Endocrine Pathology 26

THYROID GLAND

1. Multinodular goiter (nontoxic goiter) refers to an enlarged thyroid gland with multiple colloid nodules. Females are affected more frequently than males. Multinodular goiter is frequently asymptomatic, and the patient is typically euthyroid, with normal T4, T3, and TSH. Plummer syndrome is the development of hyperthyroidism (toxic multinodular goiter) late in the course.

a.Microscopically, the tissue shows nodules of varying sizes composed of colloid follicles. Calcification, hemorrhage, cystic degeneration, and fibrosis can also be present.

HYPERTHYROIDISM

1.The term hyperthyroidism is used when the mean metabolic rate of all cells is increased due to increased T4 or T3. Clinical features include tachy­ cardia and palpitations; nervousness and diaphoresis; heat intolerance; weakness and tremors; diarrhea; and weight loss despite a good appetite. Laboratory studies show elevated free T4. In primary hyperthyroidism, TSH is decreased, while in secondary and teritiary hyperthyroidism, TSH is elevated.

2.Graves disease is an autoimmune disease characterized by production of IgG autoantibodies to the TSH receptor. Females are affected more fre­ quently than males, with peak age 20 to 40 years. Clinical features include hyperthyroidism, diffuse goiter, ophthalmopathy (exophthalmus), and dermopathy (pretibial myxedema) . Microscopically, the thyroid has hyper­

plastic follicles with scalloped colloid.	Clinical Correlate
3. Other causes of hyperthyroidism include toxic multinodular goiter;	The most sensitive test in thyroid disease
toxic adenoma (functioning adenoma producing thyroid hormone); and	is TSH. Ifthe TSH is normal, then the
Hashimoto and subacute thyroiditis (transient hyperthyroidism) .	patient is euthyroid.

HYPOTHYROIDISM

1.The term hypothyroidism is used when the mean metabolic rate of all cells is decreased due to decreased T4 or T3.

a.Clinical features include fatigue and lethargy; sensitivity to cold tem­ peratures; decreased cardiac output; myxedema (accumulation of pro­ teoglycans and water); facial and periorbital edema; peripheral edema of the hands and feet; deep voice; macroglossia; constipation; and anovulatory cycles.

b.Laboratory studies show decreased free T4. In primary hypothyroid­ ism, TSH is elevated, while in secondary and tertiary hypothyroidism, TSH is decreased.

2.Iatrogenic hypothyroidism is the most common cause of hypothyroid­ ism in the United States, and is secondary to thyroidectomy or radioactive iodine treatment. Treatment is with thyroid hormone replacement.

Note

Long-actingthyroid stimulator (LATS): original name forthe autoantibodies of Graves disease

Thyroid-stimulating immunoglobulin (TSI): current name forthe autoantibodies of Graves disease

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Clinical Correlate

Thyroid tumors tend to be cold nodules on thyroid iodine 131 scans.

3. Congenital hypothyroidism (cretinism) in endemic regions is due to iodine deficiency duringintrauterine and neonatallife,and in nonendemic regions is due to thyroid dysgenesis. Affected individuals present with fail­ ureto thrive, stuntedbone growth and dwarfism,spasticityand motorinco­ ordination, and mental retardation. Goiter is present in endemic cretinism.

4.Endemicgoiter is due to dietary deficiency of iodine and is uncommon in the United States.

THYROIDITIS

1.Hashimoto thyroiditis is a chronic autoimmune disease characterized by immune destruction of the thyroid gland and hypothyroidism. It is the most common noniatrogenic/nonidiopathic cause of hypothyroidism in the United States; it most commonly causes painless goiter in females more than males, and has peak age 40 to 6S years.

a.Clinically, Hashimoto thyroiditis most commonly causes hypothyroid­ ism (due to destruction ofthyroid tissue), but the initial inflammation may cause transient hyperthyroidism (hashitoxicosis).

i . Hashimoto thyroiditis may be associated with other autoimmune diseases (SLE, rheumatoid arthritis, Sjogren syndrome, etc.), and it has an increased risk ofnon-Hodgkin B-cell lymphoma.

b.Pathology. Hashimoto thyroiditis grossly produces a pale, enlarged thyroid gland, which microscopically shows lymphocytic inflammation with germinal centers and epithelial "Hiirthle cell" changes.

2.Subacute thyroiditis (also called de Quervain thyroiditis and granuloma­ tous thyroiditis) is the second most common form of thyroiditis; it affects females more than males and has peak age 30 to SO years. The condition is typically preceded by a viral illness, produces a tender, firm, enlarged thyroid gland, and may be accompanied by transient hyperthyroidism. Microscopyshows granulomatous thyroiditis. The disease typically follows a self-limited course.

3.Riedel thyroiditis is a rare disease ofunknown etiology, characterized by destruction ofthe thyroid gland by dense fibrosis and fibrosis ofsurround­ ing structures (trachea and esophagus). Females are affected more fre­ quentlythan males,with most patients being middle-aged. Riedel thyroid­ itis causes an irregular, hard thyroid that is adherentto adjacent structures. The condition may clinically mimic carcinoma and present with stridor, dyspnea, or dysphagia. Microscopic examination shows dense fibrous replacement of the thyroid gland with chronic inflammation. Reidel thy­ roiditis is associated with retroperitoneal and mediastinal fibrosis.

THYROID NEOPLASIA

1 . Adenomas. Follicular adenomas are the most common. Clinically, adenomas are usually painless, solitary nodules that appear "cold" on thyroid scans. They may be functional and cause hyperthyroidism (toxic adenoma).

2.Papillary carcinoma accounts for 80% of malignant thyroid tumors. Females are affected more than males, with peak age 20 to SO years. Radiation exposure is a risk factor. Resection is curative in most cases. Radiotherapy with iodine 1 3 1 is effective for metastases. The prognosis is excellent, with 20-year survival of90% due to slow growth and metastasis to regional cervical lymph nodes.

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a.Microscopically, the tumor typically exhibits a papillary pattern.

Occasional psammoma bodies may be seen. Characteristic nuclear features include clear "Orphan Annie eye" nuclei; nuclear grooves; and intranuclear cytoplasmic inclusions. Lymphatic spread to cervical nodes is common.

3.Follicular carcinoma accounts for 15% of malignant thyroid tumors. Females are affected more often than males, with peak age 40 to 60 years. Hematogenous metastasis to the bones or lungs is common.

4.Medullary carcinoma accounts for 5% of malignant thyroid tumors. This tumor arises from C cells (parafollicular cells) and secretes calcitonin. Microscopic examination shows nests of polygonal cells in an amyloid stroma. A minority (25%) of cases are associated with MEN II and MEN III syndromes.

5.Anaplasticcarcinoma affects femalesmorethan males,withpeakagegreater than 60 years. Anaplastic carcinoma can present with a firm, enlarging, and bulky mass; or with dyspnea and dysphagia. The tumor has a tendency for early widespread metastasis and invasion of the trachea and esophagus. Microscopically, the tumor is composed of undifferentiated, anaplastic, and pleomorphic cells. This very aggressive tumor is often rapidly fatal.

PARATHYROID GLANDS

1 . Primaryhyperparathyroidism.

a.Etiology. Adenomas are the most common cause of primary hyper­ parathyroidism (80%), and they may be associated with MEN I. Parathyroid hyperplasia accounts for 15% of cases and is character­ ized by diffuse enlargement of all four glands. The enlarged glands are usually composed of chief cells. Parathyroid carcinoma is very rare. Hyperparathyroidism can also occur as a paraneoplastic syndrome of lung and renal cell carcinomas.

b.Clinical features. The excess production of parathyroid hormone (PTH) leads to hypercalcemia,withlaboratory studies showing elevated serum calcium and PTH. Primary hyperparathyroidism is often asymp­ tomatic, but may cause kidney stones; osteoporosis and osteitis fibrosa cystica, metastatic calcifications, or neurologic changes.

2.Secondary hyperparathyroidism is caused by any disease that results in hypocalcemia, leading to increased secretion of PTH by the parathyroid glands. The condition can result from chronic renal failure, vitamin D defi­ ciency, or malabsorption.

3.Hypoparathyroidism can result from surgical removal of glands during thyroidectomy, DiGeorge syndrome, or idiopathic cause.

a.Clinical features. Laboratory studies show hypocalcemia. Treatment is with vitamin D and calcium.

i.Chvostek sign demonstrates twitching of the ipsilateral facial muscles after tapping the muscles, suggestive of neuromuscular excitability caused by hypocalcemia.

u.Trousseausignis performedbyinflating a sphygmornanometer cuff above systolic blood pressure for several minutes so that if hypo­ calcemia is present, then muscular contractions, including flexion of the wrist and metacarpophalangeal joints, hyperextension of the fingers, and flexion of the thumb on the palm occur, suggesting neuromuscular excitability.

iii.Clinical problems related to hypocalcemia. The hypocalcemia may also cause psychiatric disturbances and cardiac conduction defects (ECG: prolonged QT interval).

b. Treatment is with vitamin D and calcium.

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Note

Dexamethasone suppression test:

Administration of dexamethasone (a cortisol analog) normally will suppress pituitaryACTH production, resulting in suppression of adrenal cortisol

production and a decrease in urinary free cortisol.

Bridge to Embryology

The cells ofthe adrenal medulla are derived from neural crest cells. The cells ofthe adrenal cortexare derived from mesoderm.

Clinical Correlate

Pheochromocytoma

The catecholamines produced by pheochromocytoma can affect both the alpha and beta receptors. Patients must have their hypertension controlled with an alpha blocker such as phenoxybenzamine priorto surgery. This control will help reduce the riskofsevere intraoperative hypertension, such as might occur when the tumor is manipulated, causing release of large amounts of catecholamines.

ADRENAL GLAND

1. Cushing syndrome is characterized by increased levels ofglucocorticoids.

2.Primary hyperaldosteronism (Conn syndrome) is due to an adrenocor­ tical adenoma producing aldosterone. The elevated aldosterone causes hypertension due to retention of sodium and water. Laboratory studies show hypokalemia, elevated aldosterone, and decreased renin.

3.Adrenogenital syndromes are adrenal disorders characterized by excess production of androgens and virilization. These syndromes can be due either to adrenocortical adenoma/carcinoma, which produces androgens, or to congenital adrenal hyperplasia, a cluster of autosomal recessive enzyme defects (most common is 21-hydroxylase deficiency).

4.Waterhouse-Friderichsen syndrome (acute adrenal insufficiency) is a potentially fatal bilateral hemorrhagic infarction of the adrenal glands associated with aNeisseria meningitidis infection in children. It is clinically characterized by disseminated intravascular coagulation (DIC), acute respiratory distress syndrome, hypotension and shock, and acute adrenal insufficiency. Treatment is with antibiotics and steroid replacement.

5.Addison's disease (chronic adrenocortical insufficiency) is caused by destruction of the adrenal cortex, leading to a deficiency of glucocorti­ coids, mineralocorticoids, and androgens. The most common cause is autoimmune adrenalitis, though tuberculosis and metastatic cancer are otherpossible causes. Patientspresentwithgradualonset ofweakness, skin hyperpigmentation, hypotension, hypoglycemia, poor response to stress, and loss of libido. Treatment is with steroid replacement.

6.Pheochromocytoma ("dark/dusky-colored tumor") is an uncommon benign tumor of the adrenal medulla, which produces catecholamines (norepinephrine and epinephrine). It can present with severe headache, tachycardia and palpitations, diaphoresis and anxiety, or hypertensive epi­ sodes. Note the Rule of 10s:

•	10% occur in children	•	10% are malignant
•	10% are bilateral	•	10% are familial (MEN II and III)

•10% occur outside the adrenal gland

Diagnosis is by demonstrating elevated urinary vanillylmandelic acid (VMA) and catecholamines. Treatment involves controlling the patient's blood pressure and surgical removal ofthe tumor.

MULTIPLE ENDOCRINE NEOPLASIA (MEN) SYNDROMES

1. Multiple endocrine neoplasia (MEN) syndromes are autosomal domi­ nant conditions with incomplete penetrance that are characterized by hyperplasia and tumors of endocrine glands.

2.MEN I (Werner syndrome) features tumors of the pituitary gland, para­ thyroids, and pancreas. It is associated with peptic ulcers and the Zollinger­ Ellison syndrome. The affected gene is MEN I, a tumor suppressor gene that encodes a nuclear protein called menin.

3.MEN II (Ila or Sipple syndrome) features medullary carcinoma of the thyroid, pheochromocytoma, and parathyroid hyperplasia or adenoma. The genetic mutation involves RET proto-oncogene, which is a receptor tyrosine kinase for members ofthe glial cell line-derived neurotrophic fac­ tor family ofextracellular signaling molecules.

4.MEN III (IIb) features medullarycarcinoma ofthe thyroid, pheochromo­ cytoma, and mucocutaneous neuromas. There is a genetic mutation of RET ("rearranged during transfection") proto-oncogene.

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Chapter Summary

•Multinodular goiter is an enlarged thyroid gland with multiple colloid nodules that is frequently asymptomatic and euthyroid.

•General features of hyperthyroidism include tachycardia, nervousness, diaphoresis, heat intolerance, weakness, tremors, diarrhea, and weight loss. FreeT4 is elevated and TSH is decreased in primary hyperthyroidism and increased in secondary and tertiary hyperthyroidism.

•Graves disease is an autoimmune disease characterized by production of lgG autoantibodies to the TSH receptor. Clinical features include hyperthyroidism, goiter, exophthalmos, and pretibial myxedema. Hyperthyroidism can also be caused by toxic multinodular goiter, toxic adenoma, and transiently during Hashimoto disease and subacute thyroiditis.

•General features of hypothyroidism include fatigue, lethargy, sensitivity to cold temperatures, decreased cardiac output, myxedema, and constipation. Free T4 is decreased and TSH is elevated in primary hypothyroidism and decreased in secondary and tertiary hypothyroidism.

•Congenital hypothyroidism develops secondary to iodine deficiency during intrauterine and neonatal life and causes mental retardation, musculoskeletal problems, and goiter. Endemic goiter is uncommon in the United States and is due to dietary deficiency of iodine.

•Hashimoto thyroiditis is a chronic autoimmune disease characterized by immune destruction ofthe thyroid gland and hypothyroidism.

•Subacute thyroiditis is a cause oftransient hyperthyroidism following a viral illness.

•Riedel thyroiditis is a rare disease of unknown etiology characterized by destruction of the thyroid gland by dense fibrosis of surrounding structures.

•Thyroid adenomas are usually painless, solitary nodules.

•Thyroid carcinomas occur in a number of histologic types, including papillary (most common with excellent prognosis), follicular (tends to spread

hematogenously), medullary (secretes calcitonin, makes amyloid, and may be associated with MEN II or Ill), and anaplastic (rapidly fatal).

•Primary hyperparathyroidism is most often due to parathyroid adenoma or parathyroid hyperplasia, and can be characterized by elevated serum calcium and PTH, kidney stones, osteoporosis and osteitis fibrosa cystica, metastatic calcifications, and neurologic changes. Many cases are asymptomatic. Secondary hyperparathyroidism can be seen in any disease that results in hypocalcemia leadingto increased secretion of PTH by the parathyroid glands, including chronic renal failure, vitamin D deficiency, and malabsorption.

•Hypoparathyroidism is characterized by hypocalcemia, tetany, psychiatric disturbances, and cardiac conduction defects. It can be the result of surgical removal ofthe glands during thyroidectomy, DiGeorge syndrome, or it can be idiopathic.

(Continued)

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