Pathology of Thyroid

Thyroid gland
- 30 g, just inferior to the larynx
- Right and left lobes connected by isthmus (in 50% a small pyramidal lobe extends upward from isthmus)
- ↓ T3 & T4 stimulate release of TRH and TSH , ↑ T3 & T4 feed back to suppress the secretion of both TRH and TSH
- TSH binds to TSH receptor on thyroid follicular epithelium, causing activation of G proteins, cAMP-mediated synthesis
and release of T3 & T4
- In the periphery, T3 & T4 interact with the thyroid hormone receptor (TR) to form a hormone receptor complex that
translocates to the nucleus and binds to thyroid response elements (TREs) on target genes to initiate transcription
Structure of thyroid follicles
- Single layer of follicular epithelial cells, Basement membrane, Lumen filled with colloid: Synthesis of thyroid hormones
(T3 & T4)
- Parafollicular (C) cells : Synthesis of calcitonin
- The follicle is the morpho-functional unit of the thyroid gland
Follicular cells: effect of activity
- In inactive gland
o Follicles are large, Lining cells are flattened, Abundant colloid
- In active gland
o Follicles are smaller, Lining cells are increased in size, Colloid is reduced (cells absorb colloid adjacent to their
apical surface)
- Ex. A 47-year-old woman has had increasing fatigue with dyspnea and reduced exercise tolerance for the past year. On examination she has nonpitting edema of the
lower extremities. Laboratory studies show a serum TSH level of 10 mU/L and T4 level of 2 μg/dL. She is most likely to have pathologic findings affecting which of the
following cells? Thyroid follicular cells
o The normal feedback loop of peripheral thyroid hormones (T3 and T4) onto the basophils (thyrotrophs) of the adenohypophysis regulates TSH release (under
tropic control of TRH from the hypothalamus). When patients with primary thyroid failure, the most common cause for hypothyroidism with myxedema in
adults, do not have sufficient residual functioning thyroid follicular cells producing thyroid hormones, then the TSH will rise, as in this case, in conjunction
with a low T4 level.
Functions of thyroid hormone
1. Controls basal metabolic rate
2. Growth and maturation of tissue (Brain)
3. Turnover of hormones and vitamins
4. Cell regeneration
5. Synthesis of low-density lipoprotein (LDL) receptors for LDL (main vehicle for transporting cholesterol)
6. Synthesis of β-adrenergic receptors for catecholamines
Thyroid function tests
Total serum T4 {T4 bound to TBG + free T4 (FT4)}
1. Normal TBG, ↑ FT4/FT3 - Graves disease or Thyroiditis (release of FT4 from colloid in the damaged thyroid)
2. Normal TBG, ↓FT4/FT3 - Hypothyroidism
3. ↓TBG, Normal FT4/FT3 - Anabolic steroids, or nephrotic syndrome with loss of TBG (↓TBG: ↓total serum T4 but FT4 and TSH
remain normal, hence no hypothyroidism)
4. ↑TBG, Normal FT4/FT3 - Woman taking estrogen or during pregnancy (Estrogen: ↑TBG → ↑total serum T4 but not FT4, TSH is normal because FT4 is normal, hence
no hyperthyroidism)

Typical Thyroid hormone levels in Thyroid disease TSH T4 T3

Underfunctioning thyroid Low T4 when TSH is elevated
Hypothyroidism High Low Low
Pituitary problem Low T4 with low TSH
Hyperthyroidism Low High High
123I(radioactive) uptake
- ↑ 123I uptake : ↑synthesis of T4
o Graves disease
o Toxic nodular goiter
- ↓ uptake of 123I indicates inactivity
o Patient taking thyroid hormone → ↓ TSH → ↓ uptake of 123I
o Inflammation interferes with normal function of the gland
- To evaluate functional status of thyroid nodules
o ↓ 123I uptake in a nodule: “Cold” nodule (Cyst, Adenoma, Cancer)
o ↑ 123I uptake in a nodule: “Hot” nodule (Toxic Nodular Goiter)
Lingual thyroid
- Failed descent of thyroid anlage from the base of the tongue
- Usually represents all of the thyroid tissue, usually hypofunctional
- Clinical findings
o Dysphagia for solids, Mass lesion
- 123I scan locates the lesion

- Lingual thyroid- mass lesion at the base of the tongue (white arrow).
- Treatment
o Suppression with thyroxine
o Ablation with radioactive iodine
o Surgery if obstructive
Thyroglossal duct cyst
- Cystic midline mass that is close to or within the hyoid bone
- Moves with deglutition
- Surgery with removal of the proximal duct and a portion of the hyoid bone

Hypothyroidism
- Cretinism (Hypothyroidism in infancy/early childhood)
o Dietary iodine deficiency endemic to certain regions (Himalayas, inland China, Africa)
o Genetic defects that interfere with the biosynthesis of thyroid hormone
o Severe mental retardation, (severity related to time of deficiency) if maternal thyroid deficiency before development of the fetal thyroid gland (starts in 7th
week, produces hormone by 12th week)
 o In congenital hypothyroidism, the child is born normal because during pregnancy, it receives thyroid hormones from the mother (lipid soluble, can cross the
placenta)
o Short stature, ↑ weight, coarse facial features, protruding tongue, umbilical hernia
o Ex. A 2-year-old child has failure to thrive since infancy. Physical examination shows that the child is short and has coarse facial features, a protruding tongue,
and an umbilical hernia. As the child matures, profound intellectual disability becomes apparent. A deficiency of which of the following hormones is most
likely to explain these findings? Thyroxine (T4)
 Cretinism is a condition that is uncommon whenever routine newborn screening is available for testing and treatment at birth for hypothyroidism.
Hypothyroidism that develops in older children and adults is known as myxedema
o Ex. The parents of a 4-week-old girl complain that their baby is apathetic and sluggish. On physical examination, the child’s abdomen is large and exhibits an
umbilical hernia. The skin is pale and cold, and the temperature is 35°C (95°F). Which of the following provides a plausible explanation for the signs and
symptoms of this child? Thyroid agenesis
 Cretinism denotes physical and mental insuffi ciency that is secondary to congenital hypothyroidism. Cretinism may be endemic, sporadic, or
familial and is twice as frequent in girls as in boys. Iodination of salt has reduced the incidence of cretinism in the United States and other
countries. The most common cause of neonatal hypothyroidism today is agenesis of the thyroid, which occurs at a rate of 1 in 4,000 newborns.
Hypothyroidism in pregnant women also has grave neurologic consequences for the fetus, expressed after birth as cretinism. Symptoms of
congenital hypothyroidism appear in the early weeks of life and include sluggishness, a large abdomen often with umbilical herniation, low body
temperature, and refractory anemia. Mental retardation, stunted growth, and characteristic facies become evident. If thyroid hormone
replacement therapy is not promptly provided, congenital hypothyroidism results in mentally retarded dwarfs.
- Myxedema (Hypothyroidism in older child/adults)
o Generalized fatigue, apathy, mental sluggishness (may mimic depression)
o Speech and intellectual functions are slowed (no mental retardation)
o Listlessness, cold intolerance, and overweight
o ↓Sympathetic activity – constipation, ↓sweating, ↓ blood flow – cool/pale skin
o ↓Cardiac output - shortness of breath and decreased exercise capacity
o Atherogenic profile - an increase in total cholesterol and LDL levels
o Accumulation of matrix substances (glycosaminoglycans and hyaluronic acid) in skin/ other sites - Non-pitting edema
o EDEMA caused by accumulation of interstitial substance, NOT WATER (hence non-pitting), swollen puffy face
- Diagnosis of Hypothyroidism
o Patients with unexplained increases in body weight or hypercholesterolemia
o Diastolic hypertension (due to retention of sodium and water)
o Dilated cardiomyopathy with biventricular heart failure
o Muscle weakness common complaint
o Delayed relaxation of deep tendon reflexes (Woltman sign)
o Primary: TSH ↑, Secondary (hypothalamic/pituitary) – TSH not increased
o T4 ↓in individuals with hypothyroidism of any origin
- Hashimoto Thyroiditis
o Autoimmune destruction of thyroid gland with thyroid failure
o Most common cause of hypothyroidism in non-endemic areas, children
o 45 to 65 years of age, HLA-DR3 and HLA-DR5 associations
o Female predominance of 10 : 1 to 20 : 1, 45 to 65 yrs, HLA-DR3 & HLA-DR5
o Breakdown in self-tolerance to thyroid autoantigens, circulating autoantibodies against thyroglobulin and thyroid
peroxidase
o Morphology
 Diffusely enlarged thyroid, cut surface is pale, yellow-tan and firm
 Parenchymal infiltration by small lymphocytes and plasma cells
 Thyroid follicles are atrophic and are lined by Hürthle cells
 Interstitial connective tissue is increased and may be abundant but unlike Reidel thyroiditis, the fibrosis does not extend beyond the capsule of
the gland
o Clinical Course
 Painless enlargement of thyroid + hypothyroidism, middle-aged woman
 Hypothyroidism may be preceded by transient thyrotoxicosis caused by disruption of thyroid follicles,
leading to release of thyroid hormones (“Hashitoxicosis”)
 Risk for developing other autoimmune diseases
 Endocrine (Type 1 diabetes, Autoimmune adrenalitis)
 Non-endocrine (SLE , Myasthenia gravis, and Sjögren syndrome)
 ↑risk for extranodal marginal zone B-cell lymphomas within thyroid
 Possible predisposition to Papillary carcinoma thyroid
o Ex. A 43-year-old woman has had increasing lethargy and weakness over the past 3 years. She has cold intolerance and
wears a sweater in the summer. One year ago, she had menorrhagia, but now she has oligomenorrhea. She has difficulty
concentrating, and her memory is poor. She has chronic constipation. On physical examination, her temperature is
35.5Åã C, pulse is 54/min, respirations are 13/min, and blood pressure is 110/70 mm Hg. She has alopecia, and her skin
appears coarse and dry. Her face, hands, and feet appear puffy, with doughlike skin. Laboratory findings show
hemoglobin, 13.8 g/dL; hematocrit, 41.5%; glucose, 73 mg/dL; and creatinine, 1.1 mg/dL. The representative
microscopic appearance of her causative disease is shown in the figure. Which of the following serologic test findings is
most likely to be positive in this woman? Anti–thyroid peroxidase antibody
 The lymphoid follicles and the large, pink nodules of Hü rthle cells in this photomicrograph are typical for
Hashimoto thyroiditis. The anti–thyroid peroxidase (antimicrosomal) and antithyroglobulin antibody titers
typically are increased in patients with Hashimoto thyroiditis when thyroid enlargement is still present. In
the later, “burnt-out” phase of Hashimoto thyroiditis, the antibodies are sometimes undetectable— only the hypothyroidism is. The thyroid-
stimulating hormone (TSH) level is an indication of whether there is a primary disease in the thyroid. If the patient appears hypothyroid and a
primary thyroid disease (e.g., Hashimoto thyroiditis) is suspected, the TSH level is elevated.
- Subacute Lymphocytic (Painless) Thyroiditis
o Postpartum/Sporadic thyroiditis, mostly middle-aged women
o Circulating anti-thyroid peroxidase antibodies or a family history of other autoimmune disorders
o Lymphocytic infiltration with large germinal centers within the thyroid parenchyma and patchy disruption and collapse of thyroid follicles
o NO Fibrosis or Hürthle cell metaplasia
o Painless and postpartum thyroiditis are variants of autoimmune thyroiditis
 o Ex. A 30-year-old woman has given birth to her second child. She develops heat intolerance and loses more weight than expected postpartum. On physical
examination, her thyroid gland is enlarged but painless; there are no other remarkable findings. Laboratory studies show a serum T4 level of 12 μg/dL and a
TSH level of 0.4 mU/L. A year later she is euthyroid. Which of the following is most indicative of the pathogenesis of this
patient’s disease? Anti–thyroid peroxidase antibodies
 The presence of autoantibodies in the serum in this patient with transient hyperthyroidism would suggest
Hashimoto thyroiditis (“hashitoxicosis”), but the variant called subacute lymphocytic painless thyroiditis may
affect 1 in 20 postpartum women, and a minority progress to hypothyroidism.
o Ex. A 46-year-old woman complains of increasing fatigue and muscle weakness over the past 6 months. She reports an
inability to concentrate at work and speaks with a husky voice. The patient denies drug or alcohol abuse. Physical
examination reveals cold and clammy skin, coarse and brittle hair, boggy face with puffy eyelids, and peripheral edema.
There is no evidence of goiter or exophthalmos. Laboratory studies show reduced serum levels of T3 and T4. Which of the
following is the most likely underlying cause of these signs and symptoms? Autoimmune thyroiditis.
 Hypothyroidism refers to the clinical manifestations of thyroid hormone deficiency. It can be the consequence
of three general processes: (1) defective synthesis of thyroid hormone; (2) inadequate function of thyroid
parenchyma; and (3) inadequate secretion of TSH. Dominant clinical manifestations of hypothyroidism include muscular weakness, peripheral
edema, “myxedema madness,” pallor, and enlarged tongue. Women with hypothyroidism suffer ovulatory failure, progesterone defi ciency, and
irregular and excessive menstrual bleeding. Erectile dysfunction and oligospermia are common symptoms of hypothyroidism in men. Primary
(idiopathic) hypothyroidism is often autoimmune. Three fourths of patients with primary hypothyroidism have circulating antibodies to thyroid
antigens, suggesting that these cases represent the end stage of autoimmune thyroiditis.
- Granulomatous Thyroiditis
o De Quervain thyroiditis, most common cause of thyroid pain
o Women, 40 - 50 years
o Triggered by a viral infection, seasonal incidence
o Aggregates of lymphocytes, activated macrophages, and plasma cells associated with collapsed and damaged thyroid
follicles
o Multinucleate giant cells enclose naked pools or fragments of colloid
o Unlike autoimmune thyroid disease, the immune response is virus-initiated and not self-perpetuating, so the process is
limited
o Ex. A 37-year-old woman has had difficulty swallowing and a feeling of fullness in the anterior neck for the past week. She is recovering from a mild upper
respiratory tract infection 1 month ago. On physical examination, her temperature is 37.4 deg C, pulse is 74/min, respirations are 16/min, and blood pressure
is 122/80 mm Hg. Palpation of her diffusely enlarged thyroid elicits pain. Laboratory studies show an increased serum T4 level and a decreased TSH level. Two
months later, she no longer has these complaints. The T4 level is now normal. Which of the following conditions is most likely to have produced these
findings? Subacute granulomatous thyroiditis
 Subacute granulomatous thyroiditis (de Quervain thyroiditis) is a self-limited condition that can be of viral origin because many cases are
preceded by an upper respiratory infection. The transient hyperthyroidism results from inflammatory destruction of the thyroid follicles and
release of thyroid hormone. The released colloid acts as a foreign body, producing florid granulomatous inflammation in the thyroid.
o Ex. A 43-year-old woman complains of low-grade fever and has a 3-day history of pain in her neck. Physical examination reveals a slightly enlarged thyroid. A
CBC is normal. A biopsy of the thyroid reveals granulomatous infl ammation and the presence of giant cells (shown in the image). What is the appropriate
diagnosis? Subacute (DeQuervain) thyroiditis
- Riedel thyroiditis
o Extensive fibrosis involving thyroid and contiguous neck structures with extension of fibrosis into surrounding tissue
(unlike Hashimoto)
o Hard and fixed thyroid mass (clinically simulates a thyroid carcinoma)
o Associated with fibrosis in other sites (retroperitoneum, mediastinum)
o Treatment: Corticosteroids, Tamoxifen, Surgery
o Ex. A 33-year-old woman complains of swelling in the anterior portion of her neck, which she fi rst noticed 8 months
ago. Except for some discomfort during swallowing and hoarseness, the patient does not report any symptoms.
Physical examination reveals a stony, hard thyroid gland that is adherent to other neck structures. A thyroid biopsy is
shown in the image. The pathologist reports that the thyroid parenchyma is replaced by dense, hyalinized fibrous tissue and a chronic
inflammatory infiltrate. What is the appropriate diagnosis? Riedel thyroiditis

Hyperthyroidism
Thyrotoxicosis - hypermetabolic state caused by ↑free T3 and T4
1. Diffuse hyperplasia of thyroid with Graves disease (85% of cases)
2. Hyperfunctional multinodular goiter
3. Hyperfunctional thyroid adenoma
- Hyperthyroidism
o ↑Basal metabolic rate, heat intolerance, weight loss despite ↑appetite
o Heart: tachycardia, palpitations, cardiomegaly, arrhythmias, CHF
o Overactivity of sympathetic nervous system - tremor, hyperactivity, emotional lability, anxiety, inability to concentrate, and insomnia
o GIT: hypermotility, diarrhea, and malabsorption
o Ocular changes
o Skeletal system: osteoporosis
o Muscle atrophy with fatty infiltration and focal lymphocytic infiltrates
o Minimal hepatomegaly due to fatty changes in the hepatocytes
o Generalized lymphoid hyperplasia and lymphadenopathy
o A person with hyperthyroidism showing wide-eyed, staring gaze, caused by overactivity of the sympathetic nervous system
o In Graves disease, accumulation of loose connective tissue behind the eyeballs adds to the protuberant appearance of the eyes
o Ex. A 65-year-old woman with a history of multinodular goiter complains of increasing nervousness, insomnia, and heart palpitations. She has lost 9 kg (20 lb)
over the past 6 months. Physical examination reveals a diffusely enlarged thyroid. There is no evidence of exophthalmos. Laboratory studies show elevated
serum levels of T3 and T4. Serologic tests for antithyroid antibodies are negative. Which of the following is an important complication of this patient’s
endocrinopathy? Cardiac arrhythmia
- Thyroid Storm
o Abrupt onset of severe hyperthyroidism
o Patients with underlying Graves disease
o Acute elevation in catecholamine levels, during infection, surgery, cessation of antithyroid medication, or any form of stress
o Patients - febrile , tachycardia out of proportion to the fever
o Medical emergency - significant number of untreated patients die of cardiac arrhythmias
o Ex. A 42-year-old woman has a sudden onset of fever with headache, nausea, diaphoresis, and palpitations. On physical examination her temperature is
39.2Åã C; pulse, 115/min; irregular respiratory rate, 30/min; and blood pressure, 150/85 mm Hg. Deep tendon reflexes are 4+ bilaterally. Her outstretched
hands exhibit a high frequency tremor. Which of the following drugs should she receive emergently? Propranolol
  Thyroid storm is a medical emergency. There is not enough time to wait for confirmatory laboratory thyroid testing. There are increased
catecholamine levels, and the β-blocker propranolol will help prevent emergent
death from cardiac failure.
- Apathetic hyperthyroidism
o Thyrotoxicosis occurring in older adults
o Advanced age and co-morbidities blunt the features of hyperthyroidism
o Diagnosis made during laboratory work-up for unexplained weight loss or worsening cardiovascular disease
- Diagnosis of hyperthyroidism
o Primary Hyperthyroidism: ↓ TSH, ↑ free T3 &T4
o Secondary Hyperthyroidism: pituitary associated, TSH may be ↑
o TRH stimulation test - to evaluate cases of suspected hyperthyroidism with equivocal changes in the baseline serum TSH level (Normal rise in TSH after
administration of TRH excludes secondary hyperthyroidism)
o Measurement of radioactive iodine uptake by the thyroid gland
 Graves disease: diffusely increased uptake in the whole gland
 Toxic adenoma: increased uptake in a solitary nodule
 Thyroiditis: decreased uptake
o TSH is usually not stimulated by TRH in TSH-omas
- Management of hyperthyroidism
o β-blocker to control symptoms induced by ↑ adrenergic tone
o Thionamide to block new hormone synthesis
o Iodine solution to block the release of thyroid hormone
o Agents that inhibit peripheral conversion of T4 to T3
o Radioiodine, incorporated into thyroid tissues, results in ablation of thyroid function over a period of 6 to 18 weeks
- Graves Disease
o Triad of findings
 Hyperthyroidism associated with diffuse enlargement of the gland
 Infiltrative ophthalmopathy with resultant exophthalmos
 Localized, infiltrative dermopathy, pretibial myxedema, in fewpatients
o More often in women, 20 to 40 years of age
o Autoantibodies against multiple thyroid proteins (TSH receptor)
 Thyroid stimulating immunoglobulin (TSI) in 90% of patients
o A: The patient has exophthalmos and a diffuse enlargement of the thyroid gland (goiter)
o B: Severe exophthalmos - proptosis of the eye, increased vascularity of the conjunctiva, and the enlarged lacrimal gland
o C: Pretibial myxedema (thickened area of erythema involving the pretibial area and dorsum of the foot)
o Infiltrative ophthalmopathy
 Protrusion of the eyeball (Exophthalmos) is associated with ↑volume of the retro-orbital connective tissues and extraocular
muscles
 Marked infiltration of the retro-orbital space by mononuclear cells, mainly T cells
 Inflammation with edema and swelling of extraocular muscles
 Accumulation of ECM components, specifically hydrophilic glycosaminoglycans (hyaluronic acid and chondroitin
sulfate)
 ↑numbers of adipocytes (fatty infiltration)
 Studies performed in animal models suggest that orbital preadipocyte fibroblasts, which express the TSH receptor, appear to stimulate the
autoimmune reaction
o Morphology
 Symmetric enlargement
 Parenchyma has a soft, meaty appearance resembling muscle
 Untreated cases
 Follicular epithelial cells are taller and more crowded
 Small papillae lacking fibrovascular cores encroaching on the colloid
 Colloid within the follicular lumen is pale, with scalloped margins
 Diffusely hyperplastic thyroid in Graves disease showing follicles lined by tall, columnar epithelium. The
crowded, enlarged epithelial cells project into the lumens of the follicles. These cells actively resorb the
colloid in the centers of the follicles, resulting in the scalloped appearance of the edges of the colloid
o Morphology after treatment
 After administration of iodine: involution of epithelium and accumulation of colloid (blocks thyroglobulin
secretion)
 Treatment with the anti-thyroid drug propylthiouracil: exaggerates epithelial hypertrophy and hyperplasia (stimulates TSH secretion)
 Changes in other organs
 Enlargement of the thymus in younger patients
 Hypertrophy of heart
 Hydrophilic mucopolysaccharide deposition in the tissues of the orbit
 Deposition of glycosaminoglycans and lymphocyte infiltration in dermis
o Clinical course
 Thyrotoxicosis
 Diffuse hyperplasia of the thyroid: audible “bruit”
 Ophthalmopathy: wide, staring gaze and lid lag
 Dermopathy: most common in the skin overlying the shins
 Cardiac findings: Atrial fibrillation, Sinus tachycardia, Systolic HTN, High output failure
 ↑glucose, calcium, lymphocytes; ↓cholesterol
 ↑free T4 and T3 levels and ↓TSH levels
 Radioiodine scans - diffusely increased uptake of iodine
 Treatment: β-blockers, thionamides, radioiodine ablation, thyroidectomy and surgery
o Ex. A 20-year-old woman and her twin sister both experience increasing diplopia. Their conditions develop within 3 years of each other. On physical
examination, they have exophthalmos and weak extraocular muscle movement. The thyroid gland is diffusely enlarged but painless in each sister, and there is
no lymphadenopathy in either woman. Which of the following serum laboratory findings is most likely to be reported in these sisters? Decreased thyroid-
stimulating hormone level
 Exophthalmos is a feature seen in about 40% of individuals with Graves disease. The hyperfunctioning thyroid gland leads to an increased T4 level,
with positive feedback from the pituitary to decrease thyroid-stimulating hormone (TSH) secretion. There is about 50% concordance of Graves
disease among identical twins. The autoimmune character of this disorder is evidenced by an association with HLA-DR3 and by the presence of an
autoantibody against TSH receptor that activates T4 secretion.
 o Ex. A 21-year-old woman has noted increasing fatigue and a 7-kg weight loss without dieting over the past 4 months. She also has increasing anxiety and
nervousness with diarrhea. Physical examination shows a diffusely enlarged thyroid gland. Her temperature is 37.5 deg C, pulse is 103/min, respirations are
28/min, and blood pressure is 140/75 mmHg. A radionuclide scan of the thyroid shows a diffuse increase in uptake.
The figure shows the representative microscopic appearance of the thyroid gland. What is most likely to produce these
findings? Antibodies against TSH receptor
 The tall columnar epithelium with papillary infoldings and scalloping of the colloid is characteristic of
Graves disease, which leads to hyperthyroidism. This disease is caused by autoantibodies that bind to the
thyroid-stimulating hormone (TSH) receptor and mimic the action of TSH.
o Ex. A 40-year-old man notes weight loss, increased appetite, and double vision for 6 months. On physical examination,
his temperature is 37.7deg C, pulse is 106/min, respirations are 20/min, and blood pressure is 140/80 mm Hg. A fine
tremor is observed in his outstretched hands. He has bilateral proptosis and corneal ulceration. Laboratory findings
include a serum TSH level of 0.1 mU/L. A radioiodine scan indicates increased diffuse uptake throughout the thyroid.
He receives propylthiouracil therapy, and his condition improves. Which of the following best describes the
microscopic appearance of his thyroid gland before therapy? Papillary projections in thyroid follicles and lymphoid aggregates in the stroma
 The clinical findings in this case point to hyperthyroidism, and the increased, diffuse uptake corroborates Graves disease as a probable cause
because the thyroidstimulating hormone (TSH) level is quite low. The thyroidstimulating immunoglobulins that appear in this autoimmune
condition result in diffuse thyroid enlargement and hyperfunction, and papillary projections lined by tall columnar epithelial cells.
 Differential: Destruction of thyroid follicles with lymphoid aggregates and Hürthle cell metaplasia is characteristic of Hashimoto thyroiditis. A
goiter has enlarged follicles and flattened epithelial cells; most of these patients are euthyroid. Follicular destruction and the presence of giant
cells occur in granulomatous thyroiditis. Nests of cells in a Congo red–positive hyaline stroma characterize a medullary carcinoma, which can be
multifocal, but is not diffuse and
does not lead to hyperthyroidism.
o Ex. A 55-year-old man complains of severe muscle weakness and drooping eyelids. He states that his symptoms worsen with repetitive movements but then
resolve after a short rest. A chest X-ray reveals an anterior mediastinal mass. A biopsy of this mass would most likely reveal which of the following pathologic
changes? Thymic hyperplasia
 Myasthenia gravis is an acquired autoimmune disease characterized by abnormal muscular fatigability and is caused by circulating antibodies to
the acetylcholine receptor at the myoneural junction. In two thirds of patients, thymic hyperplasia is closely associated with myasthenia gravis,
and 15% have thymoma. Conversely, one third to one half of patients with thymoma develop myasthenia gravis. Thymectomy is often an effective
treatment for
these patients.
o Ex. A 29-year-old woman complains of nervousness and muscle weakness of 6 months in duration. She is intolerant of
heat and sweats excessively. She has lost 9 kg (20 lb) pounds over the past 6 months, despite increased caloric intake.
She frequently finds her heart racing and can feel it pounding in her chest. She also states that she has missed several
menstrual periods over the past few months. Physical examination reveals warm and moist skin and bulging eyes
(exophthalmos). Laboratory studies will likely reveal which of the following endocrine abnormalities in this patient? Anti-
TSH receptor antibodies
 Ex. A thyroid biopsy obtained from the patient described in Question above is shown in the image. Which of
the following best describes the pathologic findings? Follicular hyperplasia with scalloping of colloid
o Ex. A 33-year-old woman presents with a swelling in her neck, which she fi rst noticed 2 months ago. Physical
examination reveals a solitary, nontender nodule of the thyroid gland measuring 2 cm in diameter. Thyroid function tests
are within normal limits. The nodule does not accumulate 125Iodine on thyroid scintiscan. A biopsy of the nodule is
shown in the
image. Which of the following is the most likely diagnosis? Follicular adenoma

Goiters
- Diffuse and Multinodular Goiters
o Goiter: enlargement of the thyroid due to impaired synthesis of thyroid hormone, mostly due to dietary iodine deficiency
o Impaired thyroid hormone synthesis  compensatory rise in serum TSH hypertrophy & hyperplasia of thyroid follicular cells Gross enlargement
o Compensatory increase in functional mass  Euthyroid state
o If iodine deficiency is severe  Goitrous hypothyroidism
- Diffuse Nontoxic (Simple) Goiter
o Colloid goitre, enlargement of the entire gland, NO nodularity
o Endemic goiter
 Geographic distribution (mountainous regions)
 Variations in prevalence suggest role of Goitrogens (Brassicaseae family – cabbage, cassava)
o Sporadic goiter
 Female preponderance, puberty/young adults
 Ingestion of substances that interfere with thyroid hormone synthesis
 Hereditary enzymatic defects (dyshormonogenetic goiter)
 In most cases, the cause is not apparent
o Cassava contains a thiocyanate that inhibits iodide transport within the thyroid, worsening any possible concurrent iodine deficiency
o Ex. A 45-year-old woman from Kathmandu, Nepal, reports a feeling of fullness in her neck, but has no other concerns. The enlargement has been gradual and
painless for more than 1 year. Physical examination confirms diffuse enlargement of the thyroid gland without any apparent masses or lymphadenopathy.
Laboratory studies of thyroid function show a normal free T4 level and a slightly increased TSH level. What is the most likely cause of these findings? Diffuse
nontoxic goiter
 Diffuse nontoxic goiter is most often caused by dietary iodine deficiency. This condition is endemic in regions of the world where there is a
deficiency of iodine (e.g., inland mountainous areas); it also may occur sporadically. As in this case, patients are typically euthyroid.
 Differential: A follicular adenoma rarely functions to produce excess thyroid hormone; most are “cold,” nonfunctioning nodules that do not
involve the thyroid diffusely. A chronic lymphocytic thyroiditis, such as Hashimoto thyroiditis, initially can produce
thyroid enlargement, but atrophy eventually occurs with resulting hypothyroidism. Papillary carcinomas most often
produce a mass effect or metastases and do not affect thyroid function. Subacute granulomatous thyroiditis can lead
to diffuse enlargement, and transient hyperthyroidism can occur, but the disease typically runs a course of no more
than 6 to 8 weeks. Plummer disease, or toxic multinodular goiter, occurs when there is a hyperfunctioning nodule in
a goiter.
o Ex. A 14-year-old girl noticed gradual neck enlargement during the past 8 months. On physical examination her thyroid gland is
diffusely enlarged. Her serum TSH level is normal. A dietary history is most likely to reveal that she has begun eating more of
which of the following foods? Cabbage
 She has developed a sporadic goiter. Vegetables of the Brassicaceae family, including cabbage, turnips, and Brussels
sprouts, contain glucosinolate, which can decompose to release thiocyanate, a by product that interferes with
thyroid hormone synthesis. Thus such substances are known as goitrogens. Young persons with increased demand
for thyroid hormone are at increased risk.
 o Ex. A 55-year-old woman presents with a large anterior neck mass (patient shown in the image). She also complains of dysphagia and hoarseness. Physical
examination reveals inspiratorystridor. Laboratory evaluation of this patient would most likely demonstrate which of the following? Euthyroidism
o Ex. A 52-year-old woman complains of swelling in the anterior portion of her neck, which she first noticed 6 months ago. Except for some discomfort during
swallowing, the patient does not report any significant symptoms. Physical examination reveals a symmetrically enlarged thyroid. A thyroid biopsy is shown in
the image. Which of the following is the most likely diagnosis? Nontoxic goiter
o Ex. Five years later, the patient described in Question 30 returns with symptoms of hyperthyroidism. Which of the following best summarizes the clinical
symptoms expected in this patient? Tremor, tachycardia, weight loss
- Goiter
o Enlarged thyroid
 Does not indicate functional status of gland - may be associated with hypo, hyper or euthyroidism
 Low dietary intake of iodine leads to less production of thyroid hormone – stimulates release of TSH –
leads to thyroid enlargement
 ENDEMIC GOITER: in restricted geographical regions where natural iodine supply is low
- Multinodular Goiter
o Recurrent episodes of hyperplasia and involution
o Extreme thyroid enlargements
o Frequently mistaken for neoplasms
o Intrathoracic or plunging goiter - grows behind sternum and clavicles
o Morphology
 C/s: Irregular nodules containing variable amounts of colloid
 Older lesions show hemorrhage, fibrosis, calcification, and cystic
change
 Microscopic appearance
 Colloid-rich follicles lined by flattened, inactive epithelium
 Areas of follicular hyperplasia with degenerative changes
 No capsule between the hyperplastic nodules and residual compressed thyroid parenchyma (unlike follicular neoplasms)
o A: Gross morphology demonstrating a coarsely nodular gland, containing areas of fibrosis and cystic change
o B: Photomicrograph of a hyperplastic nodule, with compressed residual thyroid parenchyma on the periphery. There is no capsule (distinguishing feature
from follicular neoplasms)
o Clinical Course
 Mostly euthyroid
 Mass effects from enlarged thyroid
 Hemorrhage into cysts produces sudden, painful, gland enlargement
 Pemberton sign: compression of the jugular vein causing neck congestion
 T3 and T4 levels are normal, TSH is usually elevated or upper normal
 Plummer syndrome: an autonomous nodule develops within a long-standing goiter and produces hyperthyroidism (toxic multinodular goiter)
 Dyshormonogenetic goiter In children may induce cretinism
o Ex. A 70-year-old man has had greater difficulty swallowing for the past 2 years. Over the past 6 months, he has lost 3 kg. On physical examination, his
temperature is 37.3 deg C, and pulse is 102/min. There is fullness to the anterior neck, with a 5 Å~ 10 cm irregular mass on palpation. Laboratory studies show
serum TSH of 0.2 mU/L. A thyroid scintigraphic scan shows a 1.5-cm nodule with increased uptake in the right thyroid lobe, and decreased uptake into the
remaining enlarged thyroid. What is the most likely diagnosis? Toxic multinodular goiter
 A long-standing diffuse goiter can evolve into a multinodular goiter, and one of the nodules can begin hyperfunctioning to cause so-called
Plummer disease. This “toxic” nodule has acquired growth and functional characteristics similar to a benign neoplasm, such as a follicular
adenoma, but one that is functional.
 Differential: Rare toxic follicular adenomas can function and produce “hot” nodules, but the remaining gland is often atrophic, not enlarged. In
Graves disease, the thyroid is enlarged, but usually diffusely, without pronounced nodularity, so that there is increased uptake into the entire
gland. In addition, clinical features such as dermopathy and ophthalmopathy that are lacking with Plummer disease are associated with Graves
disease. There may be initial diffuse thyroid enlargement with Hashimoto thyroiditis and transient hyperfunction, but over time the thyroid
atrophies, and hypothyroidism ensues. It is extremely rare for a papillary carcinoma to function, and although this would be a hot nodule,
the remaining thyroid would not be enlarged.
- Euthyroid sick syndrome (ESS)
o Serum T3 and T4 are abnormal but gland function appears normal
o Associated with: malignancy, heart failure, anorexia nervosa, chronic renal failure, sepsis, myocardial infarction
o Pathogenesis: block in outer ring deiodinase conversion of FT4 to FT3; FT4 is converted to inactive reverse T3

Neoplasms of the Thyroid

- Solitary nodule of thyroid
o A dominant nodule in multinodular goiter
o Simple cyst
o Foci of thyroiditis
o Benign neoplasm
o Malignant neoplasm
 Solitary nodules, in younger patients and males - more likely to be neoplastic
 A history of radiation treatment to head and neck: ↑ malignancy
 Functional nodules that take up radioactive iodine in imaging studies (hot nodules) - more likely to be benign
 Morphology of nodule by fine-needle aspiration and surgical resection, provides the most definitive information
 Benign neoplasms outnumber thyroid carcinomas by a ratio of nearly 10 : 1
o Ex. A 38-year-old woman felt a small bump on the right side of her neck 1 month ago, and it has not changed since then. Physical examination shows a 1-cm
painless nodule palpable in the right lower pole of the thyroid gland. There is no lymphadenopathy. Radionuclide scanning shows that the nodule does not
absorb radioactive iodine, and no other nodules are present. A fine-needle aspiration biopsy of the nodule is done, and the cytologic features are those of a
follicular neoplasm. Which of the following laboratory findings is most likely to be present in this patient? Normal TSH
 Solitary “cold” and solid (not cystic) thyroid nodules are likely to be neoplastic, and most are benign follicular adenomas that do not affect thyroid
function. If the nodule was hyperfunctioning, and produced hyperthyroidism, it would appear “hot” on the scan, and suppress thyroid-stimulating
hormone (TSH).
- Adenomas
o Discrete, solitary masses, derived from follicular epithelium
o Difficult to distinguish from dominant nodules of follicular hyperplasia or follicular carcinomas
o Mostly nonfunctional (cold nodule)
 <20% of nonfunctioning follicular adenomas have mutations of RAS or PIK3CA
o Hormone production in functional adenomas (“toxic adenomas”) is independent of TSH stimulation
 Somatic mutations of the TSH receptor signaling pathway
  Gene encoding the TSH receptor (TSHR) or the α-subunit of Gs (GNAS)
o Morphology
 Gross:
 Solitary, spherical, encapsulated lesion demarcated from surrounding thyroid parenchyma by a well-defined, intact capsule
 C/S:
 Gray-white to red-brown, depending on the cellularity and colloid content
 Areas of hemorrhage, fibrosis, calcification, and cystic change
 Microscopic:
 Uniform appearing follicles that contain colloid
 Intact, well-formed capsule encircling the tumor
 Multinodular goiters contain multiple nodules even in patients presenting clinically with a solitary dominant
nodule
 A: A solitary, well circumscribed nodule is seen
 B: The photomicrograph shows well differentiated follicles resembling normal thyroid parenchyma
 In follicular adenomas, a fibrous capsule, usually thin but occasionally more prominent, circumferentially
surrounds the neoplastic follicles and no capsular invasion is seen (arrows); compressed normal thyroid parenchyma is usually present external to
the capsule (top of the panel)
 Hürthle cell (oxyphil) adenoma - composed of cells with abundant eosinophilic cytoplasm and small
regular nuclei
o Clinical features
 Mostly unilateral painless masses discovered during a routine physical examination
 Larger masses - local symptoms (difficulty in swallowing)
 Nonfunctioning adenomas take up less radioactive iodine - “cold nodules”
 Definitive diagnosis of adenomas can be made only after careful histologic examination of the resected
specimen to evaluate capsular integrity
 Suspected adenomas of thyroid are removed surgically to exclude malignancy
 Do not recur or metastasize and have an excellent prognosis
 Ex. A 30-year-old woman has a 6-month history of weight loss (3 kg), hand tremors, mild watery diarrhea, and heat intolerance. On physical
examination, vital signs are temperature, 37.3 deg C; pulse, 103/min with sinus rhythm; respirations, 20/ min; and blood pressure, 125/85 mm Hg.
She has a 1-cm firm, painless nodule palpable on the left side of her neck. There is no lymphadenopathy. No other abnormal findings are noted.
Laboratory findings include a total serum T4 of 11.6 μg/dL with TSH of 0.2 mU/L. A scintigraphic scan shows more uptake of radioactive iodine into
the nodule than the surrounding thyroid. A partial thyroidectomy is performed, and microscopic examination of the excised nodule shows
welldifferentiated thyroid follicles without vascular or capsular invasion. Molecular analysis of this nodule is most likely to reveal which of the
following genetic changes? Gain of function mutation of TSH receptor gene
 A thyroid nodule that is well differentiated, noninvasive, and hyperfunctioning suggests a “toxic” follicular adenoma, and a large
proportion of these adenomas have activating mutations of the thyroid-stimulating hormone (TSH) receptor–signaling pathway
involving the TSH receptor or associated G protein.
 Differential: Mutation of the GNAS1 gene is seen in McCune-Albright syndrome and some pituitary adenomas. A PAX8-PPARG fusion
gene is found in certain follicular carcinomas of the thyroid. Activation of the RET gene occurs in papillary thyroid carcinomas.
Overexpression of the cyclin D1 gene (CCND1) is characteristic of parathyroid adenomas. The AIRE gene regulates expression of self-
antigens in the thymus, and mutation in this gene causes autoimmune polyendocrinopathy affecting adrenals, parathyroids, gonads,
and gastric parietal cells with destruction of these tissues and consequent hypofunction.
Carcinomas of thyroid
- Papillary carcinoma (>85% of cases)
- Follicular carcinoma (5% to 15% of cases)
- Anaplastic (undifferentiated) carcinoma (<5%)
- Medullary carcinoma (5% of cases)
- Most thyroid carcinomas (except medullary) are derived from the
thyroid follicular epithelium
- Environmental factors
o Exposure to ionizing radiation
 Particularly in first 2 decades of life
 ↑Incidence of papillary carcinomas among
children exposed to ionizing radiation after the
Chernobyl nuclear disaster in 1986
o Deficiency of dietary iodine
 Higher frequency of follicular carcinomas
- Papillary Carcinoma
o Most common thyroid cancer- 85%
o 25 to 50 years
o Associated with previous exposure to ionizing radiation
o Gross
 Solitary or multifocal
 Well circumscribed to infiltrating
 Areas of fibrosis and calcification and are often cystic
o C/S: Papillary foci may be seen
o The diagnosis of papillary carcinoma has increased markedly in the last 30 years, partly
because of the recognition of follicular variants that were misclassified in the past
o Microscopic features
 True branching papillae (fibrovascular stalk covered by a single to multiple
layers of cuboidal epithelial cells)
 Nuclear features:
 Ground glass or “Orphan Annie eye nuclei” - the nuclei of
papillary carcinoma cells contain finely dispersed chromatin,
imparting an optically clear or empty appearance
 “Pseudo-inclusions” - invaginations of the cytoplasm
 Intra-nuclear grooves
 Psammoma bodies - concentrically calcified structures within the papillae
  The diagnosis of papillary carcinoma can be made based on thenuclear features, even in the absence of
papillary architecture
 A: Macroscopic appearance of a papillary carcinoma with grossly discernible papillary structures
 B: Well-formed papillae
 C: High power shows cells with characteristic empty-appearing nuclei, sometimes called “Orphan Annie
eye”nuclei”
 D: Cells obtained by fine-needle aspiration of a papillary carcinoma showing characteristic intranuclear
inclusions in some of the aspirated cells
o Ex. A 44-year-old, otherwise healthy woman feels a small lump on the left side of her neck. A firm, painless, 1.5-cm cervical
lymph node is palpable. The thyroid gland is not enlarged. A chest radiograph is unremarkable. Laboratory findings include serum glucose, 83 mg/dL;
creatinine, 1.2 mg/ dL; calcium, 9.1 mg/dL; phosphorus, 3.3 mg/dL; thyroxine, 8.7 μg/dL; and TSH, 2.3 mU/L. The hemoglobin is 14 g/dL, platelet count is
240,400/mm3, and WBC count is 5830/mm3. A fine-needle aspiration biopsy of the thyroid gland is done. What is
the most likely diagnosis? Papillary carcinoma
 Papillary thyroid carcinomas may present initially with metastases, and local lymph nodes are the most
common sites for metastases. The primary site may not be detectable as a palpable nodule. Papillary
carcinoma is the most common thyroid malignancy.
o Ex. A 45-year-old man has felt a lump on the left side of his neck for 4 months. Physical examination shows a
nontender nodule on the left lobe of the thyroid gland. An adjacent cervical lymph node is enlarged and nontender.
Laboratory studies show no thyroid autoantibodies in his serum, and the T4 and TSH levels are normal. A
thyroidectomy is performed; the figure shows the microscopic appearance of the nodule. Which of the following
etiologic factors is most likely to be involved in the pathogenesis of the thyroid nodule in this patient? RET gene
mutation
o Ex. A 32-year-old woman presents with a solitary, nontender, firm nodule on the left side of her neck. Thyroid function tests are within normal limits. A fi ne-
needle biopsy reveals malignant cells. The tumor is excised and examined by light microscopy (shown in the image). What is the appropriate pathologic
diagnosis? Papillary carcinoma
- Follicular variant of papillary carcinoma
o Characteristic nuclear features of papillary carcinoma and an almost totally follicular architecture
o Either encapsulated or poorly circumscribed and infiltrative
o ↓RET/PTC rearrangements, ↓BRAF mutations, ↑RAS mutations
- Other variants of papillary carcinoma
o Tall-cell variant
 Older individuals
 Tall columnar cells with intensely eosinophilic cytoplasm lining the papillae
 Higher frequencies of vascular invasion, extrathyroidal extension, metastases
 BRAF mutations in most (55 to 100%) cases, also RET/PTC translocations
o Diffuse sclerosing variant of papillary carcinoma
 Younger individuals, including children
 Papillae intermixed with solid areas containing nests of squamous metaplasia
 Extensive, diffuse fibrosis and prominent lymphocytic infiltrate
 Lymph node metastases are present in almost all cases
 Lack BRAF mutations, but RET/PTC translocations are found in 50% of cases
o Papillary micro-carcinoma
 Conventional papillary carcinoma <1 cm in size
 Incidental finding in patients undergoing surgery
o Clinical course
 Asymptomatic thyroid nodules
 Mass in cervical lymph node
 Mostly single nodules that move freely with deglutition
 Cold masses on scintiscans
 Fine-needle aspiration cytology a reliable test
 10-year survival rate in excess of 95%
- Follicular Carcinoma
o More frequent in areas with dietary iodine deficiency (25 to 40%)
o More common in women (3 : 1)
o Older patients (40 to 60 years of age)
o Single nodules, well circumscribed or widely infiltrative
o C/S : gray to tan to pink, somewhat translucent due to the presence of large, colloid-filled follicles. Degenerative changes - fibrosis ,calcification
o Overall follicular carcinomas account for only 5% to 15% of primary thyroid cancers
o Microscopic features
 Uniform cells forming small follicles containing colloid to poorly differentiated
 Differences from papillary carcinoma
 No nuclear features, no psammoma bodies
 Lymphatic spread is uncommon in follicular cancers
 Minimally invasive follicular carcinoma v/s Follicular Adenoma
 Extensive histologic sampling of the tumor-capsule-thyroid interface to exclude capsular and/or vascular invasion
 Widely invasive follicular carcinomas
 Infiltrate the thyroid parenchyma and extrathyroidal soft tissues
 ↑Solid or trabecular growth pattern, ↓follicular differentiation, and ↑ mitotic activity
 The criterion for vascular invasion is applicable only to capsular vessels and vascular spaces beyond the capsule; the presence of tumor plugs
within intra-tumoral blood vessels has little prognostic significance
o Clinical course
 Slowly enlarging painless nodules, mostly cold nodules on scintigrams
 Hematogenous dissemination is common, metastases to bone, lungs, liver
 Minimally invasive follicular carcinomas: 10-year survival rate > 90%
 Widely invasive: 50% die within 10 years
 Total thyroidectomy
 Followed by the administration of radioactive iodine (to identify metastases and to ablate such lesions)
 Post operative treatment with thyroid hormone to suppress endogenous TSH
 Serum thyroglobulin levels to monitor tumor recurrence (should be barely detectable in a patient who is free of disease)
 o Ex. A 62-year-old woman has felt a lump on the right side of her neck for 5 months. On physical examination, she has no palpable lymphadenopathy. A fine-
needle aspiration biopsy is done, and she undergoes a thyroidectomy. A 3-cm solid mass within the right thyroid lobe has the microscopic appearance shown
in the figure. Six months later, she has pain in the right thigh. A radiograph shows a fracture of the right femur in an area of lytic bone destruction. A
radioiodine scan shows uptake localized to the region of the fracture. Which of the following is the most likely diagnosis? Follicular carcinoma
o Ex. A 45-year-old man presents with swelling in the anterior portion of his neck. Physical examination reveals an
enlarged nodular thyroid. Thyroid function tests are within normal limits. A thyroid scintiscan shows a dominant
“hot” nodule. A biopsy of this nodule reveals neoplastic cells with evidence of vascular and capsular invasion
(shown in the image). X-rays demonstrate distant bony metastases. What is the most likely diagnosis? Follicular
carcinoma
- Anaplastic (Undifferentiated) Carcinoma
o Aggressive, mortality rate approaching 100
o Older patients , mean age of 65 years
o 1/4th - past history of a well-differentiated thyroid carcinoma
o 1/4th - harbor a concurrent well-differentiated tumor in resected specimen
o Highly anaplastic cells
 Large, pleomorphic giant cells, including osteoclast-like multinucleate giant cells
 Spindle cells with a sarcomatous appearance
 Mixed spindle and giant cells
o Express epithelial markers (cytokeratin), negative for markers of thyroid differentiation (thyroglobulin)
o No effective therapies, and the disease is almost uniformly fatal
o Ex. A 44-year-old man with no previous illnesses has been bothered by progressive hoarseness, shortness of breath, and stridor for the past 3 weeks. On
physical examination, he has a firm, large, tender mass involving the entire right thyroid lobe. CT scan shows extension of this mass posterior to the trachea
and into the upper mediastinum. A fine-needle aspiration biopsy of the mass is done, and microscopically shows pleomorphic spindle cells. The mass is noted
at surgery to have infiltrated the adjacent skeletal muscle. Four of seven cervical lymph nodes have metastases. Pulmonary metastases also are identified on a
chest radiograph. Which of the following neoplasms is most likely to be present in this man? Anaplastic carcinoma
- Medullary Carcinoma
o Neuroendocrine neoplasms derived from parafollicular ‘C’ cells of thyroid
o Secretes calcitonin (useful in diagnosis/postoperative follow-up of patients)
 Also Serotonin, ACTH, and vasoactive intestinal peptide
o 70% Sporadic
o 30%
 MEN syndrome 2A or 2B (younger patients)
 Familial tumors without an associated MEN syndrome (Familial Medullary Thyroid Carcinoma) – 40 to 50 years of age
o Activating point mutations in the RET proto-oncogene
o Morphology
 Sporadic medullary thyroid carcinomas - solitary nodule
 Familial - bilateral and multicentric
 C/S:
 Firm, pale gray to tan, and infiltrative
 Hemorrhage and necrosis in the larger lesions
 Microscopic
 Polygonal to spindle-shaped cells, forming nests, trabeculae, and follicles
 Small, more anaplastic cells in some tumors
 Acellular amyloid deposits derived from calcitonin polypeptides
 EM: variable numbers of membrane-bound electron-dense granules within the cytoplasm of the neoplastic cells
 One of the features of familial medullary cancers is the presence of multicentric C-cell hyperplasia in the surrounding thyroid parenchyma, a
feature that is usually absent in sporadic lesions, and that is believed to be a precursor lesion in familial cases
o Clinical Course
 Sporadic cases
 Mass in the neck, sometimes associated with dysphagia or hoarseness
 Paraneoplastic syndrome (VIP –diarrhea, ACTH - Cushing syndrome)
 Hypocalcemia is not a prominent feature
 CEA is a useful biomarker (presurgical assessment of tumor load and in calcitonin-negative tumors)
 Familial syndromes
 Symptoms localized to thyroid or due to other endocrine neoplasms
 MEN-2B: generally more aggressive and metastasize more
 Asymptomatic MEN-2 patients carrying germline RET mutations are offered prophylactic thyroidectomy
o Ex. A 42-year-old woman has noted increasing fullness in her neck for the past 7 months. On physical examination, her thyroid gland is diffusely and
asymmetrically enlarged and nodular. There is no lymphadenopathy. She undergoes thyroidectomy. Gross examination of the thyroid shows a multicentric
thyroid neoplasm; microscopically, the neoplasm is composed of polygonal- to spindle-shaped cells forming nests and trabeculae. There is a prominent, pink
hyaline stroma that stains positively with Congo red. Electron microscopy shows varying numbers of intracytoplasmic, membrane-bound, electron-dense
granules. Immunohistochemical staining for which of the following antigens is most useful for diagnosis of this neoplasm? Calcitonin
 Medullary carcinomas are derived from the C cells, or parafollicular cells, of the thyroid, with embryologic origin from neural crest. Therefore they
have neuroendocrine function, including synthesis of calcitonin. An amyloid stroma is a common
feature of this tumor. These tumors occur sporadically in about 70% of cases, but they can be
familial and part
of multiple endocrine neoplasia types 2A and 2B.
o Ex. A 36-year-old woman presents with swelling in her neck that she first noticed 3 months ago. She also
complains of intermittent watery diarrhea over the same time period. Physical examination reveals a
nontender nodule in the left lobe of the thyroid. The patient’s mother died of thyroid cancer 8 years ago. The
thyroid nodule is found to be “cold” by radioiodine scintiscan. A needle biopsy of the nodule reveals malignant
cells and homogeneous eosinophilic material (shown in the image). Laboratory studies would likely show
elevated blood levels of which of the following hormones in this patient? Calcitonin
o Ex. The tumor in the patient described in Question 38 is removed, and a section stained with Congo red reveals
birefringent amyloid stroma. Genetic studies show that this patient has a familial cancer syndrome. In addition
to hyperparathyroidism, the patient is advised that she is at risk of developing which of the following neoplastic diseases? Pheochromocytoma
 Patients with the familial form of medullary carcinoma are often affected with MEN-2, which includes pheochromocytoma of the adrenal medulla
and parathyroid hyperplasia or adenoma. Somatic mutations of the RET protooncogene are found in patients with MEN-2A, and RET mutations
have been detected in 25% to 70% of cases of sporadic medullary thyroid carcinoma.