed by return to a euthyroid state within a few months. In a minority of affected
individuals, the condition eventually progresses to hypothyroidism. Except for possible mild symmetric enlargement, the thyroid appears normal
on gross inspection. The histologic features consist of lymphocytic infiltration and hyperplastic germinal centres within the thyroid parenchyma.

Other Forms of Thyroiditis

Riedel thyroiditis (RT), a rare disorder that is a manifestation of IgG4-related disease, is characterized by extensive fibrosis involving the
thyroid and contiguous neck structures. Clinical evaluation demonstrates a hard and fixed thyroid mass, simulating a thyroid neoplasm. It may
be associated with idiopathic fibrosis in other sites in the body, such as the retroperitoneum. It’s a chronic inflammatory disease of the thyroid
gland characterized by a dense fibrosis that replaces normal thyroid parenchyma. The fibrotic process invades adjacent structures of the
neck and extends beyond the thyroid capsule. This feature differentiates RT from other inflammatory or fibrotic disorders of the
thyroid. Extension beyond the thyroid also differentiates this from the fibosing variant of Hashimoto thyroiditis.

Gross pathology of Riedel thyroiditis. The cut edge is avascular, with a characteristic white colour (shown below)

Summary Thyroiditis:

• Chronic lymphocytic (Hashimoto) thyroiditis is the most common cause of hypothyroidism in regions where dietary iodine levels are sufficient.
Hashimoto thyroiditis is an autoimmune disease characterized by progressive destruction of thyroid parenchyma, Hürthle cell change, and
mononuclear (lymphoplasmacytic) infiltrates, with or without extensive fibrosis. • Multiple autoimmune mechanisms account for thyroid injury in
Hashimoto disease, including cytotoxicity mediated by CD8 + T cells, cytokines (IFN-γ), and anti-thyroid antibodies.

• Subacute granulomatous (de Quervain) thyroiditis is a self-limited disease, probably secondary to a viral infection, and is characterized by
pain and the presence of a granulomatous inflammation in the thyroid.

• Subacute lymphocytic thyroiditis is a self-limited disease that often occurs after a pregnancy (postpartum thyroiditis), typically is painless, and
is characterized by lymphocytic inflammation in the thyroid.
Graves disease
Graves disease (also known as Basedow disease, diffuse toxic goiter, and exophthalmic goiter) typically presents in young adult females with
muscle weakness, weight loss, irritability, heat intolerance, fatigue, tachycardia, goiter, and often a great increase of appetite. It can also
develop in children, in whom it constitutes the most common cause of hyperthyroidism. Atrial fibrillation may occur, particularly in older
patients. The enlargement of the thyroid gland is typically diffuse, but in case of iodide deficiency Graves disease may coexist with multinodular
goiter. The goiter is palpable in the majority of hyperthyroid patients who are younger than 60 years, as opposed to less than 50% of older
patients. Named after Robert Graves who reported in 1835 on his observations of a disease characterized by “violent and long continued
palpitations in females” associated with enlargement of the thyroid gland.

Graves ophthalmopathy (or orbitopathy) develops in 25%–30% of patients. Cigarette smoking is a risk factor and has been associated with
more aggressive ophthalmopathy. This is an autoimmune disorder of the periorbital tissues that results in increased volume of both adipose
tissue and extraocular muscles due to inflammation, the accumulation of hydrophilic glycosaminoglycans (typically hyaluronic acid) and related
edema, and tissue remodeling with activation of lipogenesis and fibrosis. Exophthalmos (or proptosis, i.e., protrusion of the eyeball) develops in
approximately 60% of patients with ophthalmopathy, but imaging can identify subtle orbital connective tissue abnormalities in 70% of patients
with Graves disease.

Late clinical manifestations of Graves disease are localized dermopathy (pretibial myxedema) and so-called thyroid acropachy ; the latter is
characterized by swelling of the extremities and clubbing of fingers and toes resulting from periosteal new bone formation.

Laboratory abnormalities include elevation of bound T4, free T4, or bound T3 levels and increased radioactive iodine uptake in the presence
of low TSH levels.

Graves disease is the most common cause of endogenous hyperthyroidism.

It is characterized by a triad of manifestations: • Thyrotoxicosis, caused by a diffusely enlarged, hyperfunctional thyroid • An infiltrative
ophthalmopathy with resultant exophthalmos, noted in as many as 40% of patients • A localized, infiltrative dermopathy (sometimes
designated pretibial myxedema), seen in a minority of cases Graves disease has a peak incidence between 20 and 40 years of age, with
women being affected up to seven times more commonly than men.

Genetic factors are important in Graves disease; the incidence is increased in relatives of affected patients, and the concordance rate
in monozygotic twins is as high as 60%. As with other autoimmune disorders, a genetic susceptibility to Graves disease is
associated with the presence of certain human leukocyte antigen (HLA) haplotypes, specifically HLA-DR3, and polymorphisms in
genes whose products regulate T-cell responses, including the inhibitory T-cell receptor CTLA-4 and the tyrosine phosphatase PTPN22.

Pathogenesis

Many manifestations of Graves disease are caused by autoantibodies against the TSH receptor that bind to, and stimulate, thyroid
follicular cells independent of endogenous trophic hormones.

Multiple autoantibodies are produced in Graves disease, including the following:

• Thyroid-stimulating immunoglobulin (TSI). This IgG antibody binds to the TSH receptor and mimics the action of TSH, stimulating
adenyl cyclase, with resultant increased release of thyroid hormones. Almost all individuals with Graves disease have detectable
amounts of this autoantibody, which is relatively specific for Graves disease.

• Thyroid growth-stimulating immunoglobulins. Also directed against the TSH receptor, these antibodies have been implicated in the
proliferation of thyroid follicular epithelium.

• TSH-binding inhibitor immunoglobulins. These anti-TSH receptor antibodies prevent TSH from binding to its receptor on thyroid epithelial cells
and in so doing may inhibit thyroid cell function. The coexistence of stimulating and inhibiting immunoglobulins in the serum of the same patient
is not unusual and may explain why some patients develop episodes of hypothyroidism.

A T-cell–mediated autoimmune phenomenon also is involved in the development of the infiltrative ophthalmopathy characteristic of Graves
disease.

In Graves ophthalmopathy, the volume of the retroorbital connective tissues and extraocular muscles is increased due to (1) marked
infiltration of the retroorbital space by mononuclear cells, predominantly T cells; (2) inflammatory oedema and swelling of extraocular
muscles; (3) accumulation of extracellular matrix components, specifically hydrophilic glycosaminoglycans such as hyaluronic acid
and chondroitin sulphate; and (4) increased numbers of adipocytes (fatty infiltration). These changes displace the eyeball forward,
potentially interfering with the function of the extraocular muscles. Autoimmune thyroid diseases thus span a continuum in which
 Graves disease, characterized by hyperfunction of the thyroid, lies at one extreme and Hashimoto disease, manifesting as
hypothyroidism, occupies the other end.

Two categories of ophthalmopathy associated with Graves disease are (1) functional abnormalities resulting from hyperactivity of the
sympathetic division of the autonomic nervous system (lag of the globe on upward gaze and of the upper lid on downward gaze) and
(2) infiltrative changes involving the orbital contents with enlargement of the ocular muscles. These changes affect more than half of
individuals with Graves disease. Orbital connective tissue accumulation, inflammation, and edema of the orbital contents result in
exophthalmos (protrusion of the eyeball), periorbital edema, and extraocular muscle weakness leading to diplopia (double vision).
The individual may experience irritation, pain, lacrimation, photophobia, blurred vision, decreased visual acuity, papilledema, visual
field impairment, exposure keratosis, and corneal ulceration.

Sometimes hyperthyroidism may supervene on preexisting Hashimoto thyroiditis, while at other times individuals with Graves disease may
spontaneously develop thyroid hypofunction; occasionally, Hashimoto thyroiditis and Graves disease may coexist within an affected kindred.
Not surprisingly, there is also an element of histologic overlap between the autoimmune thyroid disorders (most characteristically, prominent
intrathyroidal lymphoid cell infiltrates with germinal center formation). In both disorders, the frequency of other autoimmune diseases, such as
systemic lupus erythematosus, pernicious anemia, type 1 diabetes, and Addison disease, is increased.

Patients with Graves disease show a genetic predisposition to the disease, and their relatives have an unusually high incidence of other
autoimmune disorders; the gland is infiltrated by lymphocytes. Similarities to Hashimoto thyroiditis include an apparently genetically determined
defect in suppressor T cells with consequent proliferation of thyroid-directed B cells, which produce antithyroid autoantibodies. These
antibodies (thyroid receptor antibodies [TRAbs]) are directed against the thyrotropin receptor complex of the follicular epithelial cell,
which they stimulate to grow and function. Hence, the gland enlarges and secretes increased amounts of thyroid hormones, resulting
in clinical hyperthyroidism.

This is characterized by a diffuse goitre and hyperthyroidism. It mainly affects females aged 20–40 years. The gland is diffusely
hyperplastic and hyperaemic, clinically resulting in a bruit on auscultation. In the untreated case, the thyroid epithelium is
hyperplastic and there is little colloid storage. Lymphocytic infiltration is usually less marked than in Hashimoto’s thyroiditis.

Morphology : In the typical case of Graves disease, the thyroid gland is enlarged (usually symmetrically) due to diffuse hypertrophy and
hyperplasia of thyroid follicular epithelial cells. The gland is usually smooth and soft, and its capsule is intact. Grossly, the thyroid in
Graves disease is diffusely and usually symmetrically enlarged, with weights of 50 to 150 g. Vascularity is marked. Histologic
examination shows retention of lobular architecture, prominent vascular congestion, and follicular hyperplasia. The follicular cells are columnar
with enlarged nuclei. Colloid is virtually absent. Papillary infoldings of the follicular epithelium are also seen. The follicular cells in
Graves disease can demonstrate marked nuclear chromatin clearing, which in combination with papillary hyperplasia can be mistaken for
papillary carcinoma. However, the diffuse nature of the process can be a clue at low-power magnification that one is dealing with a
nonneoplastic process. Lymphocytes are often found in the stroma. Within the follicular centres, B cells predominate; T
lymphocytes, especially helper subsets, are seen in a perifollicular location.

On microscopic examination, the follicular epithelial cells in untreated cases are tall, columnar, and more crowded than usual. This crowding
often results in the formation of small papillae, which project into the follicular lumen (Fig. 20.10). Such papillae lack fibrovascular cores, in
contrast with those of papillary carcinoma. The colloid within the follicular lumen is pale, with scalloped margins. Lymphoid infiltrates, consisting
predominantly of T cells, with fewer B cells and mature plasma cells, are present throughout the interstitium; germinal centers are common. Fig.
20.10 Graves disease. The follicles are lined by tall columnar epithelial cells that are actively resorbing the colloid in the centers of the follicles,
resulting in a “scalloped” appearance of the colloid. Changes in extrathyroidal tissues include generalized lymphoid hyperplasia. In individuals
with ophthalmopathy, the tissues of the orbit are edematous because of the presence of hydrophilic glycosaminoglycans. In addition, there is
infiltration by lymphocytes, mostly T cells. Orbital muscles initially are edematous but may undergo fibrosis late in the course of the disease.
The dermopathy, if present, is characterized by thickening of the dermis, as a result of deposition of glycosaminoglycans and lymphocyte
infiltration.

Clinical Features: The clinical manifestations of Graves disease include those common to all forms of thyrotoxicosis (discussed earlier), as well
as those associated uniquely with Graves disease: diffuse hyperplasia of the thyroid, ophthalmopathy, and dermopathy. The degree of
thyrotoxicosis varies from case to case, and the related changes may sometimes be less conspicuous than other manifestations of the disease.
Increased flow of blood through the hyperactive gland often produces an audible bruit. Sympathetic overactivity produces a characteristic wide,
staring gaze and lid lag. The ophthalmopathy of Graves disease results in abnormal protrusion of the eyeball (exophthalmos). The
exophthalmos may persist or progress despite successful treatment of the thyrotoxicosis, sometimes resulting in corneal injury. The extraocular
muscles often are weak. The infiltrative dermopathy most commonly involves the skin overlying the shins, where it manifests as scaly thickening
and induration of the skin (pretibial myxedema). The skin lesions may be slightly pigmented papules or nodules and often have an orange peel
texture.

Laboratory findings in Graves disease include elevated serum free T4 and T3 and depressed serum TSH. Because of ongoing
stimulation of the thyroid follicles by TSIs, radioactive iodine uptake is increased diffusely.

Summary : Graves Disease

• Graves disease, the most common cause of endogenous hyperthyroidism, is characterized by the triad of thyrotoxicosis,
ophthalmopathy, and dermopathy. • Graves disease is an autoimmune disorder caused by autoantibodies to the TSH receptor that mimic
TSH action and activate TSH receptors on thyroid epithelial cells. • The thyroid in Graves disease is characterized by diffuse hypertrophy and
hyperplasia of follicles and lymphoid infiltrates; glycosaminoglycan deposition and lymphoid infiltrates are responsible for the ophthalmopathy
and dermopathy. • Laboratory features include elevations in serum free T3 and T4 and decreased serum TSH.

Diffuse and Multinodular Goiter

Enlargement of the thyroid, or goiter, is the most common manifestation of thyroid disease. Diffuse and multinodular goiters are the result of
impaired synthesis of thyroid hormone, most often caused by dietary iodine deficiency. Impairment of thyroid hormone synthesis leads to a
compensatory rise in the serum TSH, which drives the hypertrophy and hyperplasia of thyroid follicular cells and, ultimately, enlargement of the
thyroid gland. The degree of thyroid enlargement is proportional to the level and duration of thyroid hormone deficiency. These compensatory
changes overcome the hormone deficiency and maintain a euthyroid metabolic state in the vast majority of affected individuals. However, if the
underlying disorder is severe (e.g., a congenital biosynthetic defect), the compensatory responses may be inadequate, resulting in goitrous
hypothyroidism.

Pathogenesis : Goiters can be endemic or sporadic. • Endemic goiter occurs in geographic areas where the diet contains little iodine. The
designation endemic is used when goiters are present in more than 10% of the population in a given region. Such conditions are particularly
common in mountainous areas of the world, including the Himalayas and the Andes. With increased availability of dietary iodine
supplementation, the frequency and severity of endemic goiter have declined significantly. • Sporadic goiter occurs less frequently than endemic
goiter. The condition is more common in females than in males, with a peak incidence in puberty or young adulthood, when there is an
increased physiologic demand for T4. Sporadic goiter may be caused by several conditions, including the excessive ingestion of substances
that interfere with thyroid hormone synthesis, such as calcium and vegetables belonging to the Brassicaceae (also called Cruciferae) family
(e.g., cabbage, cauliflower, Brussels sprouts, turnips). In other instances goiter may result from inherited enzymatic defects that interfere with
thyroid hormone synthesis (dyshormonogenetic goiter). In most cases, however, the cause of sporadic goiter is not apparent.
Morphology : Early in its development, TSH-induced hypertrophy and hyperplasia of thyroid follicular cells usually result in diffuse, symmetric
enlargement of the gland (diffuse goiter). The follicles are lined by crowded columnar cells, which may pile up and form projections similar to those
seen in Graves disease. If dietary iodine subsequently increases, or if the demands for thyroid hormone decrease, the follicular epithelium
involutes to form an enlarged, colloid-rich gland (colloid goiter). The cut surface of the thyroid in such cases usually is brown, glassy-appearing,
and translucent. On microscopic examination, the follicular epithelium may be hyperplastic in the early stages of disease or flattened and cuboidal
during periods of involution. 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, termed multinodular goiter. Virtually all long-standing diffuse goiters convert into multinodular
goiters. Multinodular goiters are multilobulate, asymmetrically enlarged glands that may attain a massive size. On cut surface, irregular
nodules containing variable amounts of brown, gelatinous colloid are evident Older lesions often show areas of fibrosis, hemorrhage,
calcification, and cystic change.

Multinodular goiters typically are hormonally silent, but a minority (approximately 10% over 10 years) manifest with thyrotoxicosis
secondary to the development of autonomous nodules that produce thyroid hormone independent of TSH stimulation. This condition,
known as toxic multinodular goiter or Plummer syndrome, is not accompanied by the infiltrative ophthalmopathy and dermopathy of Graves
disease–associated thyrotoxicosis. The incidence of malignancy in long-standing multinodular goiters is low (< 5%) but not zero, and concern
for malignancy arises with goiters that demonstrate sudden changes in size or associated symptoms (e.g., hoarseness).

Thyroid Neoplasms

Thyroid tumors range from circumscribed, benign adenomas to highly aggressive, anaplastic carcinomas. From a clinical standpoint, the
possibility of a tumor is of major concern in patients who present with thyroid nodules. Fortunately, the overwhelming majority of solitary nodules
of the thyroid prove to be either benign adenomas or localized, non-neoplastic conditions (e.g., a dominant nodule in multinodular goiter, simple
cysts, or foci of thyroiditis). Carcinomas of the thyroid, by contrast, are uncommon, accounting for less than 1% of solitary thyroid nodules.
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 very young (< 20 years) or very old (> 70 years) individuals are more likely to be neoplastic. • Nodules in
males are more likely to be neoplastic than are those in females. • A history of radiation exposure 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. Such associations,
however, are of little significance in the evaluation of a given patient, in whom the timely recognition of a malignancy may be lifesaving.
Ultimately, morphologic evaluation of a thyroid nodule by fine-needle aspiration, combined with the histologic study of surgically resected thyroid
tissue, provide the most definitive information about the nature of the nodule.

Adenomas

Adenomas of the thyroid are benign neoplasms derived from follicular epithelium. Follicular adenomas usually are solitary. On clinical
and morphologic grounds, they may be difficult to distinguish from a dominant nodule in multinodular goiter, for example, or from less common
follicular carcinomas. Although the vast majority of adenomas are nonfunctional, a small proportion produce thyroid hormones (toxic
adenomas), causing clinically apparent thyrotoxicosis. In general, follicular adenomas are not forerunners to carcinomas; nevertheless, shared
genetic alterations support the possibility that at least a subset of follicular carcinomas arise in preexisting adenomas.

Morphology

The typical thyroid adenoma is a solitary, spherical lesion that compresses the adjacent nonneoplastic thyroid. The neoplastic cells are
demarcated from the adjacent parenchyma by a well-defined, intact capsule. On microscopic examination, the constituent cells are arranged in
uniform follicles that contain colloid. Occasionally, the neoplastic cells acquire brightly eosinophilic granular cytoplasm (oxyphil or Hürthle cell
change) .

Essential techniques used in the preoperative evaluation of suspected adenomas are ultrasonography and fine-needle aspiration biopsy.
Because of the need for evaluating capsular integrity, the definitive diagnosis of thyroid adenoma can be made only after careful microscopic
examination of the resected specimen. Suspected adenomas of the thyroid are therefore removed surgically to exclude malignancy. Thyroid
adenomas carry an excellent prognosis and do not recur or metastasize.

Thyroid Carcinomas

The detection of small , clinically asymptomatic cancerous nodules of the thyroid gland has increased dramatically i over the last few years,
largely due to the increasing use of thyroid ultrasound and other imaging studies. Nonetheless, deaths from thyroid cancer have remained
relatively stable during this period, underscoring the favourable outcome for such incidentally detected thyroid carcinomas (and also raising
questions about the value of detecting clinically insignificant cancers). A female predominance has been noted among patients who develop
thyroid carcinoma in the early and middle adult years. By contrast, cases seen in childhood and late adult life are distributed equally between
males and females.
 Most thyroid carcinomas (except medullary carcinomas) are derived from the thyroid follicular epithelium, and of these, the vast majority are
well-differentiated lesions. The major subtypes of thyroid carcinoma and their relative frequencies are as follows: • Papillary carcinoma
• Follicular carcinoma • Anaplastic (undifferentiated) carcinoma • Medullary carcinoma. Because of the unique clinical and biologic
features associated with each type of thyroid carcinoma, these are described separately.

Summary of FOUR key-types of primary thyroid carcinoma:

Papillary Carcinoma, thyroid

Papillary carcinomas are the most common form of thyroid cancer. These tumors may occur at any age, and they account for the vast
majority of thyroid carcinomas associated with previous exposure to ionizing radiation.

Morphology of Papillary carcinoma, thyroid

Papillary carcinomas are solitary or multifocal lesions. Some tumours may be well circumscribed and encapsulated; others infiltrate the adjacent
parenchyma and have ill-defined margins. The cut surface sometimes reveals papillary foci that point to the diagnosis. The microscopic
hallmarks of papillary neoplasms include the following: • Branching papillae having a fibrovascular stalk covered by a single to multiple layers of
cuboidal epithelial cells . In most cases, the epithelium covering the papillae has well-differentiated, uniform, orderly cuboidal cells, but more
pleomorphic or even anaplastic morphologies may be seen. • Nuclei with finely dispersed chromatin, which imparts an optically clear or empty
appearance, giving rise to the designation ground-glass or Orphan Annie eye nuclei. In addition, invaginations of the cytoplasm often give the
appearance of intranuclear inclusions (“pseudo-inclusions”) or intranuclear grooves. These nuclear features are sufficient for the diagnosis of
papillary carcinoma, even in the absence of papillary architecture. • Concentrically calcified structures termed psammoma bodies are often
present within the lesion, usually within the cores of papillae. These structures are almost never found in follicular and medullary carcinomas. •
Foci of lymphatic invasion by tumour are often present, but involvement of blood vessels is relatively uncommon, particularly in smaller lesions.
Metastases to adjacent cervical lymph nodes occur in up to one-half of cases. • There are over a dozen variants of papillary thyroid carcinoma,
the most common of which is the so-called encapsulated follicular variant, comprised of follicles lined by cells harbouring nuclear features of
papillary cancers.
Clinical Features of Papillary carcinoma

Papillary carcinomas are non-functional tumours, so they manifest most often as a painless mass in the neck, either within the thyroid or
as a metastasis in a cervical lymph node.
A preoperative diagnosis usually can be established by fine-needle aspiration based on the characteristic nuclear features described
earlier.

Papillary carcinomas are indolent lesions, with 10-year survival rates of more than 95%.

Of interest, the presence of isolated cervical node metastases does not have a significant influence on prognosis. In a minority of patients,
hematogenous metastases are present at the time of diagnosis, most commonly to the lung. The long-term survival of patients with
papillary thyroid cancer is dependent on several factors, including age (in general, the prognosis is less favourable among patients
older than 40 years of age), presence of extrathyroidal extension, and presence of distant metastases.

Follicular Carcinoma, thyroid

Follicular carcinomas account for 5% to 15% of primary thyroid cancers. Follicular carcinomas/adenocarcinomas usually present in a similar
way to follicular adenomas, and on naked-eye inspection are often round encapsulated nodules. However, histology reveals invasion of the
capsule, blood vessels or the surrounding gland.

They are more common in women (occurring in a ratio of 3: 1) and manifest at an older age than papillary carcinomas, with a peak
incidence between 40 and 60 years of age.

Follicular carcinoma is more frequent in areas with dietary iodine deficiency (accounting for 25%–40% of thyroid cancers), while its
incidence has either decreased or remained stable in iodine-sufficient areas of the world.

Morphology

On microscopic examination, most follicular carcinomas are composed of uniform cells forming small follicles, reminiscent of normal thyroid; in
other cases, follicular differentiation may be less apparent. As with follicular adenomas, Hürthle cell variants of follicular carcinomas may be
seen. Follicular carcinomas may be widely invasive, infiltrating the thyroid parenchyma and extrathyroidal soft tissues, or minimally invasive.
The latter type are sharply demarcated lesions that may be impossible to distinguish from follicular adenomas on gross examination. The
distinction between follicular adenoma and carcinoma requires extensive histologic sampling of the tumour capsule–thyroid
interface, to exclude capsular and/ or vascular invasion .

Clinical Features

Follicular carcinomas manifest most frequently as solitary cold thyroid nodules. In rare cases, they may be hyper functional. These
neoplasms tend to metastasize through the bloodstream (hematogenous dissemination) to the lungs, bone, and liver. In contrast with
papillary carcinomas, regional nodal metastases are uncommon. As many as one-half of patients with widely invasive carcinomas
succumb to their disease within 10 years, while less than 10% of patients with minimally invasive follicular carcinomas die within the same time
span.

Follicular carcinomas are treated with surgical excision. Well-differentiated metastases may take up radioactive iodine, which can be used to
identify and also ablate such lesions.

Anaplastic Carcinoma, thyroid

Anaplastic carcinomas are undifferentiated tumours of the thyroid follicular epithelium, accounting for less than 5% of thyroid tumours.
They are aggressive, with a mortality rate approaching 100%. Patients with anaplastic carcinoma are older than those with other
types of thyroid cancer, with a mean age of 65 years. Approximately one-fourth of patients with anaplastic thyroid carcinomas have a history
of a well-differentiated thyroid carcinoma, and another one-fourth harbour a concurrent well-differentiated tumour in the resected specimen.

Morphology
Anaplastic carcinomas manifest as bulky masses that typically grow rapidly beyond the thyroid capsule into adjacent neck
structures. On microscopic examination, these neoplasms are composed of highly anaplastic cells, which may be large and pleomorphic, or
spindle shaped and in some cases mixture of the two cell types. Foci of papillary or follicular differentiation may be present in some tumours,
suggesting origin from a better-differentiated carcinoma.

Clinical Features Anaplastic carcinomas grow with wild abandon despite therapy. Metastases to distant sites are common, but in most
cases, death occurs in less than 1 year, because of aggressive local growth and compromise of vital structures in the neck.

Medullary Carcinoma, thyroid

Medullary carcinomas of the thyroid are neuroendocrine tumours derived from the parafollicular cells, or C cells, of the thyroid.

Like normal C cells, medullary carcinomas secrete calcitonin, measurement of which plays an important role in the diagnosis and
postoperative follow-up of patients.

In some cases, the tumour cells elaborate other polypeptide hormones such as somatostatin, serotonin, and vasoactive intestinal peptide.
Medullary carcinomas arise sporadically in about 70% of cases. The remaining 30% are familial, occurring in the setting of multiple
endocrine neoplasia (MEN) syndrome 2A or 2B, or familial medullary thyroid carcinoma without an associated MEN syndrome . Both
familial and sporadic medullary forms are associated with gain-of-function driver mutations in the RET receptor tyrosine kinase. Sporadic
medullary carcinomas, as well as familial cases without an associated MEN syndrome, occur in adults, with a peak incidence in the fifth and
sixth decades. Cases associated with MEN-2A or MEN-2B, by contrast, tend to occur in younger patients, including children.

Morphology

Medullary carcinomas may arise as a solitary nodule or may manifest as multiple lesions involving both lobes of the thyroid. Multicentricity is
particularly common in familial cases. Larger lesions often contain areas of necrosis and haemorrhage and may extend through the capsule of
the thyroid.

Medullary carcinomas are composed of polygonal to spindle-shaped cells, which may form nests, trabeculae, and even follicles. Histologically,
the tumour is composed of sheets of neoplastic cells with, between them, a hyaline stroma with the staining reactions of amyloid; this is
due to polymerisation of calcitonin into a beta-pleated sheet. These tumours typically contain amyloid, visible here as homogeneous
extracellular material, derived from calcitonin molecules secreted by the neoplastic cells. Amyloid deposits, derived from altered calcitonin
molecules, are present in the adjacent stroma in many cases and are a distinctive feature. Calcitonin is readily demonstrable both within
the cytoplasm of the tumour cells and in the stromal amyloid by immunohistochemical methods. One of the characteristic features of familial
medullary carcinomas is the presence of multicentric C cell hyperplasia in the surrounding thyroid parenchyma, a feature usually absents in
sporadic lesions. Foci of C cell hyperplasia are believed to represent the precursor lesions from which medullary carcinomas arise.

Clinical Features

In sporadic cases, medullary carcinoma manifests most often as a mass in the neck, sometimes associated with compression effects such as
dysphagia or hoarseness. In some instances, the initial manifestations are caused by the secretion of a peptide hormone (e.g., diarrhoea
caused by the secretion of vasoactive intestinal peptide). Screening of the patient's relatives for elevated calcitonin levels or RET mutations
permits early detection of tumours in familial cases. As discussed later, all members of MEN-2 kindreds carrying RET mutations are offered
prophylactic thyroidectomies to pre-empt the development of medullary carcinomas; often, the only histologic finding in the resected thyroid of
these asymptomatic carriers is the presence of C cell hyperplasia or small (< 1 cm) micro medullary carcinomas.

Summary: Thyroid Neoplasms

• Most thyroid neoplasms manifest as solitary thyroid nodules, but only 1% of all thyroid nodules are neoplastic.

• Follicular adenomas are the most common benign neoplasms, while papillary carcinoma is the most common malignancy.

• Multiple genetic pathways are involved in thyroid carcinogenesis. Some of the driver mutations that are fairly unique to thyroid cancers include
PAX8/ PPARG fusion (in follicular carcinoma), chromosomal rearrangements involving the RET oncogene (in papillary cancers), and mutations
of RET (in medullary carcinomas).

• Follicular adenomas and carcinomas both are composed of well-differentiated follicular epithelial cells; the latter are distinguished by
presence of capsular and/ or vascular invasion.

• Papillary carcinomas are recognized by nuclear features (ground-glass nuclei, pseudo inclusions), even in the absence of papillae. These
neoplasms typically metastasize by way of the lymphatics, but the prognosis is excellent.

• Anaplastic carcinomas are thought to arise by progression of more differentiated neoplasms. They are highly aggressive, uniformly lethal
cancers.

• Medullary cancers are nonepithelial neoplasms arising from the parafollicular C cells and can occur in either sporadic (70%) or familial (30%)
settings. Multicentricity and C cell hyperplasia are features of familial cases. Amyloid deposits are a characteristic histologic finding.

Some thyroid tumours that previously would have been classified as anaplastic carcinoma are now known, largely because of
immunohistochemistry, to be mostly non-Hodgkin lymphomas. There is an increased incidence of these types of lymphoma
originating in the thyroid in Hashimoto thyroiditis. Most thyroid lymphomas are regarded as neoplasms of mucosa-associated
lymphoid tissue and are currently classified as marginal zone B-cell non-Hodgkin lymphomas.

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