Hashimoto thyroiditis: Mainly women (10-20:1) > 40 years old Autoimmune disease with production of antibodies against thyroglobulin,

n, thyroid peroxidase, microsomal antigen (diagnostically useful) CD8+ cytotoxic T-cells, cytokineinduced, macrophage-mediated damage and Ab-dependent cell-mediated toxicity all contribute Anti-TSH receptor blocks TSH effect Genetic component with familial clustering; polymorphisms in genes associated with immune regulation Associated with other autoimmune diseases (APS 2, [ Addisons, Hashimotos and type 1 diabetes], SLE, myasthenia gravis, Sjogrens syndrome) Increased incidence in Turner and Down syndromes
Test q: A 60F has been feeling tired and sluggish for more than one year. On phys exam, her thyroid gland is not palpable; there are no other remarkable findings. Lab studies show a serum T4 level of 1.6 g/dL and a TSH level of 7.9 mU/L. Which of the following is most indicative of the pathogenesis of this patients disease? Antithyroid peroxidase antibodies. REPEATED x2 Test q: A 41F has had increasing lethargy and weakness over the past three years. She complains of being cold most of the time and wears a sweater in the summer. One year ago, she had menorrhagia but not has oligomenorrgea. She has difficulty concentrating, and her memory is poor. She has chronic constipation. On phys exam, her temp is 35.5C, pulse 54/min, respirations 13/min, and blood pressure 110/70 mm Hg. She has alopecia, and her skin appears coarse and dry. Her face, hands, and feet appear puffy, with a doughlike consistency to the skin. Lab findings show hemoglobin of 13.8 g/dL, hematocrit 41.5%, AST 26 U/L, ALT 21 U/L, total bilirubin 1.0 mg/dL, Na+ 140 mmol/L, K+ 4.1 mmol/L, Cl- 99mmol/L, CO2 25 mmol/L, glucose 73 mg/dL, and creatinine 1.1 mg/dL. Which of the following serologic test findings is most likely to be positive? Anti-thyroid peroxidase antibody. REPEATED x2 Test q: A 50F presents w/cold intolerance, delayed reflexes and weight gain. Her skin appears to be cold and dry. Laboratory findings consistent w/this clinical appearance are antibodies directed against: Peroxidase and TSH-R. Test q: A 40F has experienced increasing intolerance to cold for the past 18 months. She wears a jacket in the office while her coworkers keep turning down the thermostat. She reports a 4kg weight gain and has become constipated over the past year. Physical exam shows no remarkable findings. Which of the following is the most appropriate initial diagnostic test? Thyroid-stimulating hormone (TSH) level. (Other choices: T4, T3, Fine-needle aspiration biopsy, and Radioiodine scan) REPEATED x2

Hashimoto thyroiditis: Gland: Diffusely , often asymmetrically enlarged and pale/rubbery; capsule intact Micro: Infiltrates of lymphocytes, plasma cells (sometimes germinal centers), & macrophages, with Hurthle cell metaplasia of the follicular epithelium Fibrous variant: Usually not goitrous Hashimotos thyroiditis - Note pallor: Hashimoto thyroiditis:
Very prominent germinal centers in this case. Exceptional example of lymphoplasmacytic infiltrate. Not only lots of lymphocytes, but they are also making a lot of large, irregularlyshaped germinal centers.

Lumpy/bumpy no beefy red color pale. Reflection of lymphoid infiltrates.

Germinal center & Hrthle cell change:

Test q: A 40F, previously healthy, presents to her doctor w/a 2mo history of a painless, slowly enlarging mass. She also complains of increased fatigue, feeling cold when others are warm, weight gain, and thinning hair. The appropriate tests are done, including a thyroid panel. Her TSH is found to be high, T4 is low, T3 is low. A biopsy shows lymphoid follicles and large pink follicular epithelial cells. The history and pathology are consistent with: Hashimotos thyroiditis.

Germinal center and Hurthle cell change: Metaplastic reaction of the follicular epithelial cells they acquire large numbers of mitochondria. Causes them to develop a prominent, grainy, eosinophilic cytoplasm. Known as Hurthle cell metaplasia.

Hashimoto thyroiditis fibrous variant:

Fibrous variant (trichrome stain):

Fibrous variant is non-goiterous. See lymphoid component + Hurthle cell metaplasia + large amount of fibrous tissue laid down within gland.

Trichrome stains collagen green. See a lot of interstitial fibrosis 2 to Hashimotos fibrous variant.

Hashimoto thyroiditis: Complications: Lymphoma (Usually low-grade, B cell lymphomas MALT-like lymphomas), ? papillary carcinoma Outcome: Euthyroid progressing to hypothyroid (Single most common cause of hypothyroidism in USA)
Test q: A 40F presents w/Hashimotos thyroiditis. She is treated w/synthroid to reduce the risk for: Lymphoma. Test q: The most common cause of hypothyroidism in the USA is: Hashimotos thyroiditis.

Riedel thyroiditis: Rare; M:F = 1:3; Most common in 30 - 60 years Fibrous tissue replaces & often extends outside gland Causes dysphagia & stridor Clinical concern for cancer Gland: Asymmetric fibrosis, very firm Micro: Keloid-like bands of fibrous tissue Associated with retroperitoneal fibrosis, sclerosing cholangitis & mediastinitis, and orbital pseudotumor Outcome: about 1/3 hypothyroid Riedel thyroiditis Note keloid-like bands of collagen:

Rietel thyroiditis: Dense, scar-like fibrous tissue replaces the thyroid gland. No longer glistening, beefy-red. Looks like a healed MI.

Riedel thyroiditis dissection into strap muscles:

Not recognizable as thyroid chronic inflammatory cells have replaced structure (mostly lymphocytes). Keloid bands are eosinophilic and thick.

No cleavage plane extends directly outside gland into soft tissue.

Test q: Histologically, Riedels thyroiditis resembles: Keloid. Test q: The microscopic appearance of the thyroid in Riedels thyroiditis resembles: Keloid. Test q: A special stain that would be prominently positive in Riedels thyroiditis is: Trichrome. (Trichrome stains collagen)

Hypothyroidism: Iatrogenic A) Thyroidectomy for Graves disease or thyroid carcinomas B) Radio-iodine Hypothalamic-pituitary axis hypofunction pituitary adenoma/infarction Rarely metastatic carcinoma (although metastases to thyroid are common autopsy findings) Complications of Surgery for Hyperthyroidism: Metastatic carcinoma (renal cell) to the thyroid:

Surgery for Graves disease most frequent complication is permanent hypothyroidism

Hyperthyroidism: Graves disease Toxic multinodular goiter (Plummer syndrome) Toxic adenoma Rare causes - subacute thyroiditis (granulomatous & lymphocytic), functioning thyroid carcinoma, gestational neoplasia and non-gestational choriocarcinoma, pituitary or hypothalamic dysfunction, struma ovarii Graves disease: Diffuse toxic goiter, diffuse thyroid hyperplasia 85% of hyperthyroidism Tetrad of symptoms: Symmetric goiter, hyperthyroidism, ophthalmopathy & dermopathy M:F = 1:6, most commonly 20 - 40 years Familial clustering, HLA-DR3, & other autoimmune diseases (SLE, PA, type 1 diabetes, Addisons) Inherited polymorphisms in immune function genes that inhibit response to self antigens Circulating autoantibodies stimulate the thyroid, including TSH receptor; T-cells react with retro-orbital cells & induce matrix production, causing proptosis Gland: diffusely enlarged, hypervascular Graves disease Note neck fullness Ophthalmopathy: proptosis. Pretibial myxedema: Hypervascularity:

Can see HUGE butterfly shape.

Due to retroorbital mucopolysaccharide

Mucopolysaccharide deposits in dermis anterior surface of tibia.

Can hear bruit.

Test q: A 55F exhibits bulging eyes and pretibial myxederma and bruit are heard over the thyroid. The patient most likely has produced autoantibodies directed against: TSH receptor.

Graves Disease: Micro: columnar, papillary epithelial hyperplasia, scalloped & depleted colloid, lymphoid infiltrates Vascularity & thyroid storm make treatment prior to surgery important Thyroid storm: hyperpyrexic crisis lots of thyroid hormone into bloodstream BP soars, HR up, death.
Test q: Presurgical treatment of patients w/Graves disease includes: Suppression to prevent thyroid storm.

Colloid depleted, papillary hyperplasia Papillary projections into colloid. Follicular epithelium now has columnar profile colloid is clear and watery.

Columnar papillary epithelial hyperplasia Can see scalloping of the colloid.

Diffusely enlarged not all that nodular. Brown color depleted colloid reduced. Can see pyramidal lobe here.

Test q: All of the following are commonly seen in Graves disease EXCEPT: Lymphoid follicular hyperplasia. (Other choices: Diffuse, symmetric goiter; Ophthalmopathology; Pretibial myxederma; Columnar epithelial hyperplasia.) Test q: Which of the following histopathologic findings are most commonly associated with Graves disease? Diffuse papillary hyperplasia w/small acini, little colloid, tall follicular cells. Test q: A 40M sees his physician because of weight loss, increased appetite, and double vision. On phys exam, his temp is 37.7C, pulse 106/min, respirations 15/min, and BP 140/80 mmHg. A fine tremor is observed in his outstretched hands. He has bilateral proptosis and corneal ulceration. Lab findings include a serum TSH level of 0.1 U/mL. 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 the patients thyroid gland? Papillary projections in thyroid follicles. (Robbins explanation: probable cause is Graves disease)

Toxic multinodular goiter (Plummer syndrome): Iodine deficiency, goitrogens, partial enzymatic deficiencies cause T3 &T4 TSH leads to nodular hyperplasia Nodule autonomy develops, probably secondary to the development of TSH signaling pathway mutations Multinodular goiter (nodular hyperplasia): Normal feedback loops for thyroid function:

Hyperfunctioning. Cannot look at a goiter and tell if it is hyper or hypo-functioning can only tell from clinical measurements.

Multinodular goiter (nodular hyperplasia):

Negative feedback loop two of them: T3/T4 to hypothalamus and pituitary. Any condition resulting in a decrease of T3 or T4 results in an increase in TSH important in the pathogenesis of this disorder.

Note variation in follicle size. Test q: Which of the following best describes
the histologic appearance of the thyroid gland in nodular goiter? Variable follicle size, fibrous scars, evidence of hemorrhage.

Toxic adenoma: Adenoma that oversecretes thyroid hormone. A single nodule, which meets criteria for adenoma, secretes excess thyroid hormones Mutations in genes for TSH receptor or signaling proteins that result in chronic c-AMP stimulation independent of TSH Thyroid adenoma Note single, circumscribed nodule in thyroid lobe: Thyroid, follicular adenoma Note relatively uniform follicles: In contrast to nodular hyperplasia, adenoma usually do have a nicelydefined fibrous capsule. No variation in size. Helps define neoplasm from hyperplastic process. Normal thyroid on right well circumscribed fibrous capsule on the left. Hyperthyroidism: Rare causes Subacute thyroiditis (granulomatous & lymphocytic), functioning thyroid carcinoma, gestational neoplasia and nongestational choriocarcinoma, pituitary or hypothalamic dysfunction, struma ovarii HCG is made by trophoblasts have TSH-like activity. Produce paraneoplastic hyperthyroidism by secondarily stimulating the thyroid gland. Struma ovarii teratomas of ovary can make the thyroid excrete excessive amount of thyroid hormone. Subacute lymphocytic thyroiditis: 1-10% of thyroid in the USA Mostly women, especially middle age or post-partum Autoimmune, related to Hashimoto thyroiditis, with anti-thyroid Abs Usually transient thyroid; may evolve to hypothyroidism Histo: Lymphocytic infiltrates; no Hurthle cell metaplasia Euthyroid hyperplasia: (Diffuse & Multinodular non-toxic goiter) Same etiology as toxic multinodular goiter Initial diffuse hyperplasia replaced by discrete nodules Variable histology of large & small follicles Infarcts, fibrosis, calcification (ischemic changes) May compress airway stridor, dysphagia ? frequency of cancer - not greatly different from a control population (<5%) Multinodular goiter Can cause respiratory stridor/dysphagia. Multinodular goiter (nodular hyperplasia): many nodules, cystic degeneration, calcification, fibrosis Thyroid nodular hyperplasia:

Variable appearance to the follicles small big.

Thyroid nodules: Autopsy thyroid glands - 12% have single nodules & about 1/3 have multiple nodules Frequency of carcinoma in autopsy thyroids (excluding microscopic only cases) = 1-5%
Test q: A 50M presents w/a single nodule in the thyroid measuring 3cm in diameter. The risk that carcinoma will be found on the biopsy of the mass is: 3%. (Other choices: 25, 50, 75, 90%)

Carcinoma of thyroid accounts for < 0.5% of cancer mortality Therefore: most thyroid nodules are benign and most thyroid cancers are non-lethal Diagnoses in Biopsies of Clinical Thyroid Nodules:

Frequency of thyroid carcinoma in autopsy glands, including microscopic only carcinomas:

Finland cancer in 35% of the glands. Thyroid adenoma: Strict criteria necessary to avoid confusion with nodular hyperplasia: single nodule (ideally), fibrous encapsulation, compression of surrounding gland, uniform histology which is different from surrounding gland Hemorrhage may produce rapid and painful enlargement <20% share mutations seen in follicular carcinomas Follicular adenoma:

Cancer only represents 4% of thyroid nodules. Incidental thyroid nodule at autopsy The odds are that this is a benign lesion. The # of thyroid nodules (benign & malignant) has increased over several decades, likely related to radiation exposure.

Frequency of Thyroid Carcinomas: Papillary carcinoma (including follicular variants) 85% Follicular carcinoma 5-15% Medullary carcinoma 5% Anaplastic carcinoma <5%
Test q: Papillary carcinoma represents __% of primary thyroid carcinomas. 80%. (Stats must have changed for this year) Test q: The most common type of thyroid cancer is: Papillary carcinoma.

Uniform morphology, fibrous capsule, artifactual separation w/surrounding thyroid.

Papillary carcinoma: Most common type of thyroid carcinoma (includes follicular variant of papillary carcinoma) M:F = 1:3 (estrogen receptors on follicular cells); patients most commonly 25 - 50 years old Increased incidence in Gardners syndrome Mutations in MAP kinase pathway receptors (RET, NTRK1) or pathway intermediary (BRAF); BRAF correlates with more aggressive tumors Gross: small scarred areas to large, fleshy tumors; circumscribed to infiltrative; 80% are multifocal Micro: usually papillae, with fibrovascular cores, & epithelial cells with clear (Orphan Annie eye) nuclei, nuclear grooves & intranuclear inclusions of cytoplasm, psammoma bodies Prognosis: Good (worse if extrathyroid extension, male, and >45 years) Present in one of two ways asymptomatic nodule palpated in thyroid OR cervical lymph node metastases.

Metastatic papillary carcinoma

Papillary carcinoma of thyroid - a tiny microcarcinoma:

Above: Very small tumors 2-3mm. Here, in tip of thyroid.

Cervical lymph nodes, a common form of presentation, along with a palpable thyroid nodule.

Papillary carcinoma of thyroid typical palpable nodules:

Papillary carcinoma of thyroid a huge tumor in a gland w/nodular hyperplasia

Orphan Annie Eyes:

Multifocal common in thyroid papillary carcinoma 80% of tumors are multifocal.

Large papillary carcinoma. Top nodular hyperplasia. Bottom fleshy-looking papillary thyroid cancer.

Papillary carcinoma of thyroid:

Orphan Annie nuclei clear, not much vesicular chromatin. One of the nuclei features that helps us recognize papillary carcinomas. Now recognize follicular variants of papillary carcinoma: do not form papillae but have same nuclear features. Also see intranuclear cytoplasmic inclusions another feature of papillary thyroid carcinoma. Nuclei are very irregular.

The nuclei define papillary carcinoma: Follicular tumors having the nuclear features of papillary carcinoma are considered follicular variants of papillary carcinoma because both show: lymphatic invasion/metastasis, psammoma bodies, mitotic figures, blood vessel invasion, distant metastasis, encapsulation all features contrasting with follicular carcinomas
Test q: A 25F medical student finds a small nodule in her thyroid. Biopsy shows malignant cells w/clear nuclei, nuclear grooves, and intranuclear inclusions. Psammoma bodies are also present. What is the diagnosis? Papillary carcinoma. Test q: Which histopathology is consistent with papillary carcinoma of the thyroid? Vesicular nuclei and nuclear grooves.

Papillary carcinoma of thyroid

Note radial arrangement of cells on fibrovascular cores. See Orphan Annie nuclei at the periphery of these cores.

Note several psammoma bodies. Targetoid calcifications psammoma bodies.

Note targetoid psammoma bodies

Survival data papillary carcinoma of thyroid:

Stages I, II, and III had great survival rates (>80%). Only 1% of papillary carcinomas are stage 4.

Follicular carcinoma: 2nd most common form of thyroid cancer (5-15% of cases) M:F=1:3 and peak incidence at 40-60 years Two forms: adenoma-like form and invasive form Mutations in PI-3K/AKT pathway in ~33% (RAS gain of function, PTEN loss) & PAX-8 - PPAR1 translocations in 3050% Often forms follicles and occasionally the cells are either clear or oxyphilic (Hurthle cell) Metastasis frequently hematogenous Radioiodine therapy 10 year survival is ~90%, but 80% at 20 years and 70% at 30 years so late mortality may occur Adenoma-like follicular carcinoma: Vascular invasion follicular carcinoma:

Capsular invasion defines as follicular carcinoma.

Diffusely invasive form of follicular carcinoma:

Test q: A 60F presents w/a thyroid nodule measuring 3cm in diameter. A follicular neoplasm is present. Making a diagnosis of follicular carcinoma requires identification of: Vascular invasion. Test q: A follicular neoplasm is removed from the thyroid of a 26F. In order to diagnose follicular carcinoma, the pathologist must demonstrate: Vascular invasion. Test q: Follicular carcinomas are distinguished from adenomas by: Capsular or vascular invasion. Test q: Follicular adenomas are differentiated from carcinoma based on: Invasion of the capsule, and/or lymphovascular invasion within the capsule. Test q: A 52F has a nodular thyroid. Excision shows a single nodule w/a fibrous capsule and compresses the surrounding normal tissue. The mass shows tiny gland-like follicles containing pink material. The surrounding thyroid is unremarkable. There is no penetration of the capsule nor any evidence of vascular invasion. Diagnosis? Follicular adenoma.

Multiple islands of tumor cells spreading throughout the thyroid gland in a diffuse fashion.

Medullary carcinoma: ~5% of thyroid cancer May be component of MEN 2A syndrome (also has pheochromocytoma and parathyroid hyperplasia) May be component of MEN 2B (pheochromocytoma and mucosal neuromas; also marfanoid) MEN 2A & MEN 2B inherited as autosomal dominants with germline point mutations in the RET proto-oncogene on chromosome 10 causing chronic activation of RET in the parafollicular cells Sometimes, MEN 2A is called 2 and 2B is called 3. More common for medullary carcinoma to occur sporadically (70% of cases); sporadic tumors peak in 50s; MEN tumors may occur in children Derived from C-cells (parafollicular, calcitonin producing cells) of thyroid and calcitonin provides marker to detect and follow patients The one form of thyroid carcinoma not derived from follicular epithelial cells but the parafollicular cells. May also secrete ACTH, VIP (vasoactive intestinal polypeptide), serotonin and other substances Multiple Endocrine Neoplasia Syndromes: Lesions MEN1 MEN2A Parathyroid ++++ ++ Pancreas +++ -Pituitary ++ -Gastrinomas ++ -Thyroid/adrenal + -adenoma Med. Thyroid Ca -++++ Pheochromo. -+++ Neuromas --MEN 2B Mucosal neuromas:
Test q: Medullary carcinoma of the thyroid is associated with this neuroendocrine syndrome characterized by pheochromocytoma and parathyroid hyperplasia: MEN 2a. Test q: A patient exhibits mucocutaneous neuromas, pheochromocytoma, and medullary carcinoma of the thyroid. The syndrome described is: MEN IIb. Test q: Components of the multiple endocrine neoplasia (MEN) syndrome I (Werners syndrome) include all of the following EXCEPT: Medullary carcinoma of thyroid. (Other choices: Parathyroid glandular hyperplasia, adrenal cortical adenoma, pituitary adenoma, and pancreatic islet cell tumor) REPEATED x2 Test q: A 28M has a family history of multiple endocrine neoplasia syndrome. He has suffered from pituitary and parathyroid adenoma. He is at increased risk for: Pancreatic tumors. Test q: The RET oncogene is most commonly associated with: medullary carcinoma. Test q: A patient has a strong family history of medullary carcinoma of thyroid. What marker places this patient at high risk for medullary carcinoma? RET.

MEN 2B + ----+++ +++ ++++

MEN1 has 3 P syndrome. MEN 2A & MEN 2B inherited as autosomal dominants with germline point mutations in the RET protooncogene on chromosome 10.

Lumpy bumpy tongue/lip =neuromas.

Medullary carcinoma: Sporadic tumors tend to be large and fleshy at presentation; familial cases resected prophylactically are small and multifocal Microscopic: cords and trabeculae of polygonal to spindled tumor cells separated by an amyloid stroma composed of pro-calcitonin; C-cell hyperplasia in familial forms MEN-2B associated medullary carcinoma is more aggressive than other forms Overall, the 5-year survival is ~50% (not as good as papillary or follicular carcinoma)
Test q: A 40F has had an increasing feeling of fullness in her neck for the past 7mo. On phys exam, her thyroid gland is enlarged and nodular. There is no lymphadenopathy. She undergoes thyroidectomy. Gross exam 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 w/Congo red. Which of the following immunohistochemical stains is most likely to be useful in corroborating the diagnosis of this neoplasm? Calcitonin (Other choices: Cathepsin D, Parathormone, Vimentin, Cytokeratin)

Sporadic medullary carcinoma:

MEN 2A associated med. carcinoma:

Thyroid gland resected from a teenager w/MEN 2A. Had thyroid resected prophylactically because he was found to have abnormal calcitonin level. Multiple, small white nodules scattered throughout the gland. Form either polygonal or spindle cells can be arranged in small nests or trabeculae.

Large, fleshy, tan-appearing tumor several cm in diameter

Note multiple small nodules.

Medullary carcinoma:

Medullary carcinoma:

Note polygonal tumor cells and amyloid in stroma. Amorphous eosinophilic material amyloid derived from procalcitonin folds in -pleated sheets and deposits locally where tumor is growing.

See polygonal tumor cells w/adjacent amyloid (pro-calcitonin).

Test q:The amyloid present in medullary carcinoma of thyroid is composed of: Pro-calcitonin.

Medullary carcinoma Congo red stain:

Medullary carcinoma Calcitonin stain

Congo red highlights the amyloid.

Most diagnostically-helpful stain: calcitonin antibody stain. Cytoplasm is positive.

Anaplastic carcinoma: Several morphologies: giant cell, spindle cell and combinations Many patients have prior or concurrent differentiated thyroid carcinoma (follicular or papillary), supporting that anaplastic thyroid carcinoma arise from dedifferentiation Usually rapid growth in older patient (mean, 65 years) and poor prognosis Patients present with neck mass or airway obstruction secondary to tracheal invasion difficulty breathing Virtually no survivors Anaplastic carcinoma giant cell variant Anaplastic carcinoma of thyroid spindle cell type:

Very large cells, not showing any particular differentiation. Shown here growing into the wall of a blood vessel.

Very poorly differentiated; mitotic activity seen in the lower left.

Test q: A 44M w/no previous illnesses sees his physician because he has had progressive hoarseness, shortness of breath, and stridor for the past 3 weeks. On phys exam, he has a firm, large, tender mass involving the entire right thyroid lobe. CT scan shows that his mass extends posterior to the trachea and into the upper mediastinum. A fine-needle aspiration biopsy of the mass is done, and the specimen shows pleomorphic spindle cells. Surgery is performed to resect the mass, which has 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 patient? Anaplastic carcinoma.

FNA diagnosis of thyroid nodules:

FNA diagnosis of thyroid nodules:

Thyroid nodules are common almost 1/2 of people at autopsy have one. Most are benign. How do you decide who needs to have something done? How can you avoid operating on benign and make sure you arent skipping any malignancies? Fine needle aspiration diagnosis.

FNA diagnosis of thyroid nodules:

As FNA proved useful and clinicians became more confident, the number of cases that they do FNA on increased. The proportion of people w/thyroid lesions that get operated on decreases. The proportion of those who get operated on who do have thyroid cancer increases. All of this = good test.

Parathyroids: embryology & development: rd th 3rd & 4th pharyngeal pouches 3 pouch gives rise to inferior glands & 4 superior 6% of population has > 4 parathyroids; 10% have only 2 or 3 Variable locations: usually upper at level of middle 1/3 of thyroid & lower at inferior poles of thyroid, but sometimes intrathyroidal or mediastinal Fat & oxyphil cells develop at puberty and increase into young adulthood At birth, parathyroid glands are very cellular collections of chief cells. As puberty occurs, morphology changes. Fat accumulates and cells undergoes Hurthle cell metaplasia. The mature post-pubertal gland is roughly 50-50 mixture of parathyroid parenchymal cells w/adipose tissue. The lack of fat in parathyroid glands helps us identify abnormal glands. Anatomic distribution: Upper parathyroid glands: Lower parathyroid glands: Normal adult parathyroid gland

EQUAL amounts of parathyroid cells & fat

Test q: Adult normal parathyroid glands in a 25F would most likely show: 50% fat, 50% cells.

Above: Location most commonly seen for the superior glands: posterior to the thyroid, in line with the middle third. Inferior glands are even more variable. Most commonly, they are at the lower pole of the thyroid. On occasion, they may be within the thymus (mediastinal portion) surgeon may have to go into the chest.

Hypoparathyroidism: Causes: Iatrogenic (most common, usually following complete thyroidectomy) Agenesis: (associated with thymic agenesis [DiGeorge syndrome] & aortic arch abnormalities) DiGeorge = combo of hypoparathyroidism and immunodeficiency Autoimmune destruction: associated with PA, Addisons, mucocutaneous candidiasis & ectodermal dystrophy ++ (APS 1) or isolated parathyroid destruction (Abs vs Ca binding receptor) Genetic: Either autosomal recessive (parathyroid maldevelopment) or autosomal dominant (pro-PTH mutation; or calcium receptor mutation causing activation and PTH suppression) ++ ++ Mutation activates Ca receptor parathyroid gland thinks Ca is high and therefore suppresses parathormone production. Features: low calcium, high PO4, increased bone density (because bone resorption is diminished), cataracts, calcification in basal ganglia & soft tissues, tetany (prolonged contraction of muscles), Q-T lengthened, psychiatric problems
Test q: A 47F visits her physician because she noticed a lump in her neck 1 week ago. On phys exam, there is a 2cm nodule in the right lobe of the thyroid gland. A fine-needle aspiration biopsy is performed, and microscopic exam of the specimen shows cells consistent w/a follicular neoplasm. She undergoes a subtotal thyroidectomy. Which of the following lab tests should be performed on this patient in the immediate postoperative period? Calcium. REPEATED x2 (Robbins explanation: Inadvertent removal of or damage to the parathyroid glands during thyroid surgery can cause hypocalcemia secondary to hypoparathyroidism. This is the most common cause of hypoparathyroidism. Individuals w/hypocalcemia exhibit neuromuscular irritability, carpopedal spasm, and sometimes seizures.) Test q: A 41F presents w/thyroid mass, and she undergoes a complete thyroidectomy. The surgeon inadvertently removes all of the patients parathyroid tissue. Which of the following is most likely to be seen in this patient? Tetany.

Primary hyperparathyroidism: much more common than hypoparathyroidism M:F = 1:4 Presentation: calcium, stones, etc. Usually single adenoma, of inferior glands, with pleomorphism but not mitoses Double adenomas are rare Unilateral neck exploration if one large and one small gland found Sometimes need to do thyroidectomy or mediastinal exploration Asymmetric hyperplasia may mimic adenoma Several genetic changes: MEN1 inactivation (even in sporadic), cyclin D1 gene inversions (sporadic), RET activation (MEN 2 cases), inactivation of calcium sensing receptor (familial hypocalciuric hypercalcemia) MEN1 remember that parathyroid hyperplasia was a component of the MEN1 syndrome, so that gene must have something to do w/increasing parathyroid gland proliferation.
Test q: Osteoporosis and kidney stones are most likely to be associated with: Hyperparathyroidism

Clinical Causes of Hypercalcemia:

Proportion of various tumors with hypercalcemia:

Tumor that has the greatest proportion of cases is multiple myeloma (rare overall, though). The highest number overall is lung cancer.
Test q: Hypercalcemia may be associated w/malignancy. It is most commonly caused by: lung cancer.

Most common: cancer and hyperparathyroidism.

Above: Clues to diagnosis of hyperparathyroidism. Most common was renal stones, followed by bone disease.

Left: Subperiosteal resorption in hyperparathyroidism. Right: Normal bone after Rx of hyperparathyroidism. Parathyroid hormone increases bone resorption and bone formation, but it increases resorption to a greater extent. Finger (left) shows subperiosteal resorption (moth-eaten appearance). After surgery smooth interface.

Causes of primary hyperparathyroidism:

Quiz Time Gland of patient w/1 hyperparathyroidism:

Higher power view of same gland - ? your dx:

Critical distinction is parathyroid gland abnormal? If so, is it an adenoma or a hyperplastic gland? Above: looks abnormal because there is no fat.

Notice big nuclei, but the presence of pleomorphism in endocrine tumors does not mean much. Still could be either nd adenoma or hyperplasia. Need to look at a 2 gland.

Same patients 2

nd

gland Now what is Dx?

Parathyroid adenoma: Typical yellow-orange color.

2 gland is normal, so its not multi-glandular hyperplasia st (So the 1 gland was adenoma surgeon can now stop).

nd

Quiz Time Gland of patient w/1 hyperparathyroidism

nd

gland of same patient - ? Your Dx

Opposite situation here is the 1 gland hypercellular, no fat. Could be either adenoma or hyperplasia.

st

2 gland also abnormal, so its multi-glandular hyperplasia. Usual treatment is to resect 3-3.5 glands.

nd

Parathyroid Hyperplasia:

Test q: A 25M undergoes neck exploration for hypercalcemia. Histopathologic features of two parathyroid glands are: right upper 50% fat, 50% parathyroid cells; right lower 1% fat, 99% parathyroid cells. The findings indicate: Parathyroid adenoma. Test q: At surgery, 3 parathyroid glands are removed w/the following diagnoses: #1. normal lymph node #2. parathyroid gland w/normal fat #3. parathyroid gland w/o fat The surgeon should: Close, the diagnosis is adenoma. Test q: A 52M has high serum Ca++. A surgeon removes two parathyroids, both have no fat. Diagnosis? Hyperplasia. Test q: A 35M exhibits hypercalcemia, renal stones, and radiologic evidence of bone destruction. The most common cause of this disorder among those listed below is ___ of the parathyroids. Single adenoma. (Other choices: Double adenoma, Hyperplasia, and Carcinoma) Test q: A 49M presents w/recurrent renal stones and chronic peptic ulcer disease. Given his electrolyte abnormalities, it is suspected that he has primary hyperparathyroidism. What is the most likely etiology? Parathyroid adenoma.

Secondary hyperparathyroidism: Usually renal failure with hypocalcemia 1,25 di-OH vit D3 and PO4 are important factors related to hypocalcemia in chronic renal failure Kidney is responsible for hydroxylation of Vitamin D to its biologically-active form. With loss of kidney function, Vitamin D is not active (important in increasing Ca resorption from the GI tract). Also, phosphate is retained in chronic renal failure if phosphate goes up, calcium goes down. Because of chronic hypocalcemia, parathormone levels increase and the glands become hyperplastic.
Test q: In renal failure, serum calcium is increased. This increase is due to: Decreased 1,25 di-OH Vitamin D3. (2009, #9 Should this say decreased?)
++

Secondary parathyroid hyperplasia develops because of chronic Ca Development of autonomy = tertiary hyperparathyroidism On occasion, even w/correction of hypocalcemia, one or more glands will continue to function unresponsive to corrected calcium levels (3* hyperparathyroidism). Parathyroid carcinoma note growth into fat:

Parathyroid carcinoma: Rare disease ++ May cause extreme Ca Often difficult histologic diagnosis - best evidence for cancer may be invasion of the surrounding soft tissue at surgery Under microscope, does not look very different from parathyroid hyperplasia or adenoma. One of the best clues that its a carcinoma is can the surgeon easily dissect the gland out from the surrounding soft tissues? In carcinoma, it invades the soft tissues, making the removal difficult. 30-40% 5 year survival; poor prognosis if local recurrence develops within the first 2 years

Hyperparathyroid effects: Renal stones pyelonephritis O Growth of the tumor in an irregular fashion into surrounding Osteitis fibrosa cystica, with brown tumors 2 to net soft tissue marks it as carcinoma. Not well-circumscribed. osteoclastic activity Corneal calcification (band keratopathy) Peptic ulcers Test q: A 60F presents with recurrent nephrolithiasis. On further exam, you detect Pancreatitis corneal calcification, peptic ulcers, and pancreatitis. You suspect: Hyperparathyroidism. (Nephrolithiasis = kidney stones) Cardiac valve calcifications Osteitis Fibrosa: Osteitis Fibrosa: Brown tumor:

Notice two things: great deal of osteoblastic activity (bone-forming) AND osteoclastic activity (can see area of very thin trabeculae). Net result: bone loss.

Marrow space fibrosis. Portions of the bone become cystic, filled in w/a combo of fibrous tissue and osteoclastic giant cells.

Hemosiderin deposits give rusty brown appearance. Can also see fibrous tissue and osteoclastic giant cells. Consequence: pathologic fracture.

Test q: A 60F shows bone pain, polyuria, weakness, constipation, and low serum phosphate. A bone biopsy reveals? Osteitis fibrosa cystica.

Adrenal medulla/Sympathetic paraganglionic system Neural crest origin Synthesize catecholamines (epinephrine & norepinephrine) Single largest collection (of sympathetic paraganglionic cells) = adrenal medulla but other sites include neck, mediastinum, retroperitoneum & viscera Sympathetic paraganglionic cells sometimes called chromaffin cells

Pheochromocytoma/Paraganglioma: Pheochromocytoma = Adrenal paraganglioma Derived from chromaffin cells (paraganglionic tissue) - 10% tumor (extra-adrenal, malignant, bilateral [but higher if MEN or other], non-hypertensive & childhood occurrence) May be component of MEN 2/3, von Hippel Lindau (vascular tumors, RCC, cerebellar hemangioblastoma), NF1, or isolated familial form von Hippel Lindau germline mutation in tumor suppressor gene associated w/pheochromocytomas Episodic or sustained hypertension caused by catecholamine release Extra-adrenal associated with greater nor-epinephrine production Path: brown tumor with large cells having granular cytoplasm arranged in zellballen Malignancy difficult to predict short of metastasis Small pheochromocytoma
Baby pheochromocytoma can see adrenal cortex. In central portion, there is an expansion of the adrenal medulla. Often will see brownish, cystic change in these tumors very early. Larger pheochromocytoma. See stretched adrenal cortex at the periphery. Characteristic brown, sometimes hemorrhagic, appearance.

Pheochromocytoma:

Pheochromocytoma note zellballen

Pheochromocytoma:

Zellballen tight nests of tumor cells surrounded by blood vessels and supporting cells.

Hard to predict its biologic behavior (metastasis).

Neuroblastoma: 80% in < 5 year olds; median is 1.5 years Some cases associated with NF; also familial cases (germline ALK mutation) 65% are intra-abdominal of which most are in the adrenal gland Prognosis depends on age (better if <1.5 years), site (better if mediastinal), stage (better if early, except for IVS), genetic features (better if no N-myc amplification, 17q gain or 1p loss) and histology (better if differentiation & Schwannian stroma) 90% secrete catecholamines, but rarely cause hypertension Path: brown/gray, necrosis, calcification; small dark neuroblastic cells in neuropil with rosettes, sometimes ganglionic cell differentiation Prognosis: 40-50% 5 year survival overall (room for improvement) Profound prognostic implication of N-Myc amplification. Strikingly different outcome (much worse).