Thyroid gland

Week 3 (day 24) of embryonic life: appears as midline vesicular structure at foramen cecum (base of tongue) from ductlike invagination of ventral pharyngeal endoderm that grows caudally (descends) to become thyroglossal duct in neck; thyroglossal duct then atrophies

Week 7: finishes descent along midline; 2 lateral anlagens develop from 4th-5th branchial pouch, which contains ultimobranchial body; midline and lateral portions of thyroid fuse

Week 9: cords and plates of follicular cells are formed

Week 10: small follicular lumina appear

Week 11-12: colloid secretion appears

Week 14: well developed follicles are lined by follicular cells and contain thyroglobulin containing colloid in lumina

Drawings: descent of thyroid gland

Micro images: invagination of thyroid bud in mouse; week 6-7 embryo; week 8 embryo

14 week fetus - thyroid gland (arrow) is located in groove in front of laryngotracheal primordium; minute follicles are present, some with lumina (inset shows thyroglobulin+ follicular cells)

References: Endocr Rev 2004;25:722, eMedicine

Ultimobranchial body development in thyroid gland

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Ultimobranchial body is outpouch of 4th pharyngeal pouch that fuses with thyroid diverticulum, giving rise to calcitonin-producing C-cells (Dev Dyn 2006;235:1300)

Forms a small organ in many animals, but is only an embryonic structure in humans

C cells are derived from neural crest, migrate to ultimobranchial bodies

Stages of development:

Stage 1: branchial pouch stage at 5-7 weeks gestation-thick walled stratified epithelial cyst in continuity with primitive pharyngeal cavity; part of branchial pouch complexes IV and V

Stage 2: separation stage at 7-8 weeks-separates into parathyroid and ultimobranchial components

Stage 3: incorporation stage at 8-9 weeks-merges with developing lateral lobes

Stage 4: dissolution stage at 9 weeks to term-ultimobranchial body divides into central thick-walled epithelial cyst (disappears post-natally) and peripheral C cells

Drawings: figure 7

Normal anatomy of thyroid gland

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Two lateral lobes are connected by a usually thin isthmus, resembling a butterfly

Each lobe has pointed superior and blunted inferior poles

Thyroid gland is anterior to upper trachea and esophagus, just below level of cricoid cartilage

Right lobe may be longer than left

May be lingual/subhyoid (too high) or substernal (too low)

Pyramidal lobe, present in 40-55%, is vestige of thyroglossal duct; narrow projection of thyroid tissue extending upward from isthmus and lying on surface of thyroid cartilage (Surg Radiol Anat 2007;29:21)

Red-brown, normal weight in adults is 15-25g, heavier in women, increases up to 50% during early secretory phase of menstrual cycle

Thyroid has a complete but thin fibrous capsule with septa that divide gland incompletely into lobules

10% of adults have incidental nodules

Parathyroid glands are usually adjacent to posterior surface

Recurrent laryngeal nerves run in cleft between trachea and esophagus, just medial to thyroid lobes

Blood supply: left superior thyroidal artery (branch of external carotid artery) and right and left inferior thyroidal arteries (branches of subclavian artery), regulated by cervical sympathetic ganglia; venous outflow includes internal jugular vein, brachiocephalic vein, sometimes the anterior jugular vein

Regional lymph nodes: Level VI -paralaryngeal, paratracheal, prelaryngeal (Delphian) nodes adjacent to thyroid gland; Level VII - upper mediastinal

Drawings: relationship to other structures #1; #2; #relationship to other structures #1; #4; posterior view; lymph nodes

Gross images: in situ #1; #2; surgical specimen

References: eMedicine

Normal histology of thyroid gland

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Divided into lobules of 20-40 round to oval follicles, each 50-500 microns, with a single layer of cuboidal to low columnar epithelium

Lumen contains colloid, which is scalloped and pale in follicles with active secretory activity, densely eosinophilic in inactive follicles and more flocculent (“like a clump or tuft of wool”) and basophilic in elderly

Stroma contains C cells, formerly called parafollicular cells (actually are intrafollicular), derived from neural crest

C cells represent 0.1% of gland, produce calcitonin, are present in middle and upper thirds of lateral lobes along central axes, are not present in extreme upper and lower poles or in isthmus

Usually 10 C cells per low power field in adults

C cellsare more numerous in neonates, decrease in adults, increase and appear as nodular aggregates after age 60 years

C cells have pale/clear cytoplasm, oval nuclei, difficult to identify with H&E, use calcitonin stain

Sanderson’s polsters: collections of small follicles projecting into the lumen of large actively secreting follicles; may resemble papillary carcinoma

Oncocytes (Hürthle cells, oxyphilic cells, Ashkenazy cells): large cells with abundant deeply eosinophilic granular cytoplasm and numerous mitochondria

Micro images: follicles lined by flattened epithelium and filled with colloid; #2; #3; rich vascular supply; normal adult follicles are round to oval; follicles are lined by cuboidal epithelium with large, vesicular, centrally located nuclei, some with distinct nucleoli, prominent reabsorption droplets are present in colloid; colloid is flocculent-most likely artifactual and not significant; tangential section of normal thyroid follicle may resemble C cell hyperplasia; thyroid and parathyroid glands

C cells (calcitonin stain) - #1; #2-cells are polyhedral and spindled

Virtual slides: thyroid gland; thyroid and parathyroid glands

Videos: normal thyroid

Normal histology of thyroid gland (continued)

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Positive stains: follicular cells - thyroglobulin (very specific, weaker staining in oncocytic cells), TTF1, low molecular weight keratin; also EMA, vimentin, T3 (triiodothyronine), T4 (thyroxine), ER beta (not alpha), PgR

Note: thyroglobulin may leak out of follicular cells and create false positivity in adjacent cells

colloid - thyroglobulin, Alcian blue, PAS, T3, T4

C cells - calcitonin, calcitonin gene related peptide (CGRP), nonspecific enolase, low molecular weight keratin, chromogranin A , synaptophysin, CEA, somatostatin; C cells are metachromatic with toluidine blue; C cells are NEGATIVE for thyroglobulin

EM: follicular cells - abundant granular endoplasmic reticulum, well developed Golgi, prominent lysosomes, luminal (apical) microvilli, well developed desmosomes with terminal bars between cells, small mitochondria, may contain lipofuscin; nuclei are round with homogeneous chromatin

C cells – intrafollicular location (separated from thyroid interstitium by follicular basal lamina), numerous dense core neurosecretory granules (type I are 280 nm, moderately electron dense, present in most C cells; type II are 130 nm, more electron dense, rare in C cells)

EM images: follicles have luminal microvilli and are joined by junctional complexes towards the apex, cytoplasm contains mitochondria, moderate dilated endoplasmic reticulum and clusters of large lysosomes, small dark granules may be lysosomes; C cell (C) is intrafollicular with secretory granules (arrows), is separated from luminal colloid by cytoplasm of adjacent follicular cells and from the interstitium by the follicular basal lamina

Normal physiology of thyroid gland

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See also Thyroid Gland Physiology in Clinical Chemistry chapter

Purpose of thyroid gland is to produce T4 and T3, which regulate metabolism, increase protein synthesis and increase oxygen consumption in all cells in body; T4 and T3 are also important for growth and development, and maturation of peripheral and central nervous system

Hypothalamus releases thyroid releasing factor (TRF) into hypothalamic-pituitary portal blood circulation, which travels to pituitary, which releases thyroid stimulating hormone (TSH) into blood

Follicular cells normally synthesize thyroglobulin and secrete it into the follicular lumen

Thyroid peroxidase, found in apical membrane of thyroid follicular cells, catalyzes iodination of tyrosine residues on thyroglobulin molecule and coupling of iodotyrosyl residues to form T4 (thyroxine) and T3, which are still bound to thyroglobulin, making them inactive; they are then stored as colloid

In response to TSH, follicular cells pinocytize colloid, release the thyroglobulin, and secrete now active T4 and T3 into bloodstream (drawing)

Body needs 100 mg of iodine per day from diet to synthesis adequate T4; uptake is mediated by human sodium iodide symporter, then oxidized to iodine by iodide peroxidase, which binds to tyrosine

Most T4/T3 is reversibly bound to thyroid binding globulin, which maintains levels within narrow limits

Free T4/T3 enters cells, binds to nuclear receptors, increases protein synthesis and catabolism of carbohydrates and fats (basal metabolic rate)

Decreased serum T4/T3 stimulates release of TRF and TSH via negative feedback regulation; elevated levels have opposite effect

Chronically stimulated (hyperplastic) follicular cells are tall and columnar, may be papillary

C cells secrete calcitonin, which lowers serum calcium by promoting bone absorption of calcium and inhibiting bone resorption by osteoclasts; in humans, has only a minor role in calcium homeostasis

Major role of calcitonin may be to protect skeleton during periods of calcitonin stress, such as growth, pregnancy and lactation

Goitrogens: suppress T4/T3 synthesis by interfering with iodine uptake or other parts of biochemical pathways, causing an increased TSH, which causes goiter (enlargement of thyroid gland); examples include propylthiouracil, which inhibits oxidation of iodide and blocks T4/T3 production; iodides in large doses, which inhibit thyroglobulin proteolysis; vegetables including cabbage, turnips and cassava

Diagrams: feedback loop #1; #2; #3

References: Endocrinology, An Integrated Approach

Cytology / fine needle aspiration of thyroid gland-general

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See also cytology section of specific diagnoses

FNA is most accurate method for rapid diagnosis of thyroid nodules, particularly papillary carcinoma (Cancer 2007;111:306)

FNA is widely accepted as initial step in management of thyroid nodules to distinguish benign from neoplastic, although should be considered a screening test, not a diagnostic test

Main contraindication is bleeding diathesis, as formation of large hematoma at biopsy site may compress trachea

Sensitivity and specificity of FNA are > 90% if specimen adequate, although high false-negative rate exists for detecting thyroid malignancy in males (Am J Surg 2008;195:396)

Recommendations: one repeat FNA following an initially benign FNA diagnosis (AJCP 2006;125:698, Thyroid 2007;17:1061); at least two repeat FNAs following an initially nondiagnostic biopsy (Endocr Pract 2007;13:735); combination of FNA and core needle biopsy is optimal (AJCP 2007;128:370), although core biopsies are not widely performed

Technique: use 25 gauge needle, approach medial to lateral (drawing), make short rapid strokes with only slight changes in direction (CMAJ 2002;167:491); technique without aspiration may be superior (Cancer 1987;59:1201); large needle biopsies obtain more tissue and may cause fewer inadequate specimens (Histopathology 2007;51:249)

Scrapes have equal value to frozen sections in intraoperative management

Ultrafast Pap staining detects Orphan Annie-eyed clear nuclei of papillary thyroid carcinoma

Terminology: recommended to use: (a) standard diagnostic terminology and standard criteria for assessing adequacy (Diagn Cytopathol 2008;36:161), (b) synoptic cytology reporting (ANZ J Surg 2007;77:991); (c) Toyota management process for fewer diagnostic errors (AJCP 2006;126:585)

Limitations: cannot differentiate follicular or Hürthle cell adenomas from carcinoma, which requires surgical excision to detect capsular or vascular invasion; cannot diagnose follicular variant of papillary carcinoma, although cases with features suspicious for papillary carcinoma have higher malignancy rate (72%) than those diagnosed as follicular neoplasm (22%, Cytojournal 2006;3:9)

Adequate specimen: 5 groups of 10 cells each of well preserved follicular epithelium on each of 2 slides

Inadequate specimens: major source of errors (AJCP 2006;125:873); BRAF mutational analysis may be helpful, but often there are inadequate tumor cells (Cytojournal 2006;3:10)

False positives (10%): diagnosis of malignancy often based on only 1 or 2 atypical cytologic features

False negatives (25%): marginally adequate specimens; for papillary thyroid carcinoma, may also be due to nodule heterogeneity (Cancer 2008;114:27)

Lymph nodes: measurement of thyroglobulin in FNA from lymph nodes in patients with history of papillary thyroid carcinoma is useful in detecting recurrent disease, especially if specimen is or likely will be inadequate for evaluation (Cytojournal 2008;5:1)

Cytology / fine needle aspiration of thyroid gland - cytodiagnostic groups

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See Table (from Cytojournal 2005;2:12)

1. Benign colloid nodule (solitary colloid nodule, prominent nodule in multinodular goiter, macrofollicular adenoma)

Abundant thick colloid with cracking or bubble pattern and sheets of benign follicular epithelial cells in honeycomb arrangement; may have slightly hyperplastic Hürthle cells

2. Cellular microfollicular lesion (microfollicular adenoma, hyperplastic microfollicular lesion in Hashimoto’s or multinodular goiter, low grade/well differentiated follicular carcinoma)

Very challenging, often reported as indeterminate or suspicious for malignancy

Abundant follicular cells in clusters, acini and small monolayered sheets; cells have scanty, ill-defined cytoplasm and oval nuclei with regular nuclear contours; nucleoli vary from indistinct to prominent, no nuclear features of papillary carcinoma

3. Hürthle cell lesion (adenoma, carcinoma or hyperplastic nodule in Hashimoto’s or multinodular goiter)

Challenging diagnosis

Numerous lymphocytes or thick colloid in the needle aspirate; sheets and clusters of polygonal epithelial cells with abundant granular, eosinophilic or basophilic cytoplasm, oval nuclei with regular nuclear contours and conspicuous or inconspicuous nucleoli; syncytial clusters of Hürthle (oncocytic) cells and abundant naked tumor cell nuclei are suggestive of Hürthle cell carcinoma (Diagn Cytopathol 1999;20:261)

4. Primary malignant tumor (papillary, high grade microfollicular, insular, medullary or anaplastic carcinoma; lymphoma)

5. Cystic lesion (benign colloid nodule, papillary carcinoma, other thyroid neoplasm)

Most are benign, and due to hemorrhagic degeneration of a benign colloid nodule; cytology shows colloid material, benign follicular epithelial cells and hemosiderin laden macrophages; however papillary carcinoma may show similar changes with only rare tumor cells in smear, diagnostic papillary tumor cells are often present in cell block

6. Thyroiditis (acute, Hashimoto’s, subacute)

7. Other (Graves’ disease, metastatic carcinoma)

8. Nondiagnostic

Other classification groupings for cytology of thyroid gland

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Probably benign: colloid, histiocytes, normal looking follicular cells; non-diagnostic cases with no Hürthle cell change and no atypia (AJCP 2002;118:518)

Suspicious for malignancy (recommend excision): uniform microfollicular pattern, mitotic activity, predominant oncocytic cytology, nuclear atypia but no history of radiation

Follicular neoplasm: monotonous population of follicular cells in cohesive groups with nuclear overlapping and crowding, in background of scant colloid

Follicular neoplasm with features suspicious for papillary carcinoma: follicular cells in loosely cohesive monolayer sheets and follicular groups, focally with nuclear elongation, chromatin clearing and intranuclear grooves, background is watery and thick colloid

Case reports: diffuse large B cell lymphoma misdiagnosed as anaplastic carcinoma (Cytojournal 2006;3:23)

Cytology images: benign thyroid follicle; indeterminate FNA; different grades of lesions

benign colloid nodule: thick, deep blue colloid with cracking; thick, deep blue colloid with bubble pattern; monolayered sheet of benign follicular cells with honeycomb pattern; benign epithelial cells, colloid and occasional macrophages

cellular microfollicular lesion: cells with round nuclei arranged in acini and a small monolayered sheet; cells with round nuclei arranged in acini; solid cellular nodule, microfollicular lesion

Hürthle cell lesion: Hürthle cells with abundant granular cytoplasm and round, central or eccentric nuclei; Hürthle cells in loose monolayered sheets #1; #2

Follicular neoplasms: FNA shows follicular neoplasm, excision shows follicular adenoma; FNA shows follicular neoplasm suspicious for papillary carcinoma, excision shows follicular variant of papillary carcinoma; epithelial cells in follicular arrangement suggesting adenoma, but which could be from a follicular carcinoma

suspicious for papillary carcinoma: marked cellularity, papillary formation, nuclear inclusions and grooves; rare intranuclear inclusions and abundant colloid

FNA tissue effects in thyroid gland

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Acute changes are hemorrhage, granulation tissue, giant cells, hemosiderin laden macrophages, cholesterol clefts, necrosis, rarely infarction (Diagn Cytopathol 1996;15:211)

Chronic changes are infarction, oncocytes, squamous or spindle metaplasia, fibrosis, calcification, vascular thrombosis (Pathol Res Pract 2007;203:641), rarely tumor implantation along needle tract (Acta Cytol 1990;34:801, Acta Dermatovenerol Alp Panonica Adriat 2006;15:169), rarely papillary endothelial hyperplasia (Archives 1992;116:1040, Archives 1991;115:240)

Micro images: fine needle induced changes in follicular adenoma resemble invasion, but actually is growth of follicular epithelium along biopsy tract; pseudoangiosarcomatous pattern in oncocytic neoplasm after FNA is due to hemorrhage and reactive stroma

Crystals in thyroid gland

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Colloid often contains birefringent calcium oxalate crystals, particularly in nodular goiter but also other neoplasms, in both histologic sections and fine needle aspirates (Acta Cytol 1999;43:575)

Present in 79% of normal appearing thyroids at autopsy (AJCP 1987;87:443)

Crystals appear to be associated with inactive follicles (AJSP 1993;17:698)

Crystals also present after dialysis (Archives 1979;103:58)

Useful in differentiating thyroid tissue from parathyroid tissue (no crystals) at frozen section (AJSP 2002;26:813)

Micro images: calcium oxalate crystals-right side photographed with polarizing lenses to show birefringent crystals

Morphologic variations of normal thyroid gland

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See also parathyroid tissue, thymic tissue

● Adipose metaplasia (mature adipose tissue between follicles or near capsule)

Case report: in nodular goiter (Indian J Pathol Microbiol 2007;50:369)

● Intrathyroidal cartilage, skeletal muscle or salivary gland

● Melanosis of follicular cells in old age (pigment granules also contain colloid-Ultrastruct Pathol 1998;22:401), see also black thyroid

● Calcification associated with vessels in elderly, has no laminations (in contrast to psammoma bodies)

● Squamous metaplasia is rare in normal thyroid, more common in thyroid disorders

Micro images: ectopic cartilage; skeletal muscle; squamous metaplasia

Congenital anomalies

Aplasia / hypoplasia of thyroid gland

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See also screening-neonatal hypothyroidism in Clinical Chemistry chapter

Definition: total or partial absence of thyroid gland

Most common cause of congenital hypothyroidism

Occurs in 1 per 3-4K live births; rarely is familial (Acta Endocrinol (Copenh) 1981;96:188)

Hemiagenesis or aplasia of one lobe is more common in left lobe, and not associated with functional defects

Molecular: various mutations, including PAX8 (J Clin Endocrinol Metab 2001;86:3962, J Clin Endocrinol Metab 2001;86:234)

References: eMedicine

Branchial pouch / cleft anomalies and thyroid gland

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May be cyst, sinus, fistula or cartilage in anterolateral neck

Sites of cysts:

First branchial pouch: preauricular area or beneath posterior half of mandible, may be connected to external auditory canal

Second branchial pouch: anterior to sternocleidomastoid muscle in midneck, may communicate with pharynx

Third/fourth branchial pouch: suprasternal or supraclavicular neck; may be misdiagnosed as bronchogenic cysts; usually left sided and associated with neck infections, treatment is ipsilateral thyroidectomy as lesions pass through thyroid

Clinical branchial cysts may rarely: (a) arise within thyroid gland (Korean J Radiol 2006;7:149), (b) actually be cystic ultimobranchial body remnants, (c) actually be papillary thyroid carcinoma (Kaohsiung J Med Sci 2007;23:634), (d) arise within ectopic thyroid tissue that transforms to papillary carcinoma (Ear Nose Throat J 2006;85:675, World J Surg Oncol 2006;4:24)

Branchial pouch / cleft anomalies rarely are associated with squamous cell carcinoma, but cystic neck masses should be considered to be nodal metastases until proven otherwise (common sites of small primary occult tumors are tonsil, posterior tonsillar pillar, retromolar tongue, nasopharynx)

Cysts derived from branchial cleft have squamous epithelium, cysts derived from branchial pouch have respiratory epithelium, although repeated infections may cause squamous metaplasia (Ann R Coll Surg Engl 2007;89:W12)

Case reports: branchial cleft-like cysts with Hashimoto’s thyroiditis (AJSP 1989;13:45), branchial cyst extending into anterior mediastinum (The Internet Journal of Thoracic and Cardiovascular Surgery 2007; Volume 9, Number 1)

Gross drawings: third branchial pouch cyst and related structures

Micro: respiratory or squamous epithelium and lymphoid follicles; cysts may have sebaceous or mucinous glands; may be secondarily infected; occasionally found in thyroid tissue as heterotopic cartilage, thymus or solid cell nests representing ultimobranchial body remnants (see below)

Micro images: branchial cyst that extended into anterior mediastinum has thick fibrous wall and lymphocytic infiltration; intrathyroidal branchial cleft cyst (fig 1C)

Cytology: may be interpreted as suspicious for carcinoma (Cytopathology 2007;18:184)

DD: papillary carcinoma with cystic change (positive for TTF1, thyroglobulin)

References: Wikipedia #1, #2, eMedicine

Cystic ultimobranchial body remnants and thyroid gland

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See also solid cell nests (solid ultimobranchial body remnants), lymphoepithelial cyst

Usually soft tissue of neck near thyroid, occasionally within thyroid

Very common in neonates

Branchial pouch cysts located near thyroid may actually be cystic ultimobranchial body remnants

Micro: cysts lined by flattened multilayered epithelium of squamous cells, occasionally ciliated columnar epithelium; may contain dense eosinophilic material in lumen; may be adjacent to solid cell nests; variable lymphocytes and rare pancreatic tissue

Micro images: cystic solid cell nests

References: AJCP 1994;101:186, Archives 1990;114:1049

Cystinosis and thyroid gland

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Autosomal recessive

Hypothyroidism in 50% (Ann Intern Med 2007;147:242), prevented by oral cysteamine (J Clin Endocrinol Metab 1995;80:3257)