Path 1107-1126
Thyroid Gland
 Thyroid divided by thin fibrous septae into lobules composed of 20-40 evenly dispersed follicles, lined by
cuboidal to low columnar epithelium and filled with PAS-positive thyroglobulin
 In response to hypothalamic factors, TSH (thyrotropin) released by thyrotrophs in anterior pituitary
o Binding of TSH to receptor on thyroid follicular epithelium results in conformational change and
activation of receptor, allowing it to associate with Gs protein
o Activation of G protein eventually results in increase in intracellular cAMP levels, which stimulates
thyroid growth, and hormone synthesis and release via cAMP-dependent protein kinases
o Dissociation of thyroid hormone synthesis and release from controlled influence of TSH-signaling
pathways results in thyroid autonomy and hyperfunction
 Thyroid follicular epithelial cells convert thyroglobulin into T4 and lesser amounts of T3; these released into
systemic circulation, where most of these peptides reversibly bound to circulating plasma proteins, such as
thyroxine-binding globulin and transthyretin, for transport to peripheral tissues
o Binding proteins serve to maintain serum unbound (free) T3 and T4 concentrations within narrow limits
yet ensure that hormones readily available to tissues
o In periphery, majority of free T4 deiodinated to T3, which binds to thyroid hormone nuclear receptors in
target cells with 10x greater affinity than T4 and has proportionately greater activity
o Interaction of thyroid hormone with nuclear thyroid hormone receptor (TR) results in formation of
multiprotein hormone-receptor complex that binds to thyroid hormone response elements (TREs) in
target genes, regulating their transcription
 Thyroid hormone upregulates carb and lipid catabolism and stimulates protein synthesis in wide range of cells
o Net result of processes is increase in basal metabolic rfate
o One of most important functions of thyroid hormone is critical role in brain development of fetus and
neonate
 Function of thyroid gland can be inhibited by chemical agents (goitrogens); because they suppress T3 and T4
synthesis, level of TSH increases, and subsequent hyperplastic enlargement of gland (goiter) follows
o Anti-thyroid agent propylthiouracil inhibits oxidation of iodide and thus blocks production of thyroid
hormones; also inhibits peripheral deiodination of circulating T4 into T3, ameliorating symptoms of
thyroid hormone excess
o Iodide, when given to individuals with thyroid hyperfunction, blocks release of thyroid hormones
 Iodides in large doses inhibit proteolysis of thyroglobulin; thus thyroid hormone synthesized and
incorporated in increasing amounts of colloid, but isn’t released into blood
 Thyroid gland follicles also contain parafollicular cells (C cells) that synthesize and secrete calcitonin (hormone
that promotes absorption of calcium by skeletal system and inhibits resorption of bone by osteoclasts)
 Diseases of thyroid include hyperthyroidism, hypothyroidism, and mass lesions of thyroid
Hyperthyroidism
 Thyrotoxicosis – hypermetabolic state caused by elevated circulating levels of free T3 and T4; cause most
commonly by hyperfunction of thyroid gland
o In certain conditions, over supply releated to either excessive release of preformed thyroid hormone
(e.g., in thyroiditis) or to extrathyroidal source, rather than hyperfunction of gland
o 3 most common causes are associated with hyperthyroidism
 Diffuse hyperplasia of thyroid associated with Graves disease (85% of all cases)
 Hyperfunctional multinodular goiter
 Hyperfunctional adenoma of thyroid
 Clinical manifestations of hyperthyroidism include changes referable to hypermetabolic state induced by excess
thyroid hormone and to overactivity of SNS (i.e., increase in β-adrenergic tone)
o Excessive levels of thyroid hormone result in increase in basal metabolic rate; skin tends to be soft,
warm, and flushed because of increased blood flow and peripheral vasodilation to increase heat loss
o Heat intolerance common
o Sweating increased because of higher levels of calorigenesis
o Increased basal metabolic rate also results in characteristic weight loss despite increased appetite
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Cardiac manifestations among earliest and most consistent features of hyperthyroidism; can have increase in
cardiac output due to both increased cardiac contractility and increased peripheral oxidation requirements
o Tachycardia, palpitations, and cardiomegaly common
o Arrhythmias, particularly A fib, occur frequently and are more common in older patients
o Congestive heart failure may develop, particularly in elderly patients with preexisting cardiac disease
o Myocardial changes, such as foci of lymphocytic and eosinophilic infiltration, mild fibrosis in interstitium,
fatty changes in myofibers, and increase in size and number of mitochondria, have been described
o Some patients develop reversible left ventricular dysfunction and low-output heart failure (thyrotoxic or
hyperthyroid cardiomyopathy)
 In neuromuscular system, overactivity of SNS produces tremor, hyperactivity, emotional lability, anxiety,
inability to concentrate, and insomnia
o Thyroid myopathy – proximal muscle weakness and decreased muscle mass
 Ocular changes often call attention to hyperthyroidism; wide, staring gaze and lid lag present because of
sympathetic overstimulation of levator palpebrae superioris
o True thyroid ophthalmopathy associated with proptosis only seen in Graves disease
 Thyroid hormone stimulates bone resorption, increasing porosity of cortical bone and reducing volume of
trabecular bone; net effect is osteoporosis and increased risk of fractures
 Other findings include atrophy of skeletal muscle with fatty infiltration and focal interstitial lymphocytic
infiltrates; minimal liver enlargement due to fatty changes in hepatocytes; and generalized lymphoid hyperplasia
and lymphadenopathy in patients with Graves disease
 Thyroid storm – abrupt onset of severe hyperthyroidism; occurs most commonly in patients with underlying
Graves disease and results from acute elevation in catecholamine levels, as might be encountered during
infection, surgery, cessation of anti-thyroid medication, or any form of stress
o Patients often febrile and present with tachycardia out of proportion to fever
o Thyroid storm is medical emergency; significant number of untreated patients die of arrhythmias
 Apathetic hyperthyroidism – thyrotoxicosis occurring in elderly, in whom advanced age and various comorbidities may blunt typical features of thyroid hormone excess seen in younger patients
o Diagnosis of thyrotoxicosis often made during lab work for unexplained weight loss or worsening
cardiovascular disease
 Diagnosis of hyperthyroidism made using both clinical and laboratory findings; measurement of serum TSH
concentration using sensitive TSH assays provides most useful single screening test since its levels decreased
even at earliest stages when disease may be subclinical
o Low TSH value usually confirmed with measurement of free T4 (increased)
 In occasional patients, hyperthyroidism results predominantly from increased circulating levels of T3 (T3
toxicosis); in these cases, FT4 levels may be decreased, and direct measurement of serum T3 may help
 In rare cases of pituitary-associated (secondary) hyperthyroidism, TSH levels either normal or raised
 Determining TSH levels after injection of thyrotropin-releasing hormone (TRH stimulation test) used in
evaluation of cases of suspected hyperthyroidism with equivocal changes in baseline serum TSH level
o Normal rise in TSH after administration of TRH excludes secondary hyperthyroidism
 Once diagnosis of thyrotoxicosis confirmed by combination of TSH assays and free thyroid hormone levels,
measurement of radioactive iodine uptake by thyroid gland may be valuable in determining etiology
o May be diffusely increased uptake in whole gland (Graves disease), increased uptake in solitary nodule
(toxic adenoma), or decreased uptake (thyroiditis)
 Therapeutic options for hyperthyroidism include multiple medications, each of which has different mechanism
o Typically β-blocker used to control symptoms induced by increased adrenergic tone, thionamide to
block new hormone synthesis, iodine solution to block release of thyroid hormone, and agents that
inhibit peripheral conversion of T4 to T3
o Radioiodine (incorporated into thyroid tissues) results in ablation of thyroid function over period of 6-18
weeks
Hypothyroidism
 Caused by any structural or functional derangement that interferes with production of adequate levels of
thyroid hormone
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Prevalence increases with age; nearly 10x more common in women than men
Can result from defect anywhere in hypothalamic-pituitary-thyroid axis; can be primary or secondary
o Primary hypothyroidism accounts for vast majority of cases; can be accompanied by goiter; can be
congenital ,acquired, or autoimmune
Worldwide, congenital hypothyroidism most often result of endemic iodine deficiency in diet
Inborn errors of thyroid metabolism (dyshormonogenetic goiter)
o Multiple steps leading to thyroid hormone synthesis may be deficient, such as
 Iodide transport into thyrocytes
 Iodide organification (binding of iodide to tyrosine residues of storage protein (thyroglobulin))
 Iodotyrosine coupling to form hormonally active T3 and T4
o Mutations in thyroid peroxidase (TPO) gene are most common cause of dyshormonogenetic goiter
Pendred syndrome – characterized by hypothyroidism and sensorineural deafness; caused by mutations in
SLC26A4 gene, whose product (pendrin) is anion transporter expressed on apical surface of thyrocytes and in
inner ear
In rare instances, there may be complete absence of thyroid parenchyma (thyroid agenesis) or gland may be
greatly reduced in size (thyroid hypoplasia)
Germline mutations in transcription factors expressed in developing thyroid that regulate follicular
differentiation, such as thyroid transcription factor-2 (TTF-2), also known as FOXE1, and paired box-8 (PAX-8)
reported in individuals with thyroid agenesis
o Patients typically present with constellation of extra-thyroidal malformations
Inactivating germline mutations of TSH receptor (TSHR) rare genetic cause of isolated hypothyroidism (activating
somatic mutations of TSHR found in autonomous thyroid nodules)
Thyroid hormone resistance syndrome – rare autosomal-dominant disorder caused by inherited mutations in
thyroid hormone receptor, which abolish ability of receptor to bind thyroid hormones
o Patients demonstrate generalized resistance to thyroid hormone, despite high circulating levels of T3
and T4
o Since pituitary also resistant to feedback from thyroid hormones, TSH levels tend to be high as well
Acquired hypothyroidism can be caused by surgical or radiation-induced ablation of thyroid parenchyma
o Large resection of gland for treatment of hyperthyroidism of primary neoplasm can lead to
hypothyroidism
o Drugs given intentionally to decrease thyroid secretion (e.g., methimazole and propylthiouracil) can
cause acquired hypothyroidism, as can agents used to treat non-thyroid conditions (e.g., lithium, paminosalicylic acid)
Autoimmune hypothyroidism is most common cause of hypothyroidism in iodine-sufficient areas of world
o Vast majority of cases are due to Hashimoto disease; circulating autoantibodies include anti-microsomal,
anti-thyroid peroxidase, and anti-thyroglobulin antibodies
 Thyroid typically goitrous
o Autoimmune hypothyroidism can occur in isolation or in conjunction with autoimmune polyendocrine
syndrome (APS) types 1 and 2
Secondary (central) hypothyroidism caused by deficiency of TSH or (far more uncommonly) TRH
o Any cause of hypopituitarism (e.g., pituitary tumor, postpartum pituitary necrosis, trauma, and
nonpituitary tumors), or of hypothalamic damage from tumors, trauma, radiation therapy, or infiltrative
diseases can cause central hypothyroidism
Cretinism – hypothyroidism that develops in infancy or early childhood; used to be very widespread in areas of
the world without sufficient iodine, but becoming more rare as foods supplemented with iodine
o On rare occasions, cretinism may result from inborn errors in metabolism that interfere with
biosynthesis of normal levels of thyroid hormone (dyshormonogenetic goiter)
o Clinical features include impaired development of skeletal system and CNS, manifested by severe mental
retardation, short stature, coarse facial features, protruding tongue, and umbilical hernia
o Severity of mental impairment related to time at which thyroid deficiency occurs in utero; normally,
maternal hormones, including T3 and T4, cross placenta and are critical to fetal brain development
 If there is maternal thyroid deficiency before development of fetal thyroid gland, mental
retardation is severe
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Reduction in maternal thyroid hormones later in pregnancy, after fetal thyroid has developed,
allows normal brain development
 Myxedema – hypothyroidism developing in older child or adult; also called Gull disease
o Clinical manifestations vary with age of onset of deficiency; older child shows signs and symptoms
intermediate between those of cretin and those of adult with hypothyroidism; in adult condition
appears insidiously and may take years to reach level of clinical suspicion
o Clinical features characterized by slowing of physical and mental activity
o Initial symptoms include generalized fatigue, apathy, and mental sluggishness, which may mimic
depression in early stages of disease
o Speech and intellectual functions become slowed
o Patients listless, cold intolerant, and frequently overweight
o Decreased sympathetic activity results in constipation and decreased sweating
o Skin is cool and pale because of decreased blood flow
o Reduced cardiac output contributes to SOB and decreased exercise capacity
o Thyroid hormones regulate transcription of several sarcolemmal genes, such as calcium ATPases, whose
encoded products are critical in maintaining efficient cardiac output
o Hypothyroidism promotes atherogenic profile (increase in total cholesterol and LDL) probably
contributing toward adverse cardiovascular mortality rates
o Histologically, there is accumulation of matrix substances, such as GAGs and hyaluronic acid, in skin,
subcutaneous tissue, and number of visceral sites; results in non-pitting edema, broadening and
coarsening of facial features, enlargement of tongue, and deepening of voice
o Patients with unexplained increase in body weight or hypercholesterolemia should be assessed for
potential hypothyroidism
o Measurement of serum TSH is most sensitive screening test; TSH level increased in primary
hypothyroidism as result of loss of feedback inhibition of TRH and TSH production; TSH level not
increased in people with hypothyroidism due to primary hypothalamic or pituitary disease
 T4 levels decreased in individuals with hypothyroidism of any origin
Thyroiditis
 Inflammation of thyroid gland; diverse group of disorders characterized by some form of thyroid inflammation
o Include conditions that result in acute illness with severe thyroid pain (e.g., infectious thyroiditis,
subacute granulomatous thyroiditis) and disorders in which there is relatively little inflammation and
illness manifested primarily by thyroid dysfunction (e.g., subacute lymphocytic thyroiditis and fibrous
(Reidel) thyroiditis)
 Infectious thyroiditis – can be acute or chronic; acute infections can reach thyroid by hematogenous spread or
through direct seeding of the gland, such as through fistula from piriform sinus adjacent to larynx
 Other infections of thyroid, including mycobacterial, fungal, and Pneumocystis infections, are more chronic and
frequently occur in immunocompromised patients
 Inflammatory involvement may cause sudden onset of neck pain and tenderness in area of gland and is
accompanied by fever, chills, and other signs of infection
 Infectious thyroiditis can be self-limited or controlled with appropriate therapy; thyroid function usually not
significantly affected, and there are few residual effects except for possible small foci of scarring
 Hashimoto thyroiditis – most cause of hypothyroidism in areas of world where iodine levels sufficient
o Patients have goiter and intense lymphocytic infiltration of thyroid (struma lymphomatosa)
o Characterized by gradual thyroid failure because of autoimmune destruction of thyroid gland
o Most prevalent between 45-65 years of age and more common in women (10:1-20:1); can occur in
children (major cause of non-endemic goiter in pediatric population)
o Strong genetic component; increased susceptibility associated with polymorphisms in multiple immune
regulation-associated genes
 Most significant of which is cytotoxic T lymphocyte-associated antigen-4 (CTLA4) polymorphisms
 CTLA4 is negative regulator of T-cell responses, and polymorphisms result in reduced
protein level or function
 Functional polymorphism in protein tyrosine phosphatase-22 (PTPN22) gene that encodes
lymphoid tyrosine phosphatase (inhibits T-cell function)
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Susceptibility to other autoimmune diseases such as type 1 diabetes associated with
polymorphisms in both CTLA4 and PTPN22
o Caused by breakdown in self-tolerance to thyroid auto-antigens; presence of circulating antibodies
against thyroglobulin and thyroid peroxidase in vast majority of Hashimoto patients
o Inciting events leading to breakdown in self-tolerance include abnormalities of regulatory T cells (Tregs)
or exposure of normally sequestered thyroid antigens
o Induction of thyroid autoimmunity accompanied by progressive depletion of thyrocytes by apoptosis
and replacement of thyroid parenchyma by mononuclear cell infiltration and fibrosis
o Mechanisms that contribute to thyroid cell death include
 CD8+ cytotoxic T cell-mediated cell death of thyrocytes
 Cytokine-mediated cell death – excessive T-cell activation leads to production of TH1
inflammatory cytokines such as interferon-γ in 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
o Thyroid often diffusely enlarged, though more localized enlargement may be seen in some cases
o Capsule intact, and gland well demarcated from adjacent structures; cut surface is pale, yellow-tan, firm,
and somewhat nodular
o Extensive infiltration of parenchyma by mononuclear inflammatory infiltrate containing small
lymphocytes, plasma cells, and well-developed germinal centers
o Thyroid follicles atrophic and lined by epithelial cells distinguished by presence of abundant eosinophilic,
granular cytoplasm (Hürthle cells); metaplastic response of normally low cuboidal follicular epithelium
to ongoing injury
 In fine-needle aspiration biopsy samples, presence of Hürthle cells in conjunction with
heterogeneous population of lymphocytes is characteristic of Hashimoto thyroiditis
o In classic Hashimoto thyroiditis, interstitial CT increased and may be abundant
o Fibrous variant characterized by severe thyroid follicular atrophy and dense keloid-like fibrosis, broad
bands of acellular collagen encompassing residual thyroid tissue
 Fibrosis doesn’t extend beyond capsule of gland
o Remnant thyroid parenchyma demonstrates features of chronic lymphocytic thyroiditis
o Most often comes to clinical attention as painless enlargement of thyroid, usually associated with some
degree of hypothyroidism, in middle-aged woman
 Enlargement of gland usually symmetric and diffuse, but in some cases may be sufficiently
localized to raise suspicion of neoplasm
o In usual clinical course, hypothyroidism develops gradually
o In some cases, may be preceded by transient thyrotoxicosis caused by disruption of thyroid follicles with
secondary release of thyroid hormones (hashitoxicosis)
 Free T4 and T3 levels elevated, TSH diminished, and radioactive iodine uptake decreased
 As hypothyroidism supervenes, T4 and T3 levels fall, accompanied by compensatory increase in
TSH
o Patients at increased risk for developing other autoimmune diseases, both endocrine (type 1 diabetes,
autoimmune adrenalitis) and non-endocrine (systemic lupus erythematosus, myasthenia gravis, and
Sjögren syndrome); also at increased risk for development of B-cell non-Hodgkin lymphomas, especially
marginal zone lymphomas of MALT
o Might be more prone to thyroid epithelial cancers (some studies suggest predisposition to papillary
carcinomas)
Subacute (granulomatous) thyroiditis (De Quervain thyroiditis) – most common between ages of 40-50 and
affects women more than men (4:1)
o Triggered by viral infection; majority of patients have history of URI just before onset
o Seasonal incidence, peaking in summer; clusters of cases reported in association with coxsackievirus,
mumps, measles, adenovirus, and other viral illnesses
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Results from viral infection that leads to exposure to viral or thyroid antigen, which is released
secondary to virus-induced host tissue damage; antigen stimulates CTLs, which then damage thyroid
follicular cells
o Immune response is virus-initiated and not self-perpetuating, so process limited
o Gland may be unilaterally or bilaterally enlarged and firm, with intact capsule; may be slightly adherent
to surrounding structures
o On cut section, involved areas are firm and yellow-white and stand out from more rubbery, normal
brown thyroid substance
o Histologically, changes patchy and depend on stage of disease
 Early in active inflammatory phase, scattered follicles may be entirely disrupted and replaced by
neutrophils forming microabscesses
 Later, more characteristic features appear in form of aggregates of lymphocytes, activated
macrophages, and plasma cells about collapsed and damaged thyroid follicles
o Multinucleate giant cells enclose naked pools or fragments of colloid
o In later stages of disease, chronic inflammatory infiltrate and fibrosis may replace foci of injury
o Different histologic stages sometimes found in same gland, suggesting waves of destruction over period
of time
o Most common cause of thyroid pain
o Variable enlargement of thyroid
o Inflammation and hyperthyroidism transient, usually diminishing in 2-6 weeks, even if patient not
treated
o Nearly all patients have high serum T4 and T3 levels and low serum TSH levels
o Radioactive iodine uptake is diminished
o After recovery (6-8 weeks), normal thyroid function returns
 Subacute lymphocytic (painless) thyroiditis – usually comes to clinical attention because of mild
hyperthyroidism, goitrous enlargement of gland, or both
o Most often seen in middle-aged women (can occur in either gender or at any age)
o Disease process resembling painless thyroiditis can occur during postpartum period in up to 5% of
women (postpartum thyroiditis)
o Painless and postpartum thyroiditis variations of Hashimoto thyroiditis, since majority of patients have
circulating anti-thyroid peroxidase antibodies or family history of other autoimmune disorders
o As many as 1/3 of cases can evolve into overt hypothyroidism over time (10 years), and thyroid histology
reminiscent of Hashimoto thyroiditis
o Except for possible mild symmetric enlargement, thyroid appears normal on gross inspection
o Most specific histologic features consist of lymphocytic infiltration with hyperplastic germinal centers
within thyroid parenchyma and patchy disruption and collapse of thyroid follicles
o Fibrosis and Hürthle cell metaplasia NOT prominent features
o Patients can present with painless goiter, transition from hyperthyroid state to hypothyroidism before
recovery; vast majority (~80%) of individuals with postpartum thyroiditis are euthyroid by 1 year
 Postpartum thyroiditis can resemble Graves disease (no infiltrative ophthalmopaty or other
manifestations of Graves though)
 Riedel thyroiditis – rare disorder of unknown etiology characterized by extensive fibrosis involving thyroid and
contiguous neck structures
o May be associated with idiopathic fibrosis in other sites in body, such as retroperitoneum
o Presence of hard and fixed thyroid mass clinically simulates thyroid carcinoma
o Presence of circulating anti-thyroid antibodies in most patients suggests autoimmune etiology
Graves Disease
 Most common cause of endogenous hyperthyroidism
 Characterized by triad of clinical findings
o Hyperthyroidism due to diffuse, hyperfunctional enlargement of thyroid
o Infiltrative ophthalmopathy with resultant exophthalmos
o Localized, infiltrative dermopathy (pretibial myxedema) present in minority of patients
 Peak incidence between 20-40 years of age; women affected 10x more frequently
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Autoimmune thyroid disorder; genetic factors important (susceptibility linked to polymorphisms in immune
function genes CTLA4 and PTPN22 and HLA-DR3 allele)
Characterized by breakdown in self-tolerance to thyroid auto-antigens, most importantly TSH receptor; result is
production of multiple autoantibodies
o Thyroid-stimulating immunoglobulin – IgG antibody that binds to TSH receptor and mimics action of
TSH, stimulating adenyl cyclase and increasing release of thyroid hormones
 Almost all individuals with Graves disease have detectable levels of this autoantibody
 Relatively specific for Graves disease (as opposed to next two)
o Thyroid growth-stimulating immunoglobulins – directed against TSH receptor; implicated in proliferation
of thyroid follicular epithelium
o TSH-binding inhibitor immunoglobulins – anti-TSH receptor antibodies prevent TSH from binding
normally to its receptor on thyroid epithelial cells
 Some forms of TSH-binding inhibitor immunoglobulins mimic action of TSH, resulting in
stimulation of thyroid epithelial cell activity, whereas other forms may inhibit thyroid cell
function
 Not unusual to find coexistence of stimulating and inhibiting immunoglobulins in serum of same
patient; some patients with Graves disease have episodes of hypothyroidism
Autoimmunity plays role in development of infiltrative ophthalmopathy characteristic of Graves disease
o Volume of retro-oerbital CT and extraocular muscles increased because of
 Marked infiltration of retro-orbital space by mononuclear cells (predominantly T cells)
 Inflammatory edema and swelling of extraocular muscles
 Accumulation of ECM components, specifically hydrophilic GAGs such as hyaluronic acid and
chondroitin sulfate
 Increased numbers of adipocytes (fatty infiltration)
o Changes displace eyeball forward and can interfere with function of extraocular muscles
o Orbital preadipocyte fibroblasts express TSH receptor and thus become targets of autoimmune attack
 T cells reactive against fibroblasts secrete cytokines, which stimulate fibroblast proliferation and
synthesis of ECM proteins (GAGs) and increase surface TSH receptor expression, perpetuating
autoimmune response
 Result is progressive infiltration of retro-orbital space and ophthalmopathy
Thyroid gland usually symmetrically enlarged because of diffuse hypertrophy and hyperplasia of thyroid
follicular epithelial cells
On cut section, parenchyma has soft, meaty appearance resembling normal muscle
Histologically, follicular epithelial cells in untreated cases tall and more crowded than usual
o Crowding often results in formation of small papillae, which project into follicular lumen and encroach
on colloid, sometimes filling follicles
o Papillae lack fibrovascular cores in contrast to those of papillary carcinoma
Colloid within lumen pale with scalloped margins
Lymphoid infiltrates, consisting predominantly of T cells with fewer B cells and mature plasma cells, present
throughout interstitium; germinal centers common
Preoperative therapy alters morphology of thyroid in Graves disease; administration of iodine causes involution
of epithelium and accumulation of colloid by blocking thyroglobulin secretion
o Treatment with anti-thyroid drug propylthiouracil exaggerates epithelial hypertrophy and hyperplasia by
stimulating TSH secretion
o In pretreated patients, it’s impossible from histologic exam of surgical specimens to evaluate functional
activity of gland
Changes in extra-thyroidal tissue include generalized lymphoid hyperplasia
o Heart may be hypertrophied; ischemic changes may be present, particularly in patients with preexisting
coronary artery disease
o In patients with ophthalmopathy, tissues of orbit are edematous because of presence of hydrophilic
mucopolysaccharides; also infiltration by lymphocytes and fibrosis
o Orbital muscles edematous initially but may undergo fibrosis late in course of disease
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Dermopathy, if present, characterized by thickening of dermis due to deposition of GAGs and
lymphocyte infiltration
 Clinical findings include changes referable to thyrotoxicosis as well as those associated uniquely with Graves
disease (diffuse hyperplasia of thyroid, ophthalmopathy, and dermopathy)
o Degree of thyrotoxicosis varies from case to case; sometimes less conspicuous than other
manifestations of disease
o Diffuse enlargement of thyroid present in all cases; may be accompanied by increased flow of blood
through hyperactive gland, producing bruit
o SNS overactivity produces characteristic wide, staring gaze and lid lag
o Ophthalmopathy leads to exophthalmos; may persist or progress despite successful treatment of
thyrotoxicosis, sometimes resulting in corneal injury
o Extraocular muscles often weak
o Infiltrative dermopathy most common in skin overlying shins, where it presents as scaly thickening and
induration (hardening); present only in minority of patients
 Sometimes individuals spontaneously develop thyroid hypofunction
 Patients at increased risk for other autoimmune diseases, such as systemic lupus erythematosus, pernicious
anemia, type 1 diabetes, and Addison disease
 Lab findings include elevated free T4 and T3 levels and depressed TSH levels
o Because of ongoing stimulation of thyroid follicles by thyroid-stimulating Igs, radioactive iodine uptake
increased, and radioiodine scans show diffuse uptake of iodine
 Treated with β-blockers, which address symptoms related to increased β-adrenergic tone (e.g., tachycardia,
palpitations, tremulousness, and anxiety), and by measures aimed at decreasing thyroid hormone synthesis,
such as administration of thionamides (e.g., propylthiouracil), radioiodine ablation, and surgical intervention
Diffuse and Multinodular Goiters
 Goiter is most common manifestation of thyroid disease
 Diffuse and multinodular goiters reflect impaired synthesis of thyroid hormone, which is most often caused by
dietary iodine deficiency
o Impairment of thyroid hormone synthesis leads to compensatory rise in serum TSH level, which in turn
causes hypertrophy and hyperplasia of thyroid follicular cells and ultimately gross enlargement
o Compensatory increase in functional mass of gland able to overcome hormone deficiency, ensuring
euthyroid metabolic state in most individuals
o If underlying disorder sufficiently severe (e.g., congenital biosynthetic defect or endemic iodine
deficiency), compensatory responses may be inadequate to overcome impairment in hormone
synthesis, resulting in goitrous hypothyroidism
o Degree of thyroid enlargement proportional to level and duration of thyroid hormone deficiency
 Diffuse nontoxic (simple) goiter – causes enlargement of entire gland without producing nodularity
o Enlarged follicles filled with colloid (colloid goiter); occurs in both endemic and sporadic distribution
o Endemic goiter occurs in geographic areas where soil, water, and food supply contain low levels of
iodine; applies when more than 10% of population in given region have goiters
 Common in Andes and Himalayas
 Lack of iodine leads to decreased synthesis of thyroid hormone and compensatory increase in
TSH, leading to follicular cell hypertrophy and hyperplasia
 With increasing dietary iodine supplementation, frequency and severity of endemic goiter
declined significantly
o Goiter can be caused by dietary substances (goitrogens); ingestion can interfere with thyroid hormone
synthesis at some level, such as vegetables belonging to Brassicaceae (Cruciferae) family (e.g., cabbage,
cauliflower, Brussels sprouts, turnips, and cassava)
 Native populations subsisting on cassava root are particularly at risk
 Cassava contains thiocyanate that inhibits iodide transport within thyroid, worsening possible
concurrent iodine deficiency
o Sporadic goiter – occurs less frequently than endemic goiter; striking female preponderance and peak
incidence at puberty or in young adult life
 Can be caused by several conditions, including ingestion of goitrogens
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May result from hereditary enzymatic defects that interfere with thyroid hormone synthesis, all
transmitted as autosomal-recessive disorder (dyshormonogenetic goiter)
 In most cases, cause not apparent
o 2 phases in evolution of diffuse nontoxic goiter: hyperplastic phase and phase of colloid involution
 In hyperplastic phase, thyroid gland diffusely and symmetrically enlarged, although increase
usually modest
 Follicles lined by crowded columnar cells, which may pile up and form projections
 Accumulation not uniform throughout gland, and some follicles hugely distended, whereas
others remain small
 If dietary iodine subsequently increases or demand for thyroid hormone decreases, stimulated
follicular epithelium involutes to form enlarged, colloid-rich gland (colloid goiter)
 Cut surface of thyroid usually brown, somewhat glassy, and translucent
 Histologically, follicular epithelium is flattened and cuboidal; colloid abundant during periods of
involution
o Vast majority of persons with simple goiters clinically euthyroid; clinical manifestations primarily related
to mass effects from enlarged thyroid gland
o Although serum T3 and T4 normal, serum TSH usually elevated or at upper range of normal
o In children, dyshormonogenetic goiter (caused by congenital biosynthetic defect) may induce cretinism
Multinodular goiter – with time, recurrent episodes of hyperplasia and involution combine to produce more
irregular enlargement of thyroid
o Virtually all long-standing simple goiters convert into multinodular goiters
o Produce most extreme thyroid enlargements and are more frequently mistaken for neoplastic
involvement than any other form of thyroid disease
o Occur in both sporadic and endemic forms, having same female-to-male distribution and same origins
but affecting older individuals because they are late complications
o Arise because of variations among follicular cells in their response to external stimuli, such as trophic
hormones – if some cells in follicle have growth advantage, perhaps because of intrinsic genetic
abnormalities similar to those that give rise to adenomas, those cells can give rise to clones of
proliferating cells
 May result in formation of nodule whose continued growth is autonomous without external
stimulus
 Both polyclonal and monoclonal nodules coexist within same multinodular goiter; monoclonal
nodules arise because of acquisition of genetic abnormality favoring growth
o Mutations affecting proteins of TSH-signaling pathway that lead to constitutive activation of this
pathway identified in subset of autonomous thyroid nodules
o Uneven follicular hyperplasia, generation of new follicles, and uneven accumulation of colloid produce
physical stress that leads to rupture of follicles and vessels followed by hemorrhages, scarring, and
sometimes calcifications
 With scarring, nodularity appears, which may be accentuated by preexisting stromal framework
of gland
o Goiters are multilobulated, asymmetrically enlarged glands; pattern of enlargement unpredictable and
may involve one lobe far more than the other, producing lateral pressure on midline structures such as
trachea and esophagus
 In other instances, goiter grows behind sternum and clavicles to produce intrathoracic
(plunging) goiter
 Occasionally, most of it is hidden behind trachea and esophagus; in other instances, one nodule
may so stand out as to impart clinical appearance of solitary nodule
o On cut section, irregular nodules containing variable amounts of brown, gelatinous colloid present
o Older lesions have areas of hemorrhage, fibrosis, calcification, and cystic change
o Microscopic appearance includes colloid-rich follicles lined by flattened, inactive epithelium and areas of
follicular hyperplasia, accompanied by degenerative changes
o In contrast to follicular neoplasms, prominent capsule between hyperplastic nodules and residual
compressed thyroid parenchyma not present
o
Dominant clinical features caused by mass effects of enlarged gland; may cause airway obstruction and
dysphagia, and compression of large vessels in neck and upper thorax (superior vena cava syndrome)
 Most patients euthyroid or have subclinical hyperthyroidism (identified only by reduced TSH
levels)
 In substantial minority of patients, autonomous nodule may develop within long-standing goiter
and produce hyperthyroidism (toxic multinodular goiter or Plummer syndrome)
 Not accompanied by infiltrative ophthalmopathy and dermopathy of Graves disease
o Clinically apparent autonomous nodules can develop in about 10% of multinodular goiters over 10-year
follow-up
o Incidence of malignancy in long-standing multinodular goiters is low (<5%) but not zero, and concern for
malignancy arises when sudden changes in size or symptoms (e.g., hoarseness) occur
o Dominant nodules can present as solitary thyroid nodule, mimicking thyroid neoplasm
o Radioiodine scan demonstrates uneven iodine uptake (including occasional “hot” autonomous nodule)
consistent with diffuse parenchymal involvement, and admixture of hyperplastic and involuting nodules
o Fine-needle aspiration biopsy helpful and can often (but not always) facilitate distinction of follicular
hyperplasia from follicular neoplasm
Neoplasms of the Thyroid
 Solitary thyroid nodule – palpably discrete swelling in otherwise apparently normal thyroid gland; incidence
significantly higher in endemic goitrous regions
o Single nodules 4x more common in women than men
o Incidence of thyroid nodules increases throughout life
 Overwhelming majority of solitary nodules of thyroid prove to be localized, non-neoplastic conditions (e.g.,
dominant nodule in multinodular goiter, simple cysts, or foci of thyroiditis) or benign neoplasms such as
follicular adenomas
o Benign neoplasms outnumber thyroid carcinomas nearly 10:1
o Under 1% of solitary thyroid nodules malignant; most cancers indolent, permitting 90% survival at 20
years
 Several clinical criteria provide clues to nature of given thyroid nodule
o Solitary nodules in general more likely to be neoplastic than multiple nodules
o Nodules in younger patients more likely to be neoplastic than those in older patients
o Nodules in males more likely to be neoplastic than females
o History of radiation treatment to head and neck region associated with increased incidence of thyroid
malignancy
o Functional nodules that take up radioactive iodine in imaging studies (hot nodules) significantly more
likely to be benign than malignant
 Ultimately, it is morphologic evaluation of given thyroid nodule by fine-needle aspiration and histologic study of
surgically resected thyroid parenchyma that provides most definitive info about nature
 Adenomas – typicall discrete, solitary masses, derived from follicular epithelium (also called follicular adenomas)
o Clinically can be difficult to distinguish from dominant nodules of follicular hyperplasia or from less
common follicular carcinomas
o In general, follicular adenomas not forerunners to carcinomas
 Shared genetic alterations support possibility that at least subset of follicular carcinomas arise in
preexisting adenomas
o Although vast majority of adenomas nonfunctional, small proportion produce thyroid hormones and
cause clinically apparent thyrotoxicosis
 Hormone production of functional adenomas (toxic adenomas) independent of TSH stimulation
and represents thyroid autonomy
 Shares altered genetic pathway with toxic multinodular goiters
o Minority (<20%) of nonfunctioning follicular adenomas have mutations of RAS or phosphatidylinositol-3kinase subunit (PIK3CA) or bear PAX8-PPARG fusion gene, all of which are genetic alterations shared
with follicular carcinomas
o Somatic mutations of TSH receptor signaling pathway found in toxic adenomas, as well as toxic
multinodular goiter
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Gain-of-function mutations in one of 2 components of signaling system (most often TSHR itself
or α-subunit of Gs (GNAS)) allow follicular cells to secrete thyroid hormone independent of TSH
stimulation; causes symptoms of hyperthyroidism and produces hot thyroid nodule on imaging
 Overall mutations in TSH receptor signaling pathway present in slightly over half of toxic thyroid
nodules; notably TSHR and GNAS mutations rare in follicular carcinomas, so toxic adenomas and
toxic multinodular goiter not forerunners of malignancy
Typical thyroid adenoma is solitary, spherical, encapsulated lesion that is well demarcated from
surrounding thyroid parenchyma
 In freshly resected specimens, adenoma bulges from cut surfaces and compresses adjacent
thyroid
 Color ranges from gray-white to red-brown, depending on cellularity of adenoma and colloid
content
 Neoplastic cells demarcated from adjacent parenchyma by well-defined intact capsule;
important in making distinction from multinodular goiters, which contain multiple nodules on
cut surface even though patient may present clinically with solitary dominant nodule
 Areas of hemorrhage, fibrosis, calcification, and cystic change similar to those encountered in
multinodular goiters common in follicular adenomas, particularly in larger lesions
Microscopically, constituent cells often form uniform-appearing follicles that contain colloid
 Follicular growth pattern in adenoma usually distinct from adjacent non-neoplastic thyroid
 Epithelial cells composing follicular adenoma reveal little variation in cell and nuclear
morphology, and mitotic figures rare
 Extensive mitotic activity, necrosis, or high cellularity warrants careful examination of capsule to
exclude follicular carcinoma, as well as of nuclear features to exclude follicular variant of
papillary carcinoma
Occasionally neoplastic cells acquire brightly eosinophilic granular cytoplasm (oxyphil or Hürthle cell
change); clinical presentation and behavior of follicular adenoma with oxyphilia (Hürthle cell adenoma)
no different from that of conventional adenoma
Hallmark of all follicular adenomas is presence of intact, well-formed capsule encircling the tumor
Follicular carcinomas demonstrate capsular and/or vascular invasion (use this to tell difference)
Many follicular adenomas present as unilateral painless mass, often discovered during routine physical
exam; larger masses may produce local symptoms, such as difficulty swallowing
Nonfunctioning adenomas take up less radioactive iodine than does normal thyroid parenchyma
 On radionuclide scanning, nonfunctional adenomas usually appear as cold nodules relative to
adjacent thyroid tissue
 As many as 10% of cold nodules eventually prove to be malignant on histologic analysis
 Malignancy rare in hot nodules (toxic adenomas)
Because of need for evaluating capsular integrity, definitive diagnosis of adenomas can be made only
after careful histologic examination of resected specimen
 Suspected adenomas of thyroid removed surgically to exclude malignancy
Follicular adenomas have excellent prognosis and don’t recur or metastasize
o
Carcinomas
 Carcinomas of thyroid relatively uncommon in U.S., accounting for about 1.5% of all cancers
o Female predominance noted among patients who develop thyroid carcinoma in early and middle years
o Cases presenting in childhood and late adult life equally distributed among males and females
 Most thyroid carcinomas (except medullary carcinomas) derived from thyroid follicular epithelium, and of these,
vast majority are well-differentiated lesions
 Major subtypes are
o Papillary carcinomas (>85% of cases)
o Follicular carcinoma (5-15% of cases)
o Anaplastic (undifferentiated) carcinoma (<5% of cases)
o Medullary carcinoma (5% of cases)
 Distinct genetic events involved in pathogenesis of the 4 major histologic variants of thyroid cancer
o Don’t arise from follicular epithelium
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Genetic alterations in follicular cell-derived malignancies clustered along 2 oncogenic pathways
 Mitogen-activated protein (MAP) kinase pathway
 Phosphatidylinositol-3-kinase (PI3K)/AKT pathway
 In normal cells, pathways transiently activated by binding of soluble growth factor ligands to
extracellular domain of receptor tyrosine kinases, which results in autophosphorylation of
cytoplasmic domain of receptor, permitting intracellular signal transduction
 In thyroid carcinomas, gain-of-function mutations along components of pathways lead to
constitutive activation even in absence of ligand and thus promote carcinogenesis
Major risk factor predisposing to thyroid cancer in general is exposure to ionizing radiation, particularly in first 2
decades of life (marked increase in incidence of papillary carcinomas among children exposed during Chernobyl)
Deficiency of dietary iodine (and by extension, association with goiter) linked with higher frequency of follicular
carcinomas
Papillary carcinomas – most common form of thyroid cancer; occur most often between age 25-50 and account
for majority of thyroid carcinomas associated with previous exposure to ionizing radiation
o Solitary or multifocal lesions; some tumors may be well circumscribed or even encapsulated while
others may infiltrate adjacent parenchyma with ill-defined margins
o Lesions may contain areas of fibrosis and calcification and are often cystic
o Cut surface sometimes reveals papillary foci that may point to diagnosis
o Activation of MAP kinase pathway is feature of most papillary carcinomas and can occur by
rearrangement of RET or NTRK1, both of which encode transmembrane receptor tyrosine kinases or by
activating point mutations in BRAF (product is intermediate signaling component in MAP kinase
pathway)
o RET gene – receptor tyrosin kinase it encodes normally not expressed in thyroid follicular cells
o Either paracentric inversion of chromosome 10 or reciprocal translocation between chromosomes 10
and 17 places tyrosine kinase domain of RET under transcriptional control of genes that are
constitutively expressed in thyroid epithelium
 Novel fusion proteins formed are RET/PTC and present in about 20-40% of papillary thyroid
cancers
 More than 15 fusion partners of RET, and RET/PTC1 and RET/PTC2 most commonly
observed in sporadic papillary cancers
 Frequency of RET/PTC rearrangements significantly higher in papillary cancers arising in
backdrop of radiation exposure
 Irrespective of frequency, presence of RET/PTC fusion protein leads to constitutive
expression of tyrosine kinase in thyroid follicular cells, with resultant activation of MAP
kinase pathway
 Paracentric inversions or translocations of NTRK1 on chromosome 1q21 present in 5-10% of
papillary thyroid cancers, and resultant fusion proteins constitutively expressed in thyroid cells,
leading to activation of MAP kinase and other oncogenic signaling pathways
o 1/3-1/2 harbor gain-of-function mutation in BRAF gene (most commonly BRAFV600E)
 Presence of BRAF mutations correlates with adverse prognostic factors like metastatic disease
and extra-thyroidal extension
 Histologic variants demonstrate some unique characteristics in relation to frequency or nature
of BRAF mutations
o Since chromosomal rearrangements of RET or NTRK1 genes and mutations of BRAF have redundant
effects on thyroid epithelium (both mechanisms result in activation of MAP kinase signaling pathway),
papillary thyroid carcinomas demonstrate either one or other molecular abnormality, but not both
o RET/PTC rearrangements and BRAF point mutations not observed in follicular adenomas or carcinomas
o Microscopic hallmarks include
 Branching papillae having fibrovascular stalk covered by single to multiple layers of cuboidal
epithelial cells; in most neoplasms, epithelium covering papillae consists of well-differentiated,
uniform, orderly cuboidal cells, but some have fairly anaplastic (less-differentiated) epithelium
showing considerable variation in cell and nuclear morphology; when present, papillae differ
o
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from those seen in areas of hyperplasia in being more complex and having dense fibrovascular
cores
 Nuclei of carcinoma cells contain finely dispersed chromatin, which imparts optically clear or
empty appearance, giving rise to designation “ground-glass” or “Orphan Annie eye” nuclei
 Invaginations of cytoplasm may in cross-sections give appearance of intranuclear
inclusions (pseudo-inclusions) or intranuclear grooves
 Diagnosis of papillary carcinoma made based on nuclear features, even in absence of
papillary architecture
 Concentrically calcified strutures (psammoma bodies) often present in lesion, usually in cores of
papillae; almost never found in follicular and medullary carcinomas, and when present in fineneedle aspiration material, are strong indication that lesion is papillary carcinoma
 Foci of lymphatic invasion by tumor often present, but involvement of blood vessels relatively
uncommon, particularly in smaller lesions
 Metastases to adjacent cervical lymph nodes occur in up to ½ cases
Over a dozen histologic variants of papillary carcinomas that can mimic other lesions of thyroid or
harbor distinct prognostic implications
 Most common variant, and one most liable to misdiagnosis, is follicular variant, which has
characteristic nuclei of papillary carcinomas but has almost totally follicular architecture
 Genetic alterations demonstrate lower frequency of RET/PTC rearrangements and
significantly higher frequency of RAS mutations
 Often harbors distinct mutation in BRAF, which results in lower degree of BRAF kinase
activation than mutation present in conventional papillary carcinomas
 More frequently encapsulated and has lower incidence of lymph node metastases and
extra-thyroidal extension than conventional papillary carcinomas
 Encapsulated follicular variant have favorable prognosis and can be managed with
conservative surgical excision, while more infiltrative tumors associated with metastases
should be treated more aggressively
 Tall-cell variant marked by tall columnar cells with intensely eosinophilic cytoplasm lining
papillary structures; tend to occur in older individuals and have higher frequencies of vascular
invasion, extra-thyroidal extension, and cervical and distant metastases than conventional
papillary thyroid carcinoma
 Harbor BRAF mutations in most (55-100%) cases, and often have RET/PTC translocation
 Occurrence of mutations together may be responsible for aggressive behavior
 Diffuse sclerosing variant – unusual variant that occurs in younger individuals, including children
 Tumor demonstrates prominent papillary growth pattern, intermixed with solid areas
containing nests of squamous metaplasia
 Extensive, diffuse fibrosis throughout thyroid gland, often associated with prominent
lymphocytic infiltrate, simulating Hashimoto thyroiditis
 Lymph node metastases present in almost all cases
 Lack BRAF mutations, but RET/PTC translocations found in about ½ of cases
 Papillary microcarcinoma – otherwise conventional papillary carcinoma less than 1 cm in size
 Usually confined to thyroid gland
 Most often observed as incidental finding upon surgery
 Might be precursors of usual papillary cancers
Most conventional papillary carcinomas present as asymptomatic thyroid nodules, but first
manifestation may be mass in cervical lymph node
 Presence of isolated cervical nodal metastases doesn’t have significant influence on generally
good prognosis of lesions
 Carcinoma usually single nodule that moves freely during swallowing and isn’t distinguishable
from benign nodule
 Hoarseness, dysphagia, cough, or dyspnea suggests advanced disease
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In minority of patients, hematogenous metastases present at time of diagnosis, most commonly
in lung
o Variety of diagnostic tests help separate benign from malignant thyroid nodules, including radionuclide
scanning and fine-needle aspiration
 Papillary carcinomas are cold masses on scintiscans
o 10-year survival rate in excess of 95% of patients
 Between 5-20% of patients have local or regional recurrences, and 10-15% have distant
metastases
 Prognosis depends on age (prognosis less favorable among those older than 40), presence of
extra-thyroidal extension, and presence of distant metastases (stage)
Follicular carcinomas – 5-15% of primary thyroid cancers; more common in women (3:1) and present at older
age than papillary carcinomas, with peak incidence 40-60 years of age
o More frequent in areas of dietary iodine deficiency (25-40% of thyroid cancers there)
o Single nodules that may be well circumscribed or widely infiltrative
 Sharply demarcated lesions may be exceedingly difficult to distinguish from follicular adenomas
by gross examination
 Larger lesions may penetrate capsule and infiltrate well beyond thyroid capsule into adjacent
neck
 Gray to tan to pink on cut section and, on occasion, somewhat translucent due to presence of
large, colloid-filled follicles
 Degenerative changes, such as central fibrosis and foci of calcification, sometimes present
o Microscopically, most composed of fairly uniform cells forming small follicles containing colloid (like
normal thyroid); in other cases, follicular differentiation may be less apparent, and there may be nests
or sheets of cells without colloid
 Occasional tumors dominated by cells with abundant granular, eosinophilic cytoplasm (Hürthle
cell or oncocytic variant)
o Nuclei lack features typical of papillary carcinoma, and psammoma bodies not present (sometimes only
difference between papillary and follicular carcinoma)
o Nuclear features of little value in distinguishing follicular adenomas from minimally invasive follicular
carcinomas; distinction requires extensive histologic sampling of tumor-capsule-thyroid interface to
exclude capsular and/or vascular invasion
 Criterion for vascular invasion applicable only to capsular vessels and vascular spaces beyond
capsule; presence of tumor plugs within intra-tumoral blood vessels has little prognostic
significance
o Lymphatic spread uncommon
o About 1/3-1/2 harbor mutations in PI-3K/AKT signaling pathway, resulting in constitutive activation of
oncogenic pathway
 Subset of cases includes tumors with gain-of-function point mutations of RAS and PIK3CA,
tumors with amplification of PIK3CA, and those with loss-of-function mutations of PTEN (tumor
suppressor gene and negative regulator of this pathway)
 Genetic alterations activating PI-3K/AKT pathway almost always mutually exclusive in follicular
carcinomas, in line with functional equivalence
 Progressive increase in prevalence of RAS and PIK3CA mutations from benign follicular
adenomas to follicular carcinomas to anaplastic carcinomas suggests shard histogenesis and
molecular evolution among follicular cell-derived tumors
 Unique (2;3)(q13;p25) translocation described in 1/3-1/2 of follicular carcinomas; creates fusion
gene composed of portions of PAX8 (paired homeobox gene important in thyroid development)
and peroxisome proliferator-activated receptor gene (PPARG – gene product is nuclear hormone
receptor implicated in terminal differentiation of cells)
 Fewer than 10% of follicular adenomas harbor PAX8-PPARG fusion genes, and they have
not been documented in other thyroid neoplasms
o Diagnosis of carcinoma obvious in widely invasive carcinomas, which infiltrate thyroid parenchyma and
extra-thyroidal soft tissues
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Histologically, have greater proportion of solid or trabecular growth pattern, less evidence of
follicular differentiation, and increased mitotic activity
o Present as slowly enlarging painless nodules; most frequently cold nodules on scintigrams, although
rare, better differentiated lesions may be hyperfunctional (appear warm on scintiscan)
o Little propensity for invading lymphatics, so regional lymph nodes rarely involved, but vascular
(hematogenous) dissemination common, with metastases to bone, lungs, liver, and elsewhere
 Prognosis largely dependent on extent of invasion and stage at presentation
 Widely invasive carcinomas not infrequently present with systemic metastases, and as many as
½ patients succumb to disease in 10 years
 Minimally invasive carcinoma has 10-year survival rate greater than 90%
o Most treated with total thyroidectomy followed by administration of radioactive iodine (metastases
likely to take up radioactive element, which can be used to identify and ablate such lesions)
 Because any residual carcinoma may respond to TSH stimulation, patients usually treated with
thyroid hormone after surgery to suppress endogenous TSH
 Serum thyroglobulin levels used for monitoring tumor recurrence, since product should be
barely detectable in patient who is free of disease
Anaplastic (undifferentiated) carcinomas – highly aggressive and lethal tumors can arise de novo, or more
commonly be de-differentiation of well-differentiated papillary or follicular carcinoma
o Mortality rate at almost 100%
o Patients are older than those with other types of thyroid cancer, mean age of 65 years
o About ¼ of patients have past history of well-differentiated thyroid carcinoma, and another ¼ harbor
concurrent well-differentiated tumor in resected specimen
o Molecular alterations present in anaplastic carcinomas include those seen in well-differentiated
carcinomas (e.g., RAS or PIK3CA mutations) at significantly higher rate, suggesting presence of mutations
might predispose existing thyroid neoplasms to transform
o Other genetic hits, such as inactivation of p53 or activating mutations of β-catenin essentially restricted
to anaplastic carcinomas and might relate to aggressive behavior
o Microscopically, neoplasms composed of highly anaplastic cells, with variable morphology including
 Large, pleomorphic giant cells, including occasional osteoclast-like multinucleate giant cells
 Spindle cells with sarcomatous appearance
 Mixed spindle and giant cells
o Foci of papillary or follicular differentiation may be present in some tumors
o Neoplastic cells express epithelial markers like cytokeratin, but are usually negative for markers of
thyroid differentiation like thyroglobulin
o Usually present as rapidly enlarging bulky neck mass; in most cases, disease has already spread beyond
thyroid capsule into adjacent neck structures or has metastasized to lungs at time of presentation
o Symptoms related to compression and invasion – dyspnea, dysphagia, hoarseness, and cough
o No effective therapies, and disease almost uniformly fatal
o Although metastases to distant sites common, in most cases, death occurs in less than 1 year as result of
aggressive growth and compromise of vital structures in neck
Medullary thyroid carcinomas – neuroendocrine neoplasms derived from parafollicular cells; secrete calcitonin,
measurement of which plays important role in diagnosis and postoperative follow-up of patients
o Familial carcinomas that occur in multiple endocrine neoplasia type 2 (MEN-2) and are associated with
germline RET proto-oncogene mutations that lead to constitutive activation of receptor
o RET mutations seen in about ½ nonfamilial (sporadic) medullary thyroid cancers
o Chromosomal rearrangements involving RET, such as RET/PTC translocations reported in papillary
cancers, not seen in medullary carcinomas
o In some instances, tumor cells elaborate other polypeptide hormones, such as serotonin, ACTH, and
vasoactive intestinal peptide (VIP)
o 70% of tumors arise sporadically; remainder occurs as MEN syndrome 2A or 2B or as familial tumors
without associated MEN syndrome (FMTC)
 Cases associated with MEN types 2A or 2B occur in younger patients, and may even arise during
first decade of life
 Sporadic and familial carcinomas are lesions of adulthood, with peak incidence in 40s and 50s
Sporadic medullary thyroid carcinomas present as solitary nodule
Bilaterality and multicentricity common in familial cases
Larger lesions often contain areas of necrosis and hemorrhage and may extend through capsule of
thyroid; tumor tissue firm, pale gray to tan, and infiltrative
 May be foci of hemorrhage and necrosis in larger lesiosn
o Microscopically, carcinomas composed of polygonal to spindle-shaped cells, which may form nests,
trabeculae, and follicles
 Small, more anaplastic cells present in some tumors and may be predominant cell type
 Acellular amyloid deposits, derived from altered calcitonin polypeptides, present in adjacent
stroma in many cases
o Calcitonin readily demonstrable within cytoplasm of tumor cells as well as in stromal amyloid by
immunohistochemical methods
 Variable numbers of membrane-bound electron-dense granules within cytoplasm of neoplastic
cells
o One of peculiar features of familial cancers is presence of multicentric C-cell hyperplasia in surrounding
thyroid parenchyma (usually absent in sporadic lesions)
 Presence of multiple prominent clusters of C cells scattered throughout parenchyma should
raise specter of familial tumor, even if history not explicitly present
 Foci of C-cell hyperplasia represent precursor lesions from which medullary carcinomas arise
o Sporadic cases come to medical attention most often as mass in neck, sometimes associated with local
effects such as dysphagia or hoarseness; in some instances, initial manifestations are those of
paraneoplastic syndrome, caused by secretion of peptide hormone (e.g., diarrhea due to secretion of
VIP or Cushing syndrome due to ACTH)
o Hypocalcemia not prominent feature, despite presence of raised calcitonin levels
o In addition to circulating calcitonin, secretion of carcinoembryonic antigen by neoplastic cells is useful
biomarker, especially for presurgical assessment of tumor load and in calcitonin-negative tumors
o Patients with familial syndromes may come to attention because of symptoms localized to thyroid or as
result of endocrine neoplasms in other organs (e.g., adrenal or parathyroid glands)
o Carcinomas arising in context of MEN-2B generally more aggressive and metastasize more frequently
than those occurring in patients with sporadic tumors, MEN-2A, or FMTC
 All asymptomatic MEN-2 kindred carrying germline RET mutations offered prophylactic
thyroidectomy as early as possible to protect against inevitable development of medullary
carcinomas (major risk factor for poor outcome in these families)
o Sometimes only histologic finding in resected thyroid of asymptomatic carriers is presence of C-cell
hyperplasiaor small micromedullary carcinomas
o Several promising small-molecule inhibitors of RET tyrosine kinase recently developed
Congenital Anomalies
 Thyroglossal duct or cyst is most common clinically significant congenital anomaly of thyroid
 Persistent sinus tract may remain as vestigial remnant of tubular development of thyroid gland; parts of tube
may be obliterated, leaving small segments to form cysts
 Occur at any age and might not become evident until adult life
 Mucinous, clear secretions may collect within cysts to form either spherical masses or fusiform swellings;
present in midline of neck anterior to trachea
 Segments of duct and cysts that occur high in neck lined by stratified squamous epithelium, essentially identical
with that covering posterior portion of tongue in region of foramen cecum
 Anomalies that occur in lower neck more proximal to thyroid gland lined by epithelium resembling thyroidal
acinar epithelium
 Characteristically subjacent to lining epithelium, there is intense lymphocytic infiltrate; superimposed infection
may convert lesions into abscess cavities, and rarely, they give rise to cancers
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