Thyroid pathology notes

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  • 1. thyroid pathology
  • 2. Preliminary stuff Lecture information Endocrine Pathology Pathology for Dental Students (LaMP 5-100) University of Minnesota School of Dentistry Lecturer Kristine Krafts, M.D. kkrafts@d.umn.edu Has only Elvis CDs in the car. Vidistine nuper imagines moventes bonas?* Outline • Introduction • Hyperthyroidism • Hypothyroidism • Non-neoplastic diseases • Neoplastic diseases • Review Further reading Robbins Basic Pathology, 8th edition, pages 758-771 * Seen any good movies lately? thyroid pathology | 2 of 24
  • 3. introduction | hyper- | hypo- | non-neoplastic | neoplastic | review Introduction Thyroid anatomy and histology Embryology • The thyroid develops from pharyngeal epithelium that descends down into the anterior neck. • If this pathway (called the thyroglossal duct) is not fully obliterated, it may give rise to thyroglossal duct cysts (little, fluid-filled cysts in the midline neck, anterior to the trachea), which occasionally get infected. Gross • Normal thyroid weight: about 15 – 20 grams. • Situated near the parathyroid glands and the recurrent laryngeal nerves (important during surgery). Histology • The thyroid has two lobes, which are divided into lobules, each containing about 20 – 40 follicles. • The follicles are lined by cuboidal to low columnar epithelium, and are filled with colloid (which contains thyroglobulin). • Between the follicles, there are parafollicular cells (or C cells), which secrete very small amounts of calcitonin. Normal thyroid gland Post-mortem photo Normal thyroid follicles Two lobes Hematoxylin and eosin stain Low and high power thyroid pathology | 3 of 24
  • 4. introduction | hyper- | hypo- | non-neoplastic | neoplastic | review Thyroid physiology What does the hypothalamus have to do with it? The hypothalamus secretes TRH (thyrotropin-releasing hormone), which stimulates the anterior pituitary to secrete TSH (thyroid-stimulating hormone, or thyrotropin). What does the pituitary have to do with it? TRH TSH stimulates growth of the thyroid gland, uptake of iodide, and synthesis and release of thyroid hormones. TSH Remember how thyroid hormones are made? Iodide is transported into the thyroid gland, converted to iodine, and attached to tyrosine residues on the big thyroglobulin molecule. These T3 , T4 iodinated tyrosine molecules then couple to form the thyroid hormones: T4 (thyroxine) and lesser amounts of T3 (triiodothyronine). What gets out into the blood? T4 and T3 are cleaved from thyroglobulin and released into the blood. T4 is then deiodinated to form either T3 or reverse T3 (a molecule without any apparent biologic activity). What's the deal about bound vs. unbound? Most of the thyroid hormones are bound to plasma proteins (mostly TBG, or thyroxine-binding globulin) for transport to tissues. Only a small amount is in the active, free form. This means that the body can keep the level of active (free) thyroid hormone within a narrow range, while maintaining a big, easily-deployed backup reserve of inactive (bound) hormone. What does thyroid hormone do? Free T3 or T4 enters its target cell and interacts with nuclear receptors to change gene expression, increase carbohydrate and fat breakdown, and stimulate protein synthesis. Result: increased basal metabolic rate. How does the poor thyroid gland adjust? The thyroid gland is very responsive to stimuli and is in a constant state of adaptation (how exhausting). When the thyroid is more active (puberty, pregnancy, physiologic stress, thyroid-stimulating drugs such as thiourea), the follicular epithelial cells become hyperplastic (get taller, sometimes forming little buds or papillae), more thyroglobulin gets resorbed, and the body’s metabolic rate goes up. When the thyroid is less active (when stimuli abate), the epithelial cells flatten down, the amount of colloid increases, and the body’s metabolic rate goes down. thyroid pathology | 4 of 24
  • 5. introduction | hyper- | hypo- | non-neoplastic | neoplastic | review Clinical points Thyroid disease is common and easily treated… …but the symptoms are variable and often subtle, and the onset is often insidious. Thyroid disease is often overlooked. You have to think of it to diagnose it! Laboratory testing The most commonly-used laboratory tests are: TSH (thyroid stimulating hormone) Most common • This test measures the amount of TSH in the blood. It’s very sensitive, so it thyroid tests: can detect very low levels of TSH. TSH • Even a very small fluctuation in T4 will cause a rapid, inverse change in TSH. Free T4 So the TSH is a good initial test to screen for hyper- or hypothyroidism. If your patient is symptomatic, get a free T 4 too (see below). TSH is also a good test to use when following patients on thyroid medication. Free T4 (thyroxine) • This test tells you how much active (unbound, free) T4 your patient is making. • Don’t confuse this with the total T4, which gives you all the T4 (99% of which is bound and inactive). The total T4 level is more of a reflection of how much binding protein is around. • Use this test to screen for hypo- and hyperthyroidism. Here’s a simple way to interpret TSH and free T4 levels. TSH low normal high secondary secondary primary low hypothyroidism hypothyroidism1 hypothyroidism subclinical subclinical normal euthyroidism hyperthyroidism hypothyroidism primary secondary secondary or tertiary high hyperthyroidism hyperthyroidism2 hyperthyroidism T4 thyroid pathology | 5 of 24
  • 6. introduction | hyper- | hypo- | non-neoplastic | neoplastic | review 1 You wouldn't think you'd find a normal TSH with a low T4, but it can happen! Sometimes the pituitary makes TSH that's normal in quantity (so the lab test measuring TSH appears normal), but abnormal in quality (it's structurally abnormal, and it doesn't stimulate the thyroid the way it should, so the patient becomes hypothyroid). A patient with this disorder would be said to have secondary hypothyroidism, because the problem is in the pituitary. 2 Here's another strange occurrence: a normal TSH with a high T4. Sometimes, TSH-producing pituitary adenomas will show this pattern of laboratory results. The more likely findings in a patient with a TSH-producing pituitary adenoma, though, are a high TSH and a high T4 (and this is what you should try to remember, otherwise you'll get confused). thyroid pathology | 6 of 24
  • 7. introduction | hyper- | hypo- | non-neoplastic | neoplastic | review Occasionally-used laboratory tests include: Free or total serum T3 (triiodothyronine) • This test tells you how much free or total T3 your patient is making. • Sometimes, hyperthyroid patients have elevated levels of T3 instead of T4 (called “T3 thyrotoxicosis”). A serum T3 would be very useful in this setting. T3 uptake and rT3 • These tests estimate how much thyroid-binding protein a patient has. • You might see these tests mentioned once in a while, but they really aren’t used much anymore. Anti-thyroid antibody tests • These antibodies come in three flavors: anti-peroxidase (or anti-microsomal), anti-thyroglobulin, and anti-TSH-receptor. Use these when you suspect autoimmune thyroid disease. • Anti-peroxidase antibodies are pretty sensitive and specific for Hashimoto’s disease, whereas anti-thyroglobulin and anti-TSH-receptor antibodies can be present in either Hashimoto’s or Graves disease. Radioiodine thyroid scanning • The patient is given a little radioactive iodine ( 123I), and then the thyroid gland is scanned to see how well it takes up the iodine. Hot nodules: almost always benign • Areas of thyroid that are more active (making a lot of thyroid hormone) take Cold nodules: up a lot of 123I and appear “hot.” Areas of thyroid that are less active (not occasionally malignant making much hormone) take up little 123I and appear “cold.” • Two uses for this test: (1) Evaluation of thyroid nodules. Hot nodules are virtually always benign; cold nodules are usually, but not always, benign (about 10% turn out to be malignant). (2) Determination of appropriate therapeutic dose of radioactive iodine. Radioiodine scan showing cold nodule (arrow) thyroid pathology | 7 of 24
  • 8. introduction | hyper- | hypo- | non-neoplastic | neoplastic | review Hyperthyroidism Definition: a hypermetabolic state caused by elevated levels of thyroid hormone. Categories Primary hyperthyroidism: the thyroid is over-functioning because of some intrinsic thyroid gland problem (e.g., Graves disease). Secondary hyperthyroidism: the thyroid is over-functioning because there is too much TSH around (causing over-stimulation of the thyroid). Main problem here is in the pituitary (e.g., pituitary adenoma that secretes TSH). Rare! Tertiary hyperthyroidism: the thyroid is over-functioning because there is too much TRH around (causing release of too much TSH, resulting in over-stimulation of the thyroid). Main problem here is in the hypothalamus (e.g., TRH-producing adenoma). Rare, rare, rare! Signs and symptoms Cardiac manifestations (increased oxygen demand = increased contractility) • rapid pulse • cardiomegaly • arrhythmias (especially atrial fibrillation. George Bush Sr. had this.) Neuromuscular manifestations (overactivity of sympathetic nervous system) • nervousness • tremor (see this best by placing a sheet of paper on the patient’s outstretched hands) • emotional lability (can lead to a psychiatric misdiagnosis) Eye manifestations (overstimulation of the muscle opening the upper eyelid) • lid lag A patient with hyperthyroidism: • wide, staring gaze wide, staring gaze Skin manifestations (the body is trying to lose heat) • warm, moist, flushed skin Gastrointestinal manifestations (overstimulation of gut = increased motility) • diarrhea • weight loss Skeletal manifestations (thyroid hormone causes increased bone resorption) • osteoporosis. Thyroid storm • The most dreaded complication of hyperthyroidism. • Occurs when a hyperthyroid patient undergoes some other major physiologic stress. Lots and lots of thyroid hormone is released. • The patient suddenly develops extreme hypermetabolism, which can lead to coma and death. thyroid pathology | 8 of 24
  • 9. introduction | hyper- | hypo- | non-neoplastic | neoplastic | review Causes (discussed in depth later) Common Most common cause of • Graves disease (85% of cases of hyperthyroidism in US!) hyperthyroidism: • hyperfunctioning (hormone-producing) multinodular goiter Graves disease • hyperfunctioning thyroid adenoma Uncommon • thyroiditis: DeQuervain thyroiditis, lymphocytic thyroiditis • ingestion of thyroid hormones (as treatment for hypothyroidism) • hyperfunctioning thyroid carcinoma • TSH-producing pituitary adenoma • struma ovarii (an ovarian tumor composed mostly of thyroid tissue!) • factitious hyperthyroidism (patient ingesting thyroid-stimulating drugs to treat obesity or depression) Diagnosis • A diagnosis of hyperthyroidism is suspected based on clinical findings (have a Hyperthyroidism: ↑ T4 high index of suspicion!) and confirmed using laboratory tests. • Primary: ↓ TSH • Best screening tests for hyperthyroidism: TSH and free T4 • Secondary: ↑ TSH • The free T4 level is increased in hyperthyroidism (obviously). The TSH is decreased in primary hyperthyroidism, but elevated in secondary or tertiary hyperthyroidism. Most common cause of thyroid pathology | 9 of 24 hyperthyroidism: Graves disease
  • 10. introduction | hyper- | hypo- | non-neoplastic | neoplastic | review Hypothyroidism Definition: a hypometabolic state caused by decreased levels of thyroid hormone. Categories Primary hypothyroidism: the thyroid gland is under-functioning because of some intrinsic thyroid gland problem (e.g., Hashimoto thyroiditis). Secondary hypothyroidism: the thyroid is under-functioning because there is too little TSH around (causing under-stimulation of the thyroid). Main problem here is in the pituitary (e.g., pituitary gland destruction). Tertiary hyperthyroidism: the thyroid is under-functioning because there is too little TRH around (causing diminished release of TSH, resulting in under-stimulation of the thyroid). Main problem here is in the hypothalamus (e.g., tumor replacing hypothalamus). Signs and symptoms Slowing of mind and body Hypothyroidism is often • Mental slowness, fatigue, irritability, loss of interest. Often mistaken for misdiagnosed depression. as depression. • Some patients develop a bizarre sense of humor (“myxedema wit”) or frank psychosis (“myxedema madness”). • Note: People with Down syndrome often (50% of the time) get hypothyroidism – watch carefully for signs of hypothyroidism, and don’t automatically attribute mental slowness to Downsyndrome. Myxedema • Accumulation of hydrophilic ground substance (e.g., glycosaminoglycans, hyaluronic acid) throughout the connective tissues of the body • Leads to non-pitting edema, coarsening of facial features, enlargement of the tongue, and deepening of the voice Cardiac manifestations • Slow pulse • Diminished contractility • Need to treat hypothyroid patients with care! Gastrointestinal manifestations (understimulation of gut causes decreased motility) • constipation Skin manifestations (the body is trying to retain heat) • dry, cool, pale skin Cold intolerance (from poor perfusion of the extremities) Delayed deep tendon reflexes (“hung reflexes”) • a useful physical exam sign to remember Myxedema coma • For some reason, hypothyroid patients may lapse into stupor or coma when they get mild illnesses, or when they are exposed to cold weather. thyroid pathology | 10 of 24
  • 11. introduction | hyper- | hypo- | non-neoplastic | neoplastic | review Causes Congenital hypothyroidism (cretinism)* • Definition: hypothyroidism first presenting in infancy or childhood • Two causes: (1) iodine deficiency (epidemic cretinism) In the past, this was common in places far away from the sea (Himalayas, inland China, and Africa). Now, foods are supplemented with iodine, so cretinism due to iodine deficiency is less common. (2) developmental or genetic problems (sporadic cretinism) These are rare. In these cases, the thyroid gland doesn’t form; thyroxine synthesis/release is defective; or thyroid hormone receptors are defective. Two patients with cretinism • Symptoms reflect the impaired development of the skeletal and central nervous systems and vary from mild (failure to thrive) to severe (profound mental retardation, short stature, and coarse facial features). • Treatment: thyroid hormone replacement (this helps – but doesn’t reverse damage). Prevention is best (in the US, babies are screened for hypothyroidism). Acquired hypothyroidism (myxedema) • Common causes Most common cause of hypothyroidism: 1. Hashimoto thyroiditis (the most common cause of hypothyroidism in U.S.) 2. iatrogenic causes: surgery, radiation, thyroid-inhibiting drugs Hashimoto thyroiditis • Uncommon causes 1. goiter 2. infiltrative diseases (amyloidosis, sarcoidosis) 3. thyroiditis 4. dietary problems, such as excess iodine 5. secondary hypothyroidism 6. tertiary hypothyroidism Diagnosis • Hypothyroidism is easy to diagnose and treat, but you have to think of it! • Best screening tests for hypothyroidism: TSH and free T4 (sound familiar?) • The free T4 level is decreased in hypothyroidism (obviously). The TSH is increased in primary hypothyroidism, but decreased in secondary or tertiary hypothyroidism. * Cretin is from the French chrétien, meaning Christian or Christ-like. It was used to describe these children because they were considered so mentally handicapped as to be incapable of sinning. thyroid pathology | 11 of 24
  • 12. introduction | hyper- | hypo- | non-neoplastic | neoplastic | review Non-neoplastic thyroid disease Thyroiditis General information • Definition: inflammation of the thyroid gland. • Four types of thyroiditis, as listed below. • Hashimoto is by far the most common type of thyroiditis. • Women are affected more often than men. • Patients with thyroiditis may be euthyroid, hyperthyroid, or hypothyroid. • Radioactive iodine uptake is decreased in thyroiditis (radioiodine scans show diffuse “cold” thyroid tissue). Compare this to Graves disease! Hashimoto thyroiditis (aka: chronic autoimmune or chronic lymphocytic thyroiditis) 1. Clinical findings • Common (≥ 1 million cases in US! Hashimoto thyroiditis is the most common cause of hypothyroidism in areas of the world where there’s enough iodine). • Typical age range: 45 – 65. • Female predominance in Hashimoto is even more pronounced than in other types of thyroiditis (F:M = 10:1 to 20:1). This is typical of autoimmune disease. • Signs and symptoms: Enlarged, non-tender thyroid. • Patients gradually lose thyroid function and eventually become hypothyroid. (Sometimes, early on, there is transient hyperthyroidism as follicles are destroyed and colloid leaks out.) 2. Laboratory testing • Thyroid function tests reflect the patient’s thyroid status (eventually, overt hypothyroidism supervenes). Hashimoto antibodies: • Anti-thyroid autoantibodies can be useful. Anti-peroxidase antibodies are Anti-peroxidase. pretty sensitive and specific for Hashimoto thyroiditis, whereas anti- thyroglobulin and anti-TSH-receptor antibodies can be present in either Hashimoto thyroiditis or Graves disease. • These autoantibodies are often detected using immunofluorescence testing (the tissue in question is stained with a fluorescent antibody that recognizes anti-peroxidase antibodies, or whatever autoantibodies you’re looking for). If the tissue has the antibody, it will light up. 3. Histology • Whopping lymphoid infiltrate: lots and lots of lymphocytes, some Hashimoto histology: plasma cells, and germinal centers. 1. lymphoid infiltrate • Hürthle cells: big follicular epithelial cells with abundant, eosinophilic, (including germinal granular (mitochondrion-stuffed) cytoplasm. centers) • Damaged, disrupted follicles are abundant early on. Later, the gland is 2. Hürthle cells overrun by inflammation. thyroid pathology | 12 of 24
  • 13. introduction | hyper- | hypo- | non-neoplastic | neoplastic | review 4. Pathogenesis • Autoimmune destruction of thyroid gland. • Main problem lies in the T cells: they recognize thyroid antigens as foreign! So they stimulate B cells to make anti-thyroid antibodies, and are themselves cytotoxic to thyroid cells. • The unsuspecting B cells make lots of different anti-thyroid antibodies. The most important of these is the anti-TSH-receptor antibody. It blocks the action of TSH, leading to hypothyroidism. Hashimoto thyroiditis Hashimoto thyroiditis Immunofluorescent stain Hematoxylin and eosin stain Follicular epithelial cells positive Lymphoid follicle (center), lymphocytes (left), and for anti-peroxidase antibodies. Hürthle cells (big pink cells, right). DeQuervain thyroiditis (aka: subacute or granulomatous thyroiditis) 1. Clinical findings • Much less common than Hashimoto thyroiditis De Quervain follows an URI, and • Typical age range: 30 – 50. it hurts! • Recent history of upper respiratory infection. • Signs and symptoms: abrupt onset of pain in throat, radiating to ear. Painful, often enlarged, thyroid. Flu-like symptoms. • Patients are hyperthyroid for the first few weeks, then may develop transient, usually asymptomatic, hypothyroidism over the next few weeks. • The disease is self-limiting (unlike autoimmune thyroiditis, which is self- perpetuating), disappearing on its own in weeks to months. 2. Histology De Quervain histology: • lymphocytes, histiocytes, and plasma cells 1. Damaged follicles • damaged, disrupted follicles 2. FBGC reaction • multinucleate giant cells (as in any foreign-body giant cell reaction) thyroid pathology | 13 of 24
  • 14. introduction | hyper- | hypo- | non-neoplastic | neoplastic | review 3. Pathogenesis • Caused by viral infection (most commonly coxsackie, but also mumps, measles, and others). • Many patients have the HLA-B35 antigen. Probably, some viral antigen, presented with HLA-B35, stimulates production of cytotoxic T cells that damage thyroid epithelium. • Damaged follicles leak colloid, causing a foreign-body giant cell reaction and enlargement of the thyroid gland. • The transient hyperthyroidism seen early in the disease is due to follicle damage (as in other cases of thyroiditis). The transient hypothyroidism occasionally seen late in the disease is presumably due to focal gland destruction. DeQuervain thyroiditis Note multinucleated giant cell (upper left) and residual, damaged follicle (lower right) Silent thyroiditis (aka: lymphocytic, painless, or subacute thyroiditis) 1. Clinical findings • Much less common than Hashimoto thyroiditis. • Typical age range: middle age; also occurs with increased frequency following pregnancy. • Signs and symptoms: painless, occasionally slightly enlarged, thyroid. Some patients are completely asymptomatic (hence the name “silent”). • Mild, transient hyperthyroidism may develop over the first few weeks and last up to two months. • Disease is self-limited. 2. Histology Silent thyroiditis histology: • Abundant lymphocytes. 1. lymphocytes • Some damaged, disrupted follicles. 2. no features of Hash • No germinal centers, plasma cells, or Hürthle cells (like in Hash). 3. Pathogenesis • Unresolved. • Inherited component? High frequency of HLA-DR3 and -DR5 in patients with lymphocytic thyroiditis. • Autoimmune component? Patients make anti-thyroglobulin and anti- thyroid peroxidase antibodies. Many have a family history of autoimmune thyroid disease, and some go on to develop overt autoimmune thyroiditis. thyroid pathology | 14 of 24
  • 15. introduction | hyper- | hypo- | non-neoplastic | neoplastic | review Reidel thyroiditis (aka: fibrosing thyroiditis) 1. Clinical findings • Rare. • Signs and symptoms: rock-hard, “woody” neck mass. Patients may also have fibrosis elsewhere in the body (e.g., in retroperitoneum). • If enough of the gland is involved, hypothyroidism may ensue. • If the disease progresses far enough, may need surgery to relieve pressure on the trachea. 2. Histology Reidel histology: • Fibrosis. fibrosis 3. Pathogenesis • Fibroblasts proliferate and lay down collagen. Reidel thyroiditis Tons of fibrosis with some poor little trapped follicles. Graves disease Clinical findings 1. Common disease (affects up to 2.5 % of US women!). 2. F>>M. Typical age range: 20 – 40. 3. Textbook clinical triad: • hyperthyroidism (thyroid gland is big and hyperfunctional) • ophthalmopathy (the usual “lid lag” of hyperthyroidism, plus exophthalmos) • dermopathy (“pretibial myxedema” – scaly thickening of skin over shins) 4. Real-life clinical picture: All patients with Graves have a goiter with at least some of the usual symptoms of hyperthyroidism (tachycardia, palpitations, tremor, anxiety). Many have ophthalmopathy, but only a few have dermopathy. The classic textbook triad – hyperthyroidism, ophthalmopathy (left) and dermopathy (right) – occurs in only a few patients with Graves. thyroid pathology | 15 of 24
  • 16. introduction | hyper- | hypo- | non-neoplastic | neoplastic | review Laboratory testing • ↑ free T4; ↓ TSH • ↑ uptake of radioactive iodine (scans show diffusely “hot” thyroid tissue). Histology • Crowded follicular epithelial cells form little papillae. • Lots of interstitial lymphocytes. • Scanty colloid with scalloped borders (because the epithelial cells are resorbing colloid). fibrosis Graves disease: epithelial cell papillae, scalloped colloid. Pathogenesis 1. Graves is an autoimmune disease caused by antibodies against the TSH receptor. Graves: • autoimmune • Autoantibodies bind to TSH receptors, where they cause thyroid hormone • anti-TSH-receptor antibodies. release and follicular epithelial proliferation.* • Thyroid over-functions (makes too much hormone) and overgrows (gets big). 2. The exact trigger for this autoimmune reaction is unknown. Genetic factors play a role in causing Graves disease, but it’s unclear exactly what that role is. What other disease has anti- TSH receptor antibodies? 3. Autoimmune factors also cause ophthalmopathy and pretibial myxedema. • T cells and autoantibodies cross-react with eye muscles and with retro-orbital tissues, leading to inflammation and accumulation of matrix components. The increased pressure leads to exophthalmos. • T cells and autoantibodies probably also cross-react with pre-tibial fibroblasts, Nobody except Ross reads causing accumulation of matrix components and myxedema. these little comments. Treatment 1. Decrease symptoms. • A β-blocker will help alleviate the symptoms of hyperthyroidism related to increased sympathetic tone (tachycardia, palpitations, tremor, anxiety). • If exophthalmos is severe enough, it can occlude retinal vessels and lead to blindness. Surgical decompression of the orbit may be necessary. 2. Decrease thyroid hormone synthesis. • drugs (propylthiouracil) • radioiodine ablation (a one-time dose of 123I. Many patients will later become hypothyroid and need hormone replacement.) • surgery Simple and multinodular goiters * The anti-TSH antibodies in Graves’ disease and the anti-TSH antibodies in Hashimoto’s disease recognize different epitopes on the TSH receptor! They also produce different results when bound to the TSH receptor. This is why the anti- TSH antibodies in Graves’ cause hyperthyroidism and the anti-TSH antibodies in Hashimoto’s cause hypothyroidism. thyroid pathology | 16 of 24
  • 17. introduction | hyper- | hypo- | non-neoplastic | neoplastic | review General points 1. “Goiter”1 just means a big thyroid gland (for whatever reason). 2. Plain old garden-variety goiters (in other words, enlarged thyroids that don’t show features of Graves disease or thyroiditis) are caused by defects in thyroid hormone synthesis. Either the patient is not getting enough iodine (endemic goiter), or there is some other defect (sporadic goiter). Bottom line: the thyroid makes less thyroid hormone, the TSH level goes up, and the thyroid grows bigger. 2. Simple and multinodular goiters are just two stages in this process. Simple goiter (diffuse nontoxic goiter, colloid goiter) • the first stage (most long-standing simple goiters eventually evolve into multinodular goiters) • the thyroid may be normal in size or enlarged, and is smooth (no nodules) Multinodular goiter • the second stage (develops from a preexisting simple goiter) multinodular goiter • the thyroid is huge and nodular (bumpy) Clinical findings • Early on, patients have a simple goiter. • Years later, multinodular (and huge!) goiter develops. • Most patients are euthyroid. • Some patients have hyperfunctioning nodules, which produce lots of thyroid hormone and cause hyperthyroidism (this is called Plummer syndrome or toxic multinodular goiter). • A few patients, even with their great big thyroids, just can’t make enough thyroid hormone and become hypothyroid. Laboratory testing 1. Most patients with goiters are euthyroid. Some (with a hyperfunctioning nodule) are hyperthyroid, and a few (especially those with hereditary enzyme defects) are hypothyroid. Laboratory values in patients with goiters thyroid status T4 TSH euthyroid normal ↑ A patient with a multinodular hyperthyroid ↑ ↑ goiter hypothyroid ↓ ↑ 2. Radioiodine uptake is uneven, with “hot” active areas, and “cold” inactive areas. Histology 1 The word goiter comes from the middle French word goitron which comes from the Latin guttur, which means throat. thyroid pathology | 17 of 24
  • 18. introduction | hyper- | hypo- | non-neoplastic | neoplastic | review • Early on (in simple goiter), the follicular epithelial cells, stimulated by all the TSH around, become hyperplastic (cells get taller, pile up). • Later (still in simple goiter stage), the epithelium gets exhausted and involutes, resulting in oversized, colloid-packed follicles. • Hyperplasia and involution occur in cycles. Some areas of the thyroid may be hyperplastic, and others may be involuting. All this hyperplasing (hyperplasing?) and involuting causes hemorrhage and fibrosis. • Finally (this is the multinodular stage), the hemorrhage and fibrosis become massive, and the thyroid gets really big (>100 grams). The parenchyma separates into nodules (composed of follicles) bound by fibrotic bands. Goiter Hematoxylin and eosin stain Proliferating (left) and involuting (right) follicular epithelium. Pathogenesis 1. Endemic goiter is caused primarily by iodine deficiency. • Lack of iodine in the diet (→ can’t make thyroid hormone → TSH goes up → thyroid gland becomes hyperplastic). • A diet rich in foods called goitrogens (such as cabbage, brussels sprouts, turnips, cauliflower, cassava root) doesn’t help matters. Goitrogens interfere with T3 and T4 synthesis, causing TSH elevation and thyroid gland hyperplasia. 2. Sporadic goiter is caused by things other than iodine deficiency. In most patients, a specific cause is never found. Some of the known causes include: Eat your goitrogens • ingestion of substances that interfere with thyroid hormone synthesis • hereditary enzyme defects that interfere with thyroid hormone synthesis (but not too many). (for example, defects in iodide absorption or transport). Treatment • Often these patients are treated with levothyroxine (acts like thyroid hormone) in the hope that TSH will be suppressed, and the goiter will shrink. • Caution! The iodine-deficient multinodular goiter is under heavy TSH stimulation…if you give iodine to this patient (even the small amount given in radiographic procedures), acute hyperthyroidism and even hyperthyroid crisis can occur! This is called the Jod-Basedow phenomenon. thyroid pathology | 18 of 24
  • 19. introduction | hyper- | hypo- | non-neoplastic | neoplastic | review Neoplastic thyroid disease Introduction: the thyroid nodule The bump that gets attention • Most thyroid neoplasms are discovered when the patient (or physician) feels a bump (or nodule) on the thyroid. • Thyroid nodules are common! 5 million people (2-4% of adults) in the US have one. • Fortunately, most turn out to be benign: either adenomas, or big nodules in a multinodular goiter. • Thyroid carcinoma is uncommon (accounts for <1% of all thyroid nodules) and is usually not very aggressive (most patients live at least 20 nodule nodule years after diagnosis). • Still, every thyroid nodule needs a work-up. Is it cancer? How to work up a thyroid nodule: 1. Clinical clues • You can look at all sorts of things for clues to whether a nodule is cancerous: patient’s age and sex, whether nodule is solitary or multiple, whether it takes up radioactive iodine or not (see Robbins p. 1140 for what these clues mean). • BUT: these things just hint at the likelihood of cancer. If you are at all concerned about malignancy, you need to look at the nodule under a microscope. 2. Making a diagnosis • First, get a fine-needle aspiration (FNA). Fine needle aspiration has become a routine procedure (and not just for thyroid nodules, but for any suspicious lump or bump within needle’s reach). It’s a great screening technique (cheap, fast, pretty painless) to find out which bumps need to be cut out.. • The nodule needs to be cut out if the FNA shows any of these: • obvious cancer • lots of follicles (even if they look benign) • Orphan Annie nuclei, or nuclei with grooves thyroid pathology | 19 of 24
  • 20. introduction | hyper- | hypo- | non-neoplastic | neoplastic | review Thyroid adenoma Clinical findings • Common. Most patients are adults. • Most patients are euthyroid. Occasionally, an adenoma will become hyperfunctional (produce lots of thyroid hormone); these patients may become hyperthyroid. Laboratory testing • Most patients have normal levels of thyroid hormone and TSH. • Radioiodine scanning: most adenomas look “cold.” The few adenomas that are hyperfunctional look “hot.” Histology • Lots of thyroid follicles. • Follicles are lined by well-differentiated epithelial cells (that is, cells that look almost exactly like normal (non-neoplastic) follicular epithelial cells). • Don’t memorize the different adenoma subtypes that Robbins lists (non gradus anus rodentum)*. All adenomas, whatever their histologic appearance, act the same. Treatment/prognosis • Remove it surgically. Why, if it’s just a benign tumor? Because it’s often difficult (on biopsy or FNA) to distinguish an adenoma (benign, with lots of follicles) from a follicular adenocarcinoma (malignant, with lots of follicles). So just take the thing out, to make sure it’s not cancer. • Excellent prognosis (thyroid adenomas are benign, and have virtually no tendency to turn malignant). Thyroid adenoma Lots and lots of follicles. * Not worth a rat’s ___. thyroid pathology | 20 of 24
  • 21. introduction | hyper- | hypo- | non-neoplastic | neoplastic | review Thyroid carcinoma Papillary adenocarcinoma 1. Clinical findings • Most common type of thyroid carcinoma (80% of all cases). • Best prognosis of all types of thyroid carcinoma. • Affects adults, primarily, but also occurs in children. 2. Histology • Growth pattern: papillary (looks like inside-out, branching glands). • Cells: • origin: follicular epithelium • nuclei look empty or cleared-out, like Orphan Annie’s eyes* • contain nuclear grooves and pseudo-inclusions (from cytoplasmic invaginations) • Other features: psammoma bodies • concentrically lamellated calcium structures • also seen in papillary carcinomas of other organs • not seen in other types of thyroid carcinoma 3. Treatment/prognosis • Surgical removal • Metastases are usually via lymphatics, to adjacent nodes • Excellent prognosis (10-year survival is 98%) nuclear pseudo-inclusion cleared-out nuclei nuclear grooves papillary pattern psammoma body * Papillary adenocarcinoma memory aid: think of Orphan Annie! 1. often affects younger women. 2. tends to stay around for years without getting any bigger. 3. is usually well-behaved; seldom kills people. 4. has nuclei that resemble Orphan Annie’s eyes 5. has psammoma bodies (from the Greek psammos, or sand): Annie’s dog is named Sandy. (From Ed’s pathology notes at www.pathguy.com) thyroid pathology | 21 of 24
  • 22. introduction | hyper- | hypo- | non-neoplastic | neoplastic | review Follicular adenocarcinoma 1. Clinical findings • Uncommon (~15% of all thyroid carcinomas) 2. Histology • Growth pattern: follicular (can look a lot like normal thyroid! • Cells: • origin: follicular epithelium • uniform; often well-differentiated* • no papillary carcinoma cell features follicular pattern vascular invasion 3. Future pathologists beware: • This tumor can be hard to distinguish from a thyroid adenoma! * • Sometimes the only signs of malignancy are: 1. epithelial cells invading blood vessels (“vascular invasion”) 2. tumor cells extending through the thyroid capsule 4. Treatment/prognosis • Surgical excision. May give some thyroid hormone to suppress the patient’s TSH (to prevent tumor stimulation). • Metastasis is usually via blood vessels, to lungs or bone. • Good prognosis. * A well-differentiated tumor is one that closely recapitulates its tissue of origin. A poorly-differentiated tumor looks very little like its tissue of origin (sometimes, it’s hard to tell what kind of tumor it is). Well-differentiated follicular adenocarcinomas of the thyroid have lots of easily-recognizable follicles lined by cells that look a lot like normal, benign follicular epithelial cells. Well-differentiated tumors can be hard to distinguish from their benign neoplastic counterparts – or even from normal tissue! In general, well-differentiated tumors tend to behave better than poorly-differentiated tumors. thyroid pathology | 22 of 24
  • 23. introduction | hyper- | hypo- | non-neoplastic | neoplastic | review Medullary carcinoma 1. Clinical findings • Rare (~5% of all thyroid carcinomas) • Medullary carcinoma is an endocrine tumor (papillary and follicular thyroid carcinomas are epithelial tumors). The cell of origin is the thyroid C-cell. • It may occur sporadically, or as part of MEN-II, or as part of familial thyroid carcinoma syndrome. 2. Histology • Pattern: cells often form vague nests • Cells: large, polygonal • Other features: amyloid deposits 3. Treatment/prognosis Medullary carcinoma. • Anyone you suspect of having MEN-II or familial thyroid Vague nesting pattern (left) carcinoma needs genetic counseling and close follow-up. and amyloid (right). • Bad prognosis overall (5 year survival is 50%), and it’s even worse when in the setting of MEN-II. Anaplastic thyroid carcinoma 1. Clinical findings • Rare (<5% of all thyroid carcinomas) • Presents as a rapidly-enlarging, bulky neck mass, which has often already metastasized widely. 2. Histology • Pattern: cells often in sheets • Cells: anaplastic* • Future pathologists: because this tumor is so poorly- differentiated, it can be hard to distinguish it from other types of tumors (e.g., lymphoma). Special stains (that stain calcitonin brown) can help. 3. Treatment/prognosis Anaplastic thyroid carcinoma. • No effective treatment. Wild anaplasia, including a giant • Very bad prognosis (most patients die within one year). tumor cell and an abnormal mitosis. * Anaplastic means undifferentiated. Anaplastic cells of any type tend to be pleomorphic (varying in size and shape), with a high nuclear-cytoplasmic ratio, hyperchromatic (dark-staining) nuclei, and visible nucleoli. See Robbins p. 273 for a refresher. thyroid pathology | 23 of 24
  • 24. introduction | hyper- | hypo- | non-neoplastic | neoplastic | review Review 1. Describe the common signs and symptoms, causes, and laboratory workup of: • Hypothyroidism (congenital and acquired) • Hyperthyroidism 2. Fill in the following tables. Try to pick just 2 or 3 words so you can remember them. Hypo-, hyper- and/or AKA Clinical findings Histology Pathogenesis euthyroid? Hashimoto De Quervain silent Reidel Graves Common or rare? Histology Other unique features, if any Prognosis Adenoma Papillary CA Follicular CA Medullary CA Anaplastic CA 3. Fill in the following table with the most likely diagnoses. Which are the most common combinations? TSH low normal high low free T4 normal high 4. How would you work up a patient with a thyroid nodule? thyroid pathology | 24 of 24
  • 25. introduction | hyper- | hypo- | non-neoplastic | neoplastic | review Can you name the disease? thyroid pathology | 25 of 24