Pathology Chapter 24 Endocrine Thyroid P 1116 Diffuse goiter Endemic iodine deficiency o Goitrogen consumption Sporadic o Female, goitrogens,

gens, hereditary enzymatic defects affecting thyroid hormone synthesis (AR), idiopathic Clinical course: mass effects, normal T3 and T4, high-normal to mildly elevated TSH

Multinodular goiter Sporadic and endemic Caused by recurrent episodes of hyperplasia and involution of long-standing single nodule goiters Arise because of variation in follicular cell response to trophic hormones Clinical course: mass effects, euthyroid or subclinical hyperthyroidism (decreased TSH), uneven iodine uptake o Plummer syndrome: toxic multinodular goiter may develop in long-standing goiter (producing hyperthyroidism) without infiltrative ophthalmopathy and dermopathy

Neoplasms benign:malignant::10:1; Malignancy is more likely in: solitary nodules, younger patients, males, history of radiation, cold nodules; DX by fine-needle aspiration Adenomas o Discrete, solitary masses derived from follicular epithelium, most are non-functional, do not give rise to carcinoma o Somatic mutations of TSH receptor signalling pathway found in toxic adenomas o Hallmark is intact, well-formed capsule (vs multinodular goiters vs follicular carcinomas); Hrthle cells o Clinical course: unilateral painless mass (can cause mass effects), non-functioning adenomas are cold, toxic adenomas are hot; surgically removed, have excellent prognosis and do not recur or metastasize Carcinomas o Papillary: 85%; derived from follicular epithelium; activation of MAPK pathway by RET or NTRK1 rearrangements or activating BRAF mutations; RET/PTC rearrangements more common in tumors with radiation history; BRAF mutations associated with metastatic disease and extra-thyroid extension; increased risk with radiation exposure; solitary or multifocal, psammoma bodies (calcifications) seen, papillary foci point to dx, ground-glass Orphan Annie eye nuclei; first manifestation may be enlarged lymph node, thyroid nodule moves with swallowing, mass effects suggests advanced disease; cold nodules; excellent prognosis (better in pts <40YOA and without extrathyroid extension) o Follicular: 5-15%; derived from follicular epithelium; 1/3-1/2 have mutations in PI-3K/AKT signalling pathway (constant activation); associated with iodine deficiency; single nodules, Hrthle cells present occasionally, do not spread to lymph nodes but may extend into surrounding soft tissue, metastasize to liver, lungs, bone; cold nodules, prognosis depends on stage and extension; tx is thyroidectomy and radioactive iodine (to ID mets), thyroid hormone after surgery o Anaplastic (undifferentiated): <5%; derived from follicular epithelium; arise de novo or by dedifferentiation of a well-differentiated papillary or follicular carcinoma; aggressive (mortality almost 100%); variable morphology (giant cells, spindle cells, mixed spindle and giant); present as rapidly-enlarging neck mass (probably already spread to lungs by time of presentation), symptoms: dysphagia, hoarseness, cough; no effective tx, death w/in 1 yr o Medullary: 5%; familial cancer occurs in MEN2 associated with germline RET mutations (constant activation); neuroendocrine neoplasms derived from parafollicular (C) cells, secrete calcitonin, serotonin, ACTH or VIP; sporadic present as solitary nodules, familial are commonly bilateral and multicentric; sx: mass effects in sporadic sometimes paraneoplastic sx; CEA marker; familial tumor sx: thyroid sx or endocrine tumors of other organs; MEN2B cancers are most aggressive

Congenital anomalies Thyroglossal duct or cyst: midline anterior to trachea, from remnants of tubular development of thyroid, mucinous or clear secretions, high in neck lined by stratified squamous epithelium, low in neck lined by thyroidal acinar epithelium, lymphocytic infiltrate present close to epithelium, infection may result in abscess or cancer

Parathyroid Glands Chief cells with secretory granules containing PTH, oxyphil cells containing mitochondria and glycogen; stromal fat in gland increases with age; activity controlled by free calcium (ionized) in blood (decreased levels stimulate PTH release) PTH: increases renal tubular reabsorption of calcium, increases conversion of vitamin D to active dihydroxy form in kidneys, increases urinary phosphate excretion, augments GI calcium absorption o Elevated levels of PTH cause hypercalcemia; malignancy is most common cause of hypercalcemia (due to increased bone reabsorption both in osteolytic metastases and tumors that have not metastasized to bone that secrete active PTHrP) PTHrP inhibits osteoprotegerin secretion by osteoblastic cells, altering RANKL/osteoprotegerin ratio in favor of osteoclastogenesis

Hyperparathyroidism Primary: autonomous, spontaneous overproduction of PTH due to lesions; associated with skeletal eroisions and kidney stones; can be asymptomatic (pts labs need to be checked periodically) or present with painful bones, renal stones, abdominal groans, and psychic moans, can also have cardiac arryhthmias and neuromuscular abnormalities o Adenoma: 85-95%, affects adult women; most cases are sporadic, familal adenomas are associated with MEN1, MEN2, and familal hypocalciuric hypercalcemia (AD, enhanced parathyroid function due to decreased sensitivity to extracellular calcium due to inactivating mutations in parathyroid calcium-sensing receptor gene (CASR)); most sporadic tumors are monoclonal; sporadic tumor defects: Cyclin D1 gene inversions, MEN1 mutations; adenomas are usually solitary and arise near thyroid glands or in ectopic site (mediastinum); bizarre and pleiomorphic nuclei seen o Primary hyperplasia: 5-10%; usually all 4 glands; usually chief cell hyperplasia o Parathyroid carcinoma: <1%; circumscribed lesions similar to adenomas or invasive; cells appear normal, diagnosis based on local invasion and metastases Secondary: seen in chronic renal insufficiency and with inadequate dietary calcium, steatorrhea, vitamin D deficiency; CRF -> decreased phosphate excretion -> hyperphosphatemia -> depression of serum calcium levels -> stimulation of PTH; CRF -> loss of renal substance -> decreased -1-hydroxylase -> decreased vitamin D activation -> decreases intestinal absorption of calcium; vitamin D has suppressive effects on parathyroid growth and PTH secretion; parathyroid glands are hyperplastic (more chief cells, less fat cells); renal osteodystrophy (bone lesions); metastatic calcification of heart, lungs, stomach, blood vessels (calcifylaxis); tx with vitamin D and phosphate binders Tertiary: parathyroid activity becomes autonomous and excessive with resultant hypercalcemia; tx is parathyroidectomy

Hypoparathyroidism Causes: o Usually due to inadvertent damage to parathyroids during thyroid surgery o Autoimmune hypoparathyroidism: associated with chronic mucocutaneous candidiasis and primary adrenal insufficiency (autoimmune polyendocrine syndrome type 1 (APS1)) caused by mutations in AIRE gene o Autosomal dominant hypoparathyroidism: caused by gain-of-function mutation of calcium-sensing receptor (CASR) gene which cause suppression of PTH -> hypocalcemia and hypercalciuria o Familal isolated hypoparathyroidism: AD mutation in PTH precursor peptide gene which impairs processing of mature hormone; AR loss of function mutation in glial cells missing-2 (GCM-2) transcription factor gene, essential for parathyroid gland development o Congenital absence of parathyroid glands: 22q11 deletion syndrome (DiGeorge) Clinical manifestations: o Tetany (neuromuscular irritability), paresthesias, carpopedal spasm, laryngospasm, generalized seizures; Chvostek sign, Trousseau sign; Mental status changes; Intracranial manifestations; ocular calcifications; cardiovascular manifestations (prolonged QT interval); dental abnormalities (hypoplasia, etc)

Pseudohyperparathyroidism: end organ resistance to actions of PTH; PTH is normal or elevated, hypocalcemia, hyperphosphatemia Albrights hereditary osteodystrophy: AD kidney unresponsiveness to PTH One form with multi-organ hormone resistance due to genetic defects in G protein second messenger signalling pathway; THS and FSH/LH resistance