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 analgens 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

Early growth and development is independent of TSH (Best Pract Res Clin Endocrinol Metab 2008;22:57)

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

14 week fetus (AFIP images) - 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; relative to pharyngeal pouches

Normal anatomy of thyroid gland

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Two lateral lobes are connected by a thin (usually) 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% (Singapore Med J 2008;49:831), is vestige of thyroglossal duct; is a 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; posterior view

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

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 cells are 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 #1; #2; #3; rich vascular supply; thyroid and parathyroid glands; Sanderson’s polsters; papillary structures #1; #2

AFIP images: follicles lined by flattened epithelium; 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

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

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), neuron specific enolase, 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 and present in most C cells; type II are 130 nm, more electron dense and rare)

EM images: follicular cells #1; #2

EM images (AFIP): 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 pinocytose colloid, release the thyroglobulin, and secrete now active T4 and T3 into bloodstream

Body needs 100 mg of iodide per day from diet to synthesize adequate T4; iodide 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 iodide 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 such as cabbage, turnips and cassava

Diagrams/drawings: hypothalamic-pituitary-thyroid axis; Iodine metabolism in normal thyroid cells

References: Endocrinology, An Integrated Approach, Wikipedia-thyroid hormone

Cytology / fine needle aspiration of thyroid gland-general

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See also cytology section of specific diagnoses

FNA is initial step in management of thyroid nodules, to distinguish benign from neoplastic and to diagnose papillary carcinoma (Cancer 2007;111:306); 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: use ultrasound guidance and on-site assessment of adequacy (Am J Clin Pathol 2008;129:763), one repeat FNA following an initially benign FNA diagnosis (Am J Clin Pathol 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 (Am J Clin Pathol 2007;128:370) or use thin, 22/20-gauge core needle biopsy crush preparations for unsatisfactory/suboptimal specimens (Cancer 2008;114:512); resection not indicated for nodules 3 cm or larger with benign cytology (Surgery 2008;144:963)

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

Thin Prep may be superior to pap stain for epithelial lesions (Cytojournal 2008 Mar 25;5:3)

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 (Am J Clin Pathol 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 (Am J Clin Pathol 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 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)

References: Cytojournal 2008 Apr 7;5:6, NCI Thyroid Fine Needle Aspiration State of the Science Conference (Feb08)

Cytology - 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

25% with diagnosis of “suggestive of follicular neoplasm” have malignancy at excision (Thyroid 2009;19:33)

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

Challenging diagnosis

Numerous lymphocytes or thick colloid in 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 (malignant disease present in 14% with repeat FNA, Am J Surg 2008;196:398)

Cytology - cytodiagnostic groups (continued)

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 (Am J Clin Pathol 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;Oct 19;3:23)

Cytology images: benign thyroid follicle; watery colloid; 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; Thin Prep versus pap stain #1; #2; hyperplastic thyroid nodule has large, single layer sheet of follicular cells folding over itself, with some well formed follicles at different levels of focus; hemorrhagic cyst

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; follicular neoplasm has enlarged follicular cells in loosely cohesive follicles plus isolated, intact cells (Romanowsky stain)

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 (Arch Pathol Lab Med 1992;116:1040, Arch Pathol Lab Med 1991;115:240)

Micro images (AFIP): 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 (Am J Clin Pathol 1987;87:443)

Crystals appear to be associated with inactive follicles (Am J Surg Pathol 1993;17:698)

Crystals also present after dialysis (Arch Pathol Lab Med 1979;103:58)

Useful in differentiating thyroid tissue from parathyroid tissue (no crystals) at frozen section (Am J Surg Pathol 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 is 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 (AFIP): 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 (aplasia of one lobe) is not associated with functional defects; has incidence of 1 per 2000 schoolchildren in iodine sufficient area (Thyroid 2008;18:637)

Associated with Williams-Beuren syndrome (Horm Res 2008;70:316)

Case reports: thyroid hemiagenesis and lingual thyroid presenting as goiter (J Laryngol Otol 2008;122:e17)

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

2-3% are bilateral (Ear Nose Throat J 2008;87:291)

Sites of cysts:

First branchial pouch: preauricular area or beneath posterior half of mandible, may be connected to external auditory canal; cysts are rarely malignant (Diagn Cytopathol 2008;36:876)

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 cyst; usually left sided and associated with neck infection, 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 remnants of ultimobranchial body, (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 (Am J Surg Pathol 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

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 #1, #2

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: Am J Clin Pathol 1994;101:186, Arch Pathol Lab Med 1990;114:1049

Cystinosis and thyroid gland

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Autosomal recessive

Hypothyroidism in 50% due to cysteine accumulation in follicles (Ann Intern Med 2007;147:242), which is prevented by oral cysteamine, which binds cysteine and promotes its excretion (J Clin Endocrinol Metab 1995;80:3257)

Micro: must fix tissue in absolute alcohol, not formalin, or crystals will be dissolved; intracellular deposits of cysteine; follicular atrophy with fibrosis and decreased colloid; focal papillary hyperplasia with dilated follicles and focal neutrophils

Micro images (not thyroid): bone marrow macrophages contain clusters of hexagonal, tubular, and rectangular cysteine crystals (fig 1), which are birefringent using polarizing (fig 2) and first-order compensator filters (fig 3); macrophage with cysteine crystals

References: eMedicine, Wikipedia

DiGeorge syndrome and thyroid gland

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Also called 22q11 deletion syndrome, velo-cardio-facial syndrome

Arrested development of third and fourth branchial pouches, causing absence of C cells, thymus and parathyroid glands and conotruncal cardiac defects

Due to del(22)(q11.22) as detected by FISH

References: Hum Pathol 1987;18:355, eMedicine

Heterotopic thyroid tissue

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Also called ectopic thyroid tissue

Very common

Most common site is base of tongue (see below); also larynx, trachea, rarely pericardium

Also found within thyroglossal duct cysts (25-65%, more sections yield higher percentage) and along path of migration of thyroglossal duct from foramen cecum to lower neck

Note: most mediastinal goiters are due to hyperplastic changes that “pull” thyroid tissue, not to ectopic thyroid tissue

Thyroid tissue in ovary (struma ovarii) usually represents teratoma

Heterotopic thyroid has same diseases as thyroid gland

Lingual thyroid: thyroid tissue at base of tongue due to failure of descent; some thyroid remnants at this site in 10% of normals; 70% with grossly evident lingual thyroid have no normal thyroid gland, so surgical excision may cause hypothyroidism; follicular epithelium may grow between skeletal muscle, simulating invasion

Case reports: adrenal gland #1 (Hum Pathol 1999;30:105), #2 (BMC Urol 2006 Aug 10;6:18), inguinal region (Arch Pathol Lab Med 2005;129:e212), intratracheal #1 (Ear Nose Throat J 2007;86:406), #2 in pregnant woman (AJR Am J Roentgenol 2008;190:W161), left ventricular outflow tract (Ann Thorac Surg 2000;69:620), neck branchial cyst with papillary thyroid carcinoma (World J Surg Oncol 2006;4:24), parotid gland (Singapore Med J 2004;45:437), posterior mediastinum (Cases J 2008 Jul 21;1:53), supraclavicular (Internet Journal of Surgery 2007. Volume 13, Number 1)

Gross images: cystic mass within adrenal gland; ectopic thyroid at lateral neck; intratracheal thyroid tissue with hyperplasia

Micro images: adrenal gland #1; #2 - thyroglobulin stain; #3 - TTF1 stain; lingual thyroid #1 (H&E and thyroglobulin); #2-ectopic thyroid tissue is beneath squamous epithelium of tongue, has hypercellular and microfollicular appearance that may cause mistaken diagnosis of malignancy, radioiodine scan showed no thyroid gland at usual location in neck (AFIP); pancreas; parotid gland; posterior mediastinal mass

DD: hyperplastic thyroid tissue outside gland in Graves’ disease, mechanical implantation outside gland due to surgery or trauma, teratoma with thyroid component, cystically dilated non-thyroid glands with flattened epithelium and inspissated secretions

Lateral aberrant thyroid

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Thyroid tissue lateral to the jugular vein, but NOT in lymph nodes, is often a developmental anomaly (heterotopic thyroid tissue)

Thyroid tissue in lateral neck may be due to surgery and trauma, which implant thyroid tissue; usually microscopic and often surrounded by a fibrous capsule; may also be due to spontaneous separation of thyroid tissue in nodular goiter or Hashimoto’s thyroiditis

Case reports: 35 year old woman with lifelong posterior lateral neck nodule (J Cutan Pathol 2004;31:195)

DD: metastatic well differentiated thyroid carcinoma

Lymph nodes (cervical) containing thyroid tissue

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May represent heterotopic thyroid tissue or metastatic carcinoma - evaluate with extreme caution (Laryngoscope 2005;115:470)

Metastatic carcinoma: primary is usually papillary, but may be occult and require embedding of entire thyroid gland; metastases may replace most of node; primary may also be salivary gland, lung, ovary, thymus

Heterotopic thyroid: usually small aggregate of follicles with no attributes of papillary carcinoma after detailed examination (i.e. no atypical nuclei, no papillary architecture, no psammoma bodies), and limited to capsule/periphery of one or two nodes

May be able to distinguish ectopic thyroid tissue from metastatic tumor by clonal analysis (ectopic tissue is polyclonal, Hum Pathol 1998;29:187) or genetic fingerprinting (Hum Pathol 2007;38:378); difficult to distinguish by morphology

Note: macrophages in lymph nodes draining thyroid tumors may contain thyroglobulin (J Clin Pathol 2001;54:314)

Case reports: primary papillary thyroid carcinoma in lateral cervical lymph node (Exp Mol Pathol 2007;82:91)

Micro images: ectopic thyroid follicles in cervical lymph node have normal architecture and cytology, and appear as a small cluster in nodal capsule (AFIP)

Lymphoepithelial cyst and thyroid gland

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See cystic ultimobranchial body remnants

Rare, benign, <30 cases reported through 2006

2/3 women

Resembles branchial cleft cyst of lateral neck

Associated with chronic lymphocytic thyroiditis (Am J Surg Pathol 1989;13:45)

Case reports: not associated with Hashimoto’s thyroiditis (Pathol Res Pract 1997;193:777)

Gross: yellow-tan cyst containing motor oil-type fluid

Gross images: yellow tan cyst; encapsulated cystic structure

Micro: epithelial lining of attenuated stratified squamous or focal respiratory-type epithelium with abundant adjacent lymphoid tissue; lymphoid follicles common in cyst wall; solid cell nests and basaloid squamous nests often found

Micro images: various images #1; #2; #3; marked lymphoid aggregate

Cytology images: neutrophils, lymphocytes and squamous cells

References: Arch Pathol Lab Med 2003;127:e205, Arch Pathol Lab Med 2003;127:251, Hum Pathol 1994;25:1238

Parasitic nodule and thyroid gland

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Definition: thyroid nodule in neck anatomically separate from thyroid gland

Also called sequestered or accessory nodule

Rosai requires that it be in same fascial plane as thyroid gland, not be associated with lymph nodes, and exhibit a similar histologic appearance as the main gland

Usually multinodular

May include lateral aberrant thyroid or some cases diagnosed as metastatic thyroid carcinoma

May actually be connected to thyroid gland by thin fibrous strand of vascular tissue, or may obtain its vascular supply from surrounding tissue separate from thyroid gland

Case reports: 53 year old woman with Hashimoto’s thyroiditis (Rev Hosp Clin Fac Med Sao Paulo 2000;55:65), 67 year old woman with Graves’ disease (Virchows Arch 1999;434:241)

Gross: 1-4 cm, often fibrovascular pedicle discovered at surgery with careful dissection that connects it to thyroid gland

Gross images: mediastinal thyroid gland with nodular hyperplasia shows anatomically separate nodules (AFIP)

Micro: normal appearing thyroid tissue with colloid-filled or hyperplastic follicles; similar findings in thyroid gland

Micro images (AFIP): small hyperplastic nodule is surrounded by fibroadipose tissue and muscle, and is anatomically separate from thyroid gland, which exhibits nodular hyperplasia (not shown); nodule in patient with Hashimoto’s has same histology as thyroid gland, #1; #2-irregular follicles are lined by oncocytes with marked lymphocytic infiltration

DD: displaced thyroid tissue due to prior surgery (may have suture material), nodular hyperplasia with sequestration

Parathyroid tissue within thyroid gland

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Intrathyroidal parathyroid glands are rare, but parathyroid tissue is not

Parathyroid tissue identified in autopsy study in 22% of fetal thyroids, usually subcapsular and occasionally deep (Pediatr Pathol 1993;13:71)

Parathyroid tissue may undergo same pathologic processes as parathyroid glands (Mod Pathol 1989;2:652, Int Surg 1997;82:87)

Case reports: hypercalcemia that corrected post-FNA (Endocr Pract 2008;14:80), intrathyroidal parathyroid cyst (Endocr Pract 2007;13:56), intrathyroidal parathyroid gland surrounded by thymic tissue (Thyroid 2008;18:1125), intrathyroidal parathyroid carcinoma (Endocr Pract 2007;13:176, Diagn Pathol 2008;3:46)

Solid cell nests of thyroid gland

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Definition: clusters of epithelial cells (main cells and C cells) dispersed between follicles

Derived from branchial cleft pouch complex; are ultimobranchial body remnants (Am J Clin Pathol 1994;101:186)

Located in posterolateral or posteromedial portion of lateral lobes

Present in 90% of neonatal thyroid glands, 30% of adult thyroids

Usually 0.1 mm

May represent a pool of stem cells in adult thyroid gland (Mod Pathol 2004;17:819)

CASTLE tumors may arise from solid cell nests (Am J Surg Pathol 2006;30:994)

Micro: small cells in solid structures; low power may show irregular branching shape; composed of main cells and C cells with intermingled cystic structures containing mucin and mixed follicles; may contain ciliated columnar cells; usually surrounded by stroma and demarcated by adjacent thyroid follicles; often adipose tissue or cartilage nearby

main cells - polygonal, elongated or spindle cells with deeply eosinophilic cytoplasm with squamoid features but no intercellular bridges, nuclei are centrally located, oval to fusiform, with uneven nuclear membrane, occasional nuclear grooves, finely granular chromatin

C cells - minor population of cells with clear cytoplasm and centrally located, small compact nuclei; may also contain cells with follicular lumen-like pattern (mixed follicles)

Micro images: various images #1; #2; solid cell nest between follicles has small collections of colloid; stains #1; #2; #3

Positive stains: main cells - p63 (Mod Pathol 2003;16:43), CEA, cytokeratins except CK20; also bcl2, galectin3 (J Clin Pathol 2003;56:142); C cells - calcitonin, calcitonin gene related factor, chromogranin; lumina - PAS+ colloid

Negative stains: CK20, TTF1, thyroglobulin

EM: main cells - desmosomes, intermediate filaments, intracytoplasmic vacuoles and projections; C cells - neurosecretory granules; also ciliated cells, lymphocytes (Ultrastruct Pathol 2000;24:1)

DD: squamous metaplasia, C-cell hyperplasia (uniformly positive for calcitonin, CAM5.2, AE1/AE3, CK7, p63), tangential sections of normal follicles, metastatic squamous carcinoma, papillary microcarcinoma, medullary carcinoma

References: Arch Pathol Lab Med 1990;114:1049, Hum Pathol 1994;25:684

Tay Sachs disease (amaurotic familial idiocy) and thyroid gland

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Associated with severe mental retardation and early death

Due to accumulation of lipofuscin-like pigment in neurons, ganglia and occasionally thyroid gland

Micro: follicular epithelial cells contain yellow pigmented granules with lipofuscin; are autofluorescent

EM: osmophilic deposits in cytoplasm of follicular cells

Thymic tissue within thyroid gland

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Small portion of thymic gland derives from fourth branchial pouch, together with upper parathyroid glands and ultimobranchial body, which may be source of thymic tissue within thyroid

Thymic rests present in 1% of adult thyroid glands (Virchows Arch A Pathol Anat Histopathol 1991;418:463), 5% of fetal autopsies (Pediatr Pathol 1993;13:431)

May undergo same disease processes as thymus, including thymoma and thymic carcinoma (Am J Clin Pathol 2007;127:230)

Case reports: 6 year old boy (Thyroid 2008;18:377), 22 year old woman with slow growing neck mass (Arch Pathol Lab Med 2001;125:842), intrathyroidal parathyroid gland surrounded by thymic tissue (Thyroid 2008;18:1125)

Gross images: intrathyroidal thymus gland (AFIP)

Cytology: atypical lymphoid proliferation (Thyroid 2003;13:305)

Micro images: thyroid, parathyroid, and thymus; fig A/B: thyroid nodule has spindled, lymphocytic and mixed areas separated by broad fibrous septa; fig C: AE1/CAM5.2 stains spindle cells; fig D: CD3+ lymphocytes, fig E: CD99+ lymphocytes, fig F: CD20 stains focal epithelial spindle cells

Thyroglossal duct / cyst and thyroid gland

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Definition: midline lesion, due to persistent sinus tract connected to foramen cecum or suprasternal notch, or blind tubular structure

70% of congenital neck cysts, often presents as infection in children age 5+ years (Int J Pediatr Otorhinolaryngol 2007;71:1731)

Usually detected in childhood, occasionally in adults

May be familial (OMIM)

Rarely associated with papillary thyroid carcinoma (Hum Pathol 1975;6:717)

Excellent prognosis after excision, even if carcinoma present

After radiation therapy for unrelated head and neck cancer, may enlarge and undergo cystic transformation (AJNR Am J Neuroradiol 2009 Jan 8 [Epub ahead of print])

Case reports: follicular adenoma (Rev Bras Otorrinolaringol (Engl Ed) 2007;73:430), with parathyroid cyst (Kaohsiung J Med Sci 2008;24:487), with papillary carcinoma (J Med Case Reports 2008 Apr 29;2:42), coexisting papillary and squamous cell carcinoma (World J Surg Oncol 2003;1:15)

Treatment: Sistrunk procedure - excision of middle third of hyoid bone, associated sinus tract and residual thyroglossal duct

Gross: sinus tract or cyst, cysts usually 1-4 cm; fistulas may develop secondary to infection and may open into pharynx or skin; may contain viscous brown fluid

Clinical images: thyroglossal duct cysts #1; #2

Gross drawings: fig 1b: path of descent of thyroglossal duct #1; #2; #3

Gross images: thyroglossal duct cyst (AFIP); thyroglossal duct in cadaver

Micro: duct or cyst lined by squamous epithelium if high in neck (near tongue and foramen cecum) or respiratory epithelium if lower; intense lymphocytic infiltration; often mucous glands or thyroid follicles; occasionally cholesterol granuloma (Eur Arch Otorhinolaryngol 2009 Feb 11 [Epub ahead of print]), may only see granulation tissue and fibrosis if chronic infection and inflammation

Micro images: respiratory epithelium #1; #2; #3; sagittal section of 7 1/2 week embryo: arrows indicate thyroglossal tract, A is arytenoid cartilage, C is cricoid cartilage, E is epiglottis, FC is foramen cecum, H is hyoid bone, P is pharynx, T is tongue, TC is thyroid cartilage, TG is thyroid gland; cuboidal lining; follicular adenoma attached to hyoid bone; papillary carcinoma; squamous cell carcinoma

AFIP images: lining of ciliated epithelium (A) and stratified squamous epithelium (B), thyroid follicles present in cyst wall (C); papillary changes of nodular hyperplasia in thyroglossal duct cyst, inset shows columnar cells with basal, hyperchromatic nuclei

Cytology images: with papillary carcinoma

DD: pyramidal lobe of thyroid gland, epidermoid cyst (lined by squamous epithelium, contains keratin, usually no lymphoid follicles)

Endocrine abnormalities and thyroid gland

Amiodarone-induced hyperthyroidism

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Amiodarone is antiarrhythmic medication for atrial and ventricular tachyarrhythmias and less commonly for ischemic heart disease and congestive heart failure; also used for fetal tachycardia (Arch Cardiovasc Dis 2008;101:619)

Contains 37% iodine by weight, which interferes with thyroid hormone metabolic pathways, causing hypo- or hyperthyroidism

Abnormalities occur in 14-18% of amiodarone treated patients; often thyrotoxicosis

More common with iodine-deficient diets

May occur suddenly in patients treated with amiodarone for several years, likely due to its long half life, lipid solubility and accumulation in almost all tissues

Type 1 amiodarone induced thyrotoxicosis: occurs with pre-existing thyroid disease, due to iodine-induced excess thyroid hormone synthesis; microscopic changes are due primarily to pre-existing disease

Type 2 amiodarone induced thyrotoxicosis: due to destructive thyroiditis (Endocr Rev 2001;22:240)

Case reports: fatal amiodarone induced thyrotoxicosis (J Med Case Reports 2007;1:134), 66 year old man with thyrotoxicosis (Arch Pathol Lab Med 2003;127:e275), medically refractory amiodarone induced thyrotoxicosis requiring thyroidectomy (Proc (Bayl Univ Med Cent) 2008;21:382), with nodular goiter (Ann Pharmacother 2008 Dec 23 [Epub ahead of print]), with type 2 disease and papillary thyroid carcinoma (Arch Pathol Lab Med 2004;128:807)

Treatment: differs for type 1 and 2 (Minerva Endocrinol 2008;33:213); dronedarone is an alternative but less effective anti-arrhythmic agent without the adverse thyroid effects (Clin Endocrinol (Oxf) 2009;70:2)

Micro: associated with type 1 disease: changes are those of pre-existing disease

associated with type 2 disease: randomly distributed disrupted follicles filled with desquamated vacuolated epithelial cells, foamy macrophages and scattered lymphocytes, involutional changes, fibrosis

associated with hypothyroidism: involuted follicles with flattened follicular cells, dilated lumina with dense colloid; also small numbers of damaged follicles infiltrated by macrophages (Pathol Int 2008;58:55)

Micro images: degenerated and denuded follicular epithelium with foamy macrophages; destruction of follicles, inflammation and fibrosis; figures A/B: type 2 thyrotoxicosis; H&E, CD68 and cytokeratin

EM: prominent cytoplasmic vacuoles with lipid; also prominent lysosomes

References: Am J Surg Pathol 1987;11:197, eMedicine

Hyperthyroidism - thyroid chapter

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Case reports: fatal myxedema pericarditis in Christian Scientist (Am J Clin Pathol 1986;86:113), 30 year old man with Graves’ disease (Dermatology Online Journal 14 (10):8)

Clinical images: erythematous indurated skin nodules

Micro: dermal mucin accumulation

Micro images: extensive deposits of mucin in mid to upper dermis separating collagen fibers #1; #2; #3; spindled fibroblasts within myxoid stroma; Alcian blue+ dermal mucin

References: eMedicine #1, #2, Wikipedia

Thyroiditis

Acute thyroiditis

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See infectious thyroiditis (below)

Autoimmune thyroiditis

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Definition: non-neoplastic thyroid disorders with anti-thyroid antibodies and associated with specific HLA haplotypes

#1 cause of hypothyroidism in iodine sufficient areas

May be due to disturbance in suppressor T cells

Includes Graves’ disease, Hashimoto’s thyroiditis, and most forms of thyroiditis in this section except infectious

Rosai differentiates based on follicular epithelium: lymphocytic thyroiditis if relatively normal follicles, Hashimoto’s thyroiditis if oncocytic change, Graves’ disease if diffusely hyperplastic follicles

Children often present with asymptomatic goiter of short duration (J Pediatr Endocrinol Metab 2007;20:961, Arch Dis Child 2009;94:33)

Associated with female children of bipolar parents (Eur Neuropsychopharmacol 2007;17:394), radioactive iodine (Epidemiology 2006;17:604, but see JAMA 2006;295:1011), iodine supplementation (Hormones (Athens) 2007;6:25), history of pregnancy (Autoimmunity 2008;41:174)

Focal lymphocytic thyroiditis

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Definition: focal lymphocytes in thyroid gland

Usually an incidental finding

5-20% of adult autopsies, more common in elderly women (Endocr J 2000;47:575)

Associated with low levels of antithyroid antibodies, lack of clinical symptoms

May be early or mild form of autoimmune thyroiditis (J Clin Pathol 1969;22:326)

Treatment: none

Gross: no findings

Micro: focal aggregates of lymphocytes in inter- or intralobular fibrous tissue; no oxyphilic metaplasia, no follicular atrophy, no follicular disruption; may be associated with other thyroid disease

Micro images: patchy lymphocytic inflammation; predominantly small lymphocytes with occasional plasma cells and large lymphocytes

EM: extra- and intrafollicular lymphocytes (Immunobiology 1994;190:290)

EM images: chromatin is coarsely condensed at nuclear periphery, cytoplasm contains abundant single, free ribosomes, a single endoplasmic reticulum and small mitochondria

Hashimoto’s thyroiditis

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Definition: autoimmune disease with goiter, elevated circulating anti-thyroid peroxidase and anti-thyroglobulin antibodies

Also called Hashimoto’s disease, struma lymphomatosa, lymphocytic thyroiditis

First described by Hakaru Hashimoto in 1912 (World J Surg 2008;32:688)

90-95% in women, 45-65 years; clusters in families; more common in Whites than Blacks or Japanese (Am J Clin Pathol 1994;101:698)

Most common cause of sporadic goiter in children in iodine sufficient areas (J Pediatr Endocrinol Metab 2007;20:1199)

Adults present with painless, gradual thyroid failure due to autoimmune destruction, may initially have transient hyperthyroidism

Children have variable hypothyroidism and reversion to euthyroidism so must monitor thyroid function (Clin Endocrinol (Oxf) 2008 Dec 15 [Epub ahead of print]); no female predominance in children with Down’s syndrome (Horm Res 2008;70:278)

Associated with HLA-DR5 (goitrous form), HLA-DR3 (atrophic form)

May coexist with SLE, rheumatoid arthritis, Sjögren’s syndrome, pernicious anemia, type 2 diabetes, Graves’ disease, chronic active hepatitis, adrenal insufficiency, MALT lymphoma of gastrointestinal tract (80:1 relative risk), other B cell lymphomas

Associated with well differentiated thyroid cancer (J Am Coll Surg 2007;204:764); may evolve into thyroid lymphoma (J Clin Pathol 2008;61:438); at thyroidectomy, cancer is common, even if not suspected preoperatively (Thyroid 2008;18:729)

Laboratory: autoantibodies include anti-TSH (specific for Hashimoto’s and Graves’ disease); anti-thyroglobulin (less sensitive but similar specificity as anti-thyroid peroxidase, Clin Chem Lab Med 2006;44:837) and anti-thyroid peroxidase (previously called antimicrosomal antibody, sensitive but not specific as 20% of adult women without disease have these antibodies); anti-iodine transporter (rare)

Note: anti-TSH antibodies block the TSH receptor in Hashimoto’s disease but stimulate the TSH receptor in Graves’ disease

Hashitoxicosis: features of Hashimoto’s thyroiditis and Graves’ disease

Case reports: 41 year old woman with hypothyroidism (Arch Pathol Lab Med 2003;127:e253), associated with mood disorders (Clin Pract Epidemol Ment Health 2007;3:31)

Treatment: often no treatment needed, thyroid hormone for hypothyroidism (may remain euthyroid after 1 year when drug is withdrawn), subtotal thyroidectomy to relieve mass effect; rarely progresses to lymphoma

Gross: diffuse symmetric enlargement of thyroid gland (25 to 250g) with intact capsule, pyramidal lobe may be prominent; may have adhesions but thyroid gland is easily separated from other structures; cut surface resembles lymph nodes with tan-yellow color; may be fibrotic, particularly in elderly patients; may have increased interlobular fibrosis; gland may atrophy; occasionally gland is nodular or asymmetric; no necrosis or calcification

Gross images: atrophic gland; symmetrical enlargement with lobular yellow-gray color (AFIP); nodular gland #1; #2

Hashimoto’s thyroiditis (continued)

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Micro: extensive lymphocytic infiltrate with germinal center formation; lymphocytes are predominantly T cells and plasma cells (polyclonal); atrophic follicles with abundant Hürthle cells/oncocytes but no/reduced colloid; fibrosis may be increased but does not extend beyond capsule; may see giant cells; epithelium may have enlarged or overlapping nuclei with partial nuclear clearing, large squamous nests, hyperplastic follicles, ductal metaplasia (Am J Surg Pathol 2006;30:774); occasionally is nodular

Initial lesion is focal, then oxyphilic metaplasia of follicular cells and nodularity; later little thyroid parenchyma is present

Cytology: moderately cellular with aggregates of oncocytes (finely granular cytoplasm, large hyperchromatic nuclei, variable pleomorphism) and mature lymphocytes; also follicular cells, plasma cells, macrophages, neutrophils; can grade based on lymphocytic infiltration from 0 to 3+ (Table), but does not correlate with clinical parameters (Cytojournal 2007;4:10)

Micro images: nodular gland with prominent lymphoid follicles #1; #2; atrophic thyroid follicles and prominent lymphoid follicles #1; #2; lymphoid follicle and prominent Hürthle cells; lymphocytes, plasma cells, Hürthle cells and giant cells #1; #2; chronic inflammation and Hürthle cells; lymphoplasmacellular inflammation, destroyed follicles with sparse colloid, prominent Hϋrthle cells #1; #2; #3; #4; #5; oxyphilic degeneration of epithelium; prominent lymphoid follicles, abundant colloid in this section; with residual Graves’ disease; various images

AFIP images: low power shows cyst lined by squamous epithelium with septa containing lymphoid follicles and germinal centers; clear cell change (probably due to secondary clear cell change in oncocytes); clear nuclei resemble papillary thyroid carcinoma; circumscribed nodules: left nodule has follicular features, right nodule is more solid and irregular

stains: H&E, CD3; CD68+ giant cells #1; #2; antimicrosomal antibody; antithyroglobulin antibody

cytology images: lymphoid cells mixed with follicular epithelial cells; sheet of follicular cells with oncocytic change mixed with benign lymphoid cells #1; #2; #3-also giant cells; oncocytic cells with atypical nuclei; resembles lymphoma; grade 1-mild lymphocytic inflammatory infiltrate; grade IIa-moderate lymphocytic inflammation, IIb-epithelioid granuloma, IIc-multinucleated giant cell; grade III-marked inflammation with polymorphous lymphocytes; Thin Prep versus pap stain

Virtual slides: #1; #2

Videos: Hashimoto’s thyroiditis

Positive stains: high molecular weight keratin, p63 (Hum Pathol 2003;34:764); may have elevated kappa/lambda ratio (Am J Clin Pathol 2006;125:42); mixture of T and B cells

EM: oncocytic cells have many large mitochondria, reduced numbers of other organelles

Molecular: not monoclonal (Hum Pathol 1988;19:1444)

Hashimoto’s thyroiditis (continued)

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DD: MALT lymphoma (mostly B cells, clonal, destructive lymphoepithelial lesions, Am J Clin Pathol 1998;110:327), Hürthle cell neoplasms, lithium intake causes similar morphologic findings (Hum Pathol 1983;14:737), papillary carcinoma (similar nuclear features, but diffuse, compared to focal features in Hashimoto’s)

References: eMedicine, Wikipedia

Fibrous (fibrosing) variant of Hashimoto’s thyroiditis

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10-12% of all cases

Large symptomatic goiter, marked hypothyroidism

Laboratory: hypothyroidism with increased TSH; markedly elevated antithyroglobulin antibody

Treatment: surgery to relieve dysphagia or dyspnea

Gross: large goiter does not adhere to surrounding structures; may not be recognizable as thyroid tissue

Micro: extensive dense (keloid-like) hyaline fibrosis within thyroid capsule; often extensive squamous metaplasia; marked follicular atrophy, although lobular architecture of gland is maintained

Micro images (AFIP): small and irregular metaplastic squamous follicles; dilated lumen of metaplastic follicle is filled with mucinous material; left: metaplastic follicles are keratin+, top right: mucicarmine stains intraluminal and intracytoplasmic mucin, bottom right: thyroglobulin stains normal follicles but not metaplastic squamous follicles;

Micro images: fibrous tissue (upper left), metaplasia and lymphocytes

DD: Riedel’s thyroiditis (adherence to adjacent structures with infiltration into nerve, fat, muscle and parathyroid glands; vasculitis; fibrous tissue is active proliferative type, residual thyroid tissue is relatively normal, phlebitis present, J Endocrinol Invest 2003;26:444, Histopathology 1983;7:739), carcinoma, MALT lymphoma (Pathol Oncol Res 2008 Oct 17 [Epub ahead of print])

Fibrous atrophy variant of Hashimoto’s thyroiditis

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Features similar to fibrous variant (above), but thyroid gland is much smaller

Small fibrotic gland associated with hypothyroidism or idiopathic myxedema

Gland weighs 1-6 g

Often high titers of antithyroid antibodies and severe hypothyroidism

Micro: extensive destruction of thyroid parenchyma with minimal residual follicles; extensive fibrosis and lymphoplasmacytic infiltrate

Infectious thyroiditis

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Via blood or direct seeding from upper respiratory infections, causes sudden onset of pain and glandular enlargement

Risk factors: malnourished infant, debilitated elderly, immunosuppression, trauma

Often Streptococcus haemolyticus, Streptococcus pneumoniae, Staphylococcus aureus; gram negative bacteria associated with trauma; also Pneumocystis carinii in HIV+ patients with low CD4 counts (Mycoses 2007;50:443)

Is rarely suppurative (Pediatr Emerg Care 2008;24:764); may be associated with pyriform sinus fistula (Pediatr Surg Int 2007;23:779)

Diagnosis: usually based on serologic tests

Case reports: Allescheria boydii in post-transplant patient (Arch Pathol Lab Med 1978;102:158), Aspergillus in AIDS patient (Postgrad Med J 2001;77:336), blastomycosis in woodcutter (Thyroid 2008;18:659), odontogenic origin (Minerva Stomatol 2007;56:461), Salmonella in renal transplant recipient (Transplant Proc 2008;40:3759), septic emboli from endocarditis (Postgrad Med J 2008;84:445)

Treatment: drainage, antibiotics, fistulectomy

Gross: normal or slightly enlarged thyroid gland; may have suppurative areas

Gross images: aspergillus septic foci

Micro: neutrophils, possibly microabscesses and tissue necrosis; fungi are associated with necrosis, acute inflammation and granulomas

Cytology images: Aspergillus, Nocardia

Stains: Gram stain or GMS/PAS may help identify bacteria or fungi; use ISH or IHC for viruses

DD: subacute thyroiditis, ischemic necrosis

References: Thyroid Manager

Tuberculous thyroiditis

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Associated with disseminated TB, immunosuppression or spread from cervical lymph nodes or larynx

Primary disease in thyroid is very rare (Am J Otolaryngol 2007;28:267, Hormones (Athens) 2008;7:330)

Case reports: isolated thyroid nodule (J Coll Physicians Surg Pak 2008;18:121), confirmed by positive immunocytochemistry with monoclonal antibody to Mycobacterium tuberculosis complex (Acta Cytol 2008;52:602), with discharging sinus (The Internet Journal of Pathology 2008; Volume 7, Number 2)

Micro: caseating epithelioid granulomas

DD: granulomatous thyroiditis

References: Medicina (Kaunas) 2004;40:201

Lithium thyroiditis

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Lithium directly damages thyroid follicular cells, which releases thyroglobulin, which may be hydrolyzed to thyroxine, causing hyperthyroidism

Case reports: 53 year old man with sudden cardiac arrest (Case of Week #139)

Micro: small follicles with atrophy and minimal colloid; follicles contain desquamated follicular cells, macrophages and multinucleated giant cells; some giant cells contain birefringent calcium oxalate crystals (J Clin Pathol 1995;48:582)

Micro images: #1; #2; #3; #4; #5; #6

DD: lithium induced autoimmune thyroiditis (prominent lymphocytic inflammation, lymphoid follicles and Hürthle cells, J Clin Pathol 1997;50:172)

Palpation thyroiditis

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Also called multifocal granulomatous thyroiditis

Common (85%+ of surgically resected thyroids) but clinically insignificant

More often associated with goiter than autoimmune thyroiditis (J Korean Med Sci 1988;3:27)

May be due to minor trauma, such as vigorous physical examinations (Am J Clin Pathol 1975;64:639)

Self-limited, no treatment necessary

Case reports: causing new onset atrial fibrillation (Thyroid 2008;18:571)

Gross: normal, or small foci of hemorrhage

Micro: multiple small granulomas centered in disrupted follicles, composed of lymphocytes (usually T cells), macrophages (some foamy), occasional multinucleated giant cells associated with colloid breakdown, usually no necrosis, no neutrophils

Micro images (AFIP): histiocytes within follicle #1; #2-histiocytes are strongly lysozyme+

Micro images; granuloma

DD: sarcoidosis (interstitial granulomas, systemic disease), fungi (PAS+/GMS+, necrosis usually present), subacute thyroiditis (acute inflammatory cells)

Post-operative necrotizing granulomas in thyroid gland

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Similar process as observed in prostate (post-TURP) and bladder

Rare, less than 0.5% of surgical cases (Chir Ital 2007;59:149)

Micro: resembles rheumatoid nodules

Post-partum thyroiditis

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Definition: autoimmune thyroiditis occurring within one year after delivery

Painless enlargement of thyroid, transient thyrotoxicosis, low radioactive iodine uptake, late hypothyroid phase

Resembles chronic lymphocytic thyroiditis with increase in B cells and decrease in suppressor T cells

Present in 44% with Graves’ disease (Thyroid 2007;17:767); associated with smoking (Eur J Epidemiol 2007;22:467)

Hypothyroidism persists in 56% with post-partum hypothyroidism (Thyroid 2005;15:1177)

Laboratory: may have antimicrosomal (antithyroid peroxidase) antibodies

Gross: mild enlargement, no nodules

Micro: lymphocytic infiltration with variable disruption of thyroid glands

DD: Hashimoto’s thyroiditis (oncocytic cells, mild fibrosis), Graves’ disease (different laboratory values, J Endocrinol Invest 2006;29:244)

References: J Clin Endocrinol Metab 2002;87:4042, Eur J Endocrinol 2002;146:275

Radiation thyroiditis (radiation induced changes in thyroid gland)

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Histologic changes vary with dose and type of radioactive isotope

Low doses to tonsils cause nodular hyperplasia of thyroid, follicular disruption, focal hemorrhagic necrosis, neutrophil infiltration

Radioactive iodine may cause large bizarre cells with hyperchromatic nuclei and prominent nucleoli or nuclear features of papillary carcinoma; cells are in clusters and sheets accompanied by lymphocytes, histiocytes and Hürthle cells (Am J Clin Pathol 1997;107:20)

External radiation (for lymphoma) causes hypercellularity, lymphocyte infiltration, adenomatous nodules, oncocytic metaplasia, fibrosis and atypia; chronic changes include fibrosis, atrophy and vascular change

Post-Chernobyl changes include antithyroperoxidase antibodies, but no thyroid dysfunction (J Clin Endocrinol Metab 2008;93:2729)

Childhood radiation is associated with high frequency of allelic loss (Mod Pathol 2008;21:1176)

Micro images (AFIP): bizarre nuclear changes are seen in this hyperplastic thyroid after radiation therapy; papillary changes and marked nuclear atypia in hyperplastic thyroid after radiation therapy

Micro images: hyperplastic epithelium and atypia #1; #2

Riedel’s thyroiditis

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Definition: densely fibrotic inflammatory process involving thyroid gland and adjacent neck tissue

Also called Riedel’s struma, fibrous thyroiditis

Described in 1896 by German surgeon Bernhard Moritz Carl Ludwig Riedel (Wikipedia)

Rare (0.05% of thyroidectomy specimens); slight female predominance, usually age 40-60 years

Associated with inflammatory fibrosclerosis / multifocal systemic fibrosclerosis (mediastinal or retroperitoneal fibrosis, sclerosing cholangitis, inflammatory pseudotumor of orbit)

65% have antithyroid antibodies

Clinically resembles carcinoma

Case reports: prior subacute thyroiditis (Endocr J 2007;54:559), resembling anaplastic carcinoma (Int J Surg 2008;6:e24), with bilateral orbital pseudotumors (J Fr Ophtalmol 2008;31:715e1)

Treatment: surgery to decompress, steroids or tamoxifen (Endocr Pract 2004;10:483)

Gross: extensive stony hard fibrosis involving a goitrous thyroid gland and infiltration into adjacent muscle and other structures, obliterating tissue planes at surgery; binds soft tissues of neck in an “iron collar”, may compress trachea; tan-gray, woody and avascular, no lobules apparent

Micro: no normal lobular pattern; follicles are obliterated or compressed by extensive dense fibrous tissue, which also infiltrates adjacent skeletal muscle; patchy lymphocytes (B & T cells), plasma cells (IgA, lambda) and eosinophils, inflammation in walls of trapped veins; 25% have adenoma centrally in fibrous mass; no oncocytic cells, no giant cells

Cytology: moderate cellularity with fragments of fibrous tissue containing bland spindle cells and myofibroblasts (Diagn Cytopathol 2004;30:193)

Micro images: broad bands of fibrosis with keloid like fibers #1; #2; infiltrative borders; massive scarring and lymphohistiocytic infiltrate #1; #2; obliterating phlebitis #1; #2

AFIP images: atrophic thyroid follicles are surrounded by dense inflammatory infiltrate of lymphocytes, plasma cells and eosinophils, accompanied by dense fibrosis, also characteristic wide bands of keloid-type collagen between individual follicles and surrounding clusters of follicles; stellate scar resembles papillary microcarcinoma; follicles within scar are irregular, but lack nuclear features of papillary carcinoma; heavy inflammatory infiltrate in venous wall

Cytology images: spindled mesenchymal cells

DD: fibrous variant of Hashimoto’s thyroiditis (limited to thyroid, non-infiltrative, less abundant fibrous reaction, oncocytic cells present, more plasma cells, no granulocytes, monocytes or eosinophils, J Endocrinol Invest 2003;26:444), sarcoma (atypical spindle cells, J Clin Pathol 2001;54:570), subacute thyroiditis-late phase (Ann Pathol 2008;28:263)

References: Am J Clin Pathol 1988;90:715, Am J Clin Pathol 1976;65:274, Am J Clin Pathol 2004;121:S50, eMedicine

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Severe acute respiratory syndrome is associated with low T3 and T4 levels in 7% (Clin Endocrinol (Oxf) 2005;63:197)

Micro: distorted, dilated and collapsed follicles; follicular cells are exfoliated into follicle, many cells are undergoing apoptosis (Hum Pathol 2007;38:95); no calcitonin+ cells (Zhonghua Yi Xue Za Zhi 2005;85:667)

EM images: coronavirus that causes SARS

Silent thyroiditis

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Definition: transient, painless hyperthyroidism that spontaneously resolves

Also called painless or sometimes chronic lymphocytic thyroiditis

Relatively uncommon; usually women

Cause unknown, although hyperfunction is due to destruction of thyroid follicles

Is rarely recurrent (Thyroid 2007;17:671) or familial (Endocr J 2005;52:617)

Laboratory: elevated T3/T4, low radioactive iodine uptake

Case reports: with lithium therapy (Rev Med Interne 2007;28:46), post-interferon therapy for Hepatitis C, evolving to Graves’ disease (Eur J Endocrinol 2006;154:367)

Treatment: usually none, beta-blockers possibly in hyperthyroid phase

Gross: diffuse goiter or slightly enlarged thyroid gland

Micro: preserved lobular pattern with follicular destruction, variable lymphocytic infiltrate, rare/no oncocytic change, no/focal fibrosis; T cells present in paracortex, B cells predominate in germinal center

Micro images: mild lymphocytic infiltrate

DD: post-partum thyroiditis (similar, but during pregnancy), chronic thyroiditis (usually no follicular destruction)

Subacute thyroiditis

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Definition: inflammation of thyroid gland that includes granulomas

Also called de Quervain’s thyroiditis or granulomatous thyroiditis

Rare, much less common than Hashimoto’s thyroiditis, but most common cause of thyroid pain

Etiology may be systemic viral infection, since associated with epidemics of measles, mumps, Coxsackie, adenovirus and influenza

Self limited, usually resolves in 6-8 weeks with only 1% having permanent hypothyroidism

75% in women, usually 30-50 years; associated with HLA-B35, rarely familial (Presse Med 2007;36:808)

Painful swallowing (odynophagia), sore throat, thyroid region tenderness, fever, fatigue, malaise

May be transient hypothyroidism at 2-8 weeks

Laboratory: high T3/T4 (initially), elevated sedimentation rate (ESR), suppression of iodine uptake; later hypothyroidism and anti-thyroid antibodies; after weeks to months, patients become euthyroid

Case reports: presenting as fever of unknown origin (Int J Clin Pract 2007 Oct 23 [Epub ahead of print]), 3 year old girl with EBV infection (Thyroid 2005;15:1189), paraneoplastic syndrome of renal cell carcinoma (CMAJ 2003;168:985)

Treatment: none or aspirin in mild cases; prednisone in severe cases, propranolol if thyrotoxicosis; treatment may not affect the clinical course, which is often unpredictable (J Endocrinol Invest 2007;30:631, J Clin Endocrinol Metab 2003;88:2100)

Gross: focal to diffuse enlargement of thyroid gland up to 2x normal size; may be asymmetric with nodules of variable size; may be firm, but does not adhere to surrounding structures

Micro: early-neutrophils and destruction of follicles with colloid depletion; later-noncaseating granulomas surround follicles and engulf colloid; late-fibrosis

Cytology: cellular smears with clustered epithelioid cells, fibrous fragments with enmeshed inflammatory cells, scattered lymphocytes, histiocytes and neutrophils, occasional multinucleated giant cells containing up to 100 nuclei and ingesting colloid or neutrophils; also occasionally thick colloid with central cracks and frayed edges (Diagn Cytopathol 2006;34:18)

Micro images: giant cells, inflammatory cells and destruction of thyroid follicles #1; #2; #3; #4; #5; #6; #7 #8; #9; #10; #11; #12; #13; with fibrosis

Cytology images: syncytial cluster of epithelioid cells with oval nuclei; large multi-nucleated giant cell; multinucleated giant cells and individual epithelial cells; epithelioid cells and lymphocytes #1; #2; multinucleated giant cells in case associated with renal cell carcinoma

Subacute thyroiditis (continued)

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Virtual slides: #1

DD: surgery related (may have suture material), due to teflon injection, palpation thyroiditis, tuberculosis (more distinct granulomas with caseation, AFP+), Riedel’s thyroiditis (adheres to surrounding structures), silent thyroiditis

References: eMedicine #1; #2

Hyperplasia/goiter of thyroid gland

Amyloid goiter of thyroid gland

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Definition: amyloid deposits in thyroid associated with goiter and not with a neoplasm

Very uncommon

Often males, median age 54 years, range 23-75 years

Due to primary or secondary amyloidosis, usually AA type

Diagnosis often made at autopsy

Rapid enlargement of gland (months), diffuse, nontender, may have obstructive symptoms, patients usually euthyroid

Case reports: with Castleman’s disease (Arch Pathol Lab Med 1989;113:542), with diffuse fatty infiltration (Pathol Int 2007;57:449), with myeloma (Arch Pathol Lab Med 1990;114:429), with parathyroid involvement (Arch Pathol Lab Med 2000;124:281), transthyretin type in renal allograft recipient (Endocr Pathol 2008 Mar 28 [Epub ahead of print])

Treatment: thyroidectomy to relieve pressure symptoms, treatment of underlying systemic amyloidosis (Thyroid 2007;17:77)

Gross: enlarged, white-tan

Gross images: thyroid gland is enlarged and bosselated and cut surface has salmon color (AFIP); lipomatosis and amyloidosis

Micro: diffuse amyloid deposition surrounding thyroid follicles, may distort/compress architecture, occasional foreign body giant cell reaction, fatty metaplasia, squamous metaplasia or focal lymphocytic thyroiditis

Micro images (AFIP): amyloid and inflammatory cells permeate the stroma and surround atrophic follicles; apple-green birefringence present with Congo Red stain and polarized light

AFIP images: birefringent apple green staining under polarized light; various images

Positive stains: Congo red shows salmon color and birefringence of apple green staining under polarized light

Negative stains: calcitonin, thyroglobulin (in amyloid area)

DD: medullary thyroid carcinoma (calcitonin+ tumor cells, as well as amyloid)

References: Am J Clin Pathol 1995;104:306

C cell hyperplasia (CCH) of thyroid gland

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Associated with MEN2 and medullary thyroid carcinoma

Reactive CCH commonly occurs in adults (at autopsy, 41% of males and 15% of females, J Clin Endocrinol Metab 1997;82:42)

Women with elevated basal calcitonin and CCH have almost 100% risk of developing medullary thyroid carcinoma vs. 31% in men, who may have C cell hyperplasia only (Mod Pathol 2003;16:756); see also Endocr Relat Cancer 2008 Nov 5 [Epub ahead of print]

Often multifocal and bilateral in at risk patients (Arch Pathol Lab Med 2008;132:1767)

Two types (although literature does not always specify):

Reactive CCH (physiologic CCH): associated with hypercalcemia, Hashimoto’s thyroiditis, prior thyroid surgery, follicular neoplasms, non-Hodgkin’s lymphoma; neonates and elderly; not bilateral; usually does NOT evolve into medullary carcinoma (Am J Clin Pathol 1981;75:347)

Neoplastic CCH (carcinoma in situ/intraepithelial neoplasia): similar RET mutations as medullary carcinoma, is precursor lesion of familial medullary carcinoma, associated with MEN2A or 2B or sporadic; usually occurs in upper 2/3 of lateral lobes

Case reports: 58 year old man with bilateral C cell hyperplasia and chronic lymphocytic thyroiditis (Am J Surg Pathol 1991;15:599)

Treatment: total thyroidectomy, particularly if MEN2A or 2B or RET mutation positive (possibly prophylactic total thyroidectomy or isthmus preserving total bilobectomy [World J Surg 2006;30:860]); otherwise follow with serum calcitonin assays

Gross: may have 1-2 mm nodules in mid to upper thyroid lobes

Micro: total mass of C cells is increased, C cells have abundant clear cytoplasm and round/oval vesicular nuclei, are located within follicular basement membrane; do not extend through defects in follicular basal lamina, no infiltration of thyroid interstitium and no isolated infiltrating C cells in fibrous stroma (or would be micromedullary thyroid carcinoma); no amyloid deposits

Methodology: step 1-all H&E slides are screened for microscopic carcinoma or neoplastic CCH; step 2-all calcitonin stained slides are screened for C cells; in slides with greatest C cell density (aside from tumor) in each lobe, C cells are counted per 100x (low power field/LPF), and diagnosis of CCH requires one area with >50 C cells per LPF in both lobes (Am J Surg Pathol 2001;25:1245) or at least 3 LPF with >50 calcitonin stained cells (J Clin Endocrinol Metab 1997;82:42)

C cell hyperplasia (CCH) of thyroid gland (continued)

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Reactive CCH criteria: need calcitonin staining to identify; bland C cells are similar to follicular cells and histiocytes; at least 3 low power fields with >50 calcitonin stained cells (Hum Pathol 1994;25:514, Mod Pathol 2003;16:756)

Neoplastic CCH criteria: neoplastic cells can be identified without calcitonin staining; cells differ from adjacent follicular cells and resemble medullary thyroid carcinoma cells; cells are mild to moderately atypical with nuclear pleomorphism (Mod Pathol 2003;16:756); progresses from focal to diffuse to nodular hyperplasia to medullary thyroid carcinoma; can use PAS to highlight follicular basement membrane and distinguish cells within follicles (non-invasive) from those outside follicles (invasive)

Patterns of CCH are: focal - segmental proliferation of C cells within thyroid follicles; diffuse - C cells form circumferential intrafollicular collars or nodular - C cells form clusters completely obliterating follicular lumens (Cancer 1996;77:750, Am J Surg Pathol 2001;25:1245)

Cytology: scant bimodal cell population of benign follicular cells and larger calcitonin positive cells (Acta Cytol 1998;42:963)

Micro images: sporadic neoplastic CCH; nodular and non-nodular forms; high power; associated with nodular goiter; MEN2A patient

MEN 2A patients (AFIP): circumferential proliferation of C cells around follicular cells; focal proliferation of C cells (arrow); C cells form an eccentric intrafollicular proliferation

MEN 2A patients with early medullary carcinoma (AFIP): a group of C cells has extended into interstitium #1; #2

Calcitonin staining: calcitonin highlights C cells between follicular epithelium and follicular basement membrane (AFIP); C cells form ring around follicle; sporadic focal CCH; sporadic diffuse CCH #1; #2; pseudonodular CCH; sporadic diffuse and nodular CCH; nodular CCH #1; #2 (fig b/c); CCH (? neoplastic) in patient with familial medullary carcinoma; C cells adjacent to follicular carcinoma (AFIP); radiation induced CCH

Positive stains: calcitonin; also calcitonin gene related peptide, CEA, chromogranin, neural cell adhesion molecule (neoplastic cases); also ER beta (neoplastic cases, Virchows Arch 2007;450:433)

Negative stains: neural cell adhesion molecular (reactive cases), galectin3 (Clin Endocrinol (Oxf) 2002;57:813)

EM: proliferation of C cells within follicular basement membrane adjacent to luminal colloid; scattered dense core secretory granules (containing calcitonin); prominent rough endoplasmic reticulum

EM images (AFIP): MEN2A patient with focal proliferation of C cells between follicular cells (F) and follicular basal lamina (B)

Molecular: RET mutation in neoplastic (Ann Endocrinol (Paris) 2006;67:190), but not sporadic CCH (J Mol Diagn 2007;9:214)

DD nodular CCH: solid cell nests (keratin+, CEA+, variable calcitonin+, EM shows intermediate filaments and cytoplasmic projections but no dense core secretory granules), squamous metaplasia (associated with thyroiditis), parathyroid nests, thymic remnants, nests of thyroid follicular cells with tangential sectioning (cytoplasm not clear)

References: Mod Pathol 2001;14:246

Dyshormonogenetic goiter - thyroid gland

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Definition: inherited disorder causing enzymatic block in T3/T4 pathway and familial goiter

Defects may involve TSH responsiveness, iodine transport, thyroid peroxidase or thyroglobulin (J Med Genet 2005;42:379)

Rare (1 per 30-50K live births in Europe/North America), but #2 cause of congenital hypothyroidism after thyroid dysgenesis

Usually autosomal recessive, causes hypothyroidism, cretinism and death in newborns without treatment

Rarely associated with deafness

Reduced T3/T4 means negative feedback loop is inactive, leading to increased TSH and goiter (usually not present at birth)

Must use strict criteria to diagnose follicular carcinoma in these patients due to malignant appearing histology normally present

Case reports: identified enzymatic defects: iodide transport (Endocr Pathol 1998;9:225), thyroglobulin synthesis (Thyroid 1996;6:11), thyroid peroxidase gene (Clin Endocrinol (Oxf) 2006;64:514); associated with Pendred syndrome (J Pediatr Endocrinol Metab 2008;21:1179, Wikipedia); other case reports: follicular adenoma arising in dyshormonogenetic goiter (UPMC Case #425)

Treatment: symptomatic

Gross: asymmetric enlargement up to 600g, cystic change, fibrosis, new and old hemorrhage; cut surface shows nodules of varying size

Gross images: marked nodular hyperplastic changes with secondary hemorrhage and fibrosis (AFIP); multinodular and hemorrhagic goiter

Micro: markedly cellular nodules composed of trabeculae/cords, solid or microfollicular patterns of epithelial cells with reduced amounts of pale colloid; may have papillary foci, marked cellular pleomorphism (between hyperplastic nodules, not in the nodules) and mitotic figures; capsular and vascular invasion occasionally present and may be simulated by extensive fibrosis; histology varies by site of enzymatic block; true invasion is very rare (Endocr Pathol 1997;8:283)

Cytology: marked hyperplastic changes that resemble a follicular neoplasm or malignancy (Diagn Cytopathol 2005;33:252)

Micro images (AFIP): resembles nodular hyperplasia; some hyperplastic nodules show solid growth pattern; hyperplastic follicles lined by epithelium with marked atypia; left-marked fibrosis causes apparent increased lobularity, right-irregularities at edge simulate invasion

Positive stains: thyroglobulin

Negative stains: calcitonin

EM: tall follicular cells with numerous microvilli, abundant mitochondria and rough endoplasmic reticulum with dilated cisternae

DD: follicular thyroid carcinoma (must have clear cut capsular or vascular invasion if patient has inherited hormonal disorder), multinodular goiter (prominent colloid, focal hyperplasia)

Endemic goiter - thyroid gland

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Definition: goiter associated with iodine deficiency in particular geographic locations, usually distant from the sea

Endemic if prevalence is greater than 5-10%

Iodine supplementation reduces its frequency, but may increase prevalence of autoimmunity (Hormones (Athens) 2007;6:25)

May be exacerbated by goitrogens, such as cassava and cruciferous vegetables, or sewage contamination of water

May also be due to high iodine intake (Am J Public Health 2000;90:1633)

Still present in mountainous districts of Alps, Andes or Himalayas (Thyroid Manager), Bulgaria (Biol Trace Elem Res 2007;116:273), India (Indian J Med Res 2008;128:601), Russia (Georgian Med News 2005:67), Spain (An Pediatr (Barc) 2006;65:234), Turkey (Exp Clin Endocrinol Diabetes 2009;117:64)

Clinical images: endemic goiter #1; #2 (Albania)

Gross: multiple nodules with degenerative changes of fibrosis, old and new hemorrhage (similar to multinodular goiter)

Micro: follicles of varying size, thin follicular cells

Micro images: marked hyperplasia with no colloid

References: Hormones (Athens) 2002;1:157, eMedicine

Graves’ disease - thyroid gland

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Definition: autoimmune disorder with thyrotoxicosis, diffuse goiter, infiltrative ophthalmopathy and occasionally infiltrative dermopathy / pretibial myxedema (scaly thickening and induration of shin, seen late in disease in 5-10%)

Also thyroid acropachy-extremity swelling, clubbing of fingers and toes due to periosteal new bone formation, cardiac hypertrophy

Also called diffuse toxic goiter, autoimmune hyperthyroidism, Basedow’s disease (in Europe)

Cause unknown

Affects 2% of women in US, 0.3% of men

85% of patients are women, usually ages 20-40 years; men are usually older

60% concordance in identical twins; associated with HLA-B8 and HLA-DR3

#1 cause of hyperthyroidism in children

Ophthalmopathy: increased volume of retro-orbital connective tissue and extraocular muscles, due to edema and accumulation of proteoglycans and hyaluronic acid, pushes eyeball forward; sympathetic overstimulation causes wide-eyed, staring gaze; is associated with high titers of anti-TSH antibodies (images: Rodney Dangerfield, Marty Feldman)

Laboratory: increased T3/T4, increased uptake of radioactive iodine, decreased TSH

Autoantibodies: long-acting thyroid stimulator (LATS): IgG that stimulates thyroid function similar to but slower than TSH (i.e. long-acting); specific for Graves’ disease; thyroid stimulating immunoglobulins (TSI) other than LATS also stimulate TSH receptor

TSI negative in 43% of children with Graves’ disease (J Pediatr Endocrinol Metab 2008;21:1085)

TSH binding inhibitor immunoglobulins prevent TSH from binding normally, have either a stimulatory or inhibitory effect

Antibody production is probably due to primary T cell autoimmunity (specific immunoglobulin variable gene families produce antigen receptors that bind to thyroid tissue)

Also antibodies to thyroid peroxidase (microsomal antigen) and thyroglobulin, which are also present in Hashimoto’s thyroiditis

Case reports: peripartum cardiomyopathy (Int J Cardiol 2009 Jan 21 [Epub ahead of print]), occurring after excision of multinodular goiter (Exp Clin Endocrinol Diabetes 2009;117:95)

Treatment: beta blockers, propylthiouracil or other drugs, radioiodine ablation, rituximab, surgery (subtotal thyroidectomy, Endocr J 2008;55:161, World J Surg 2008;32:1269); surgery may improve exophthalmos (Chirurgia (Bucur) 2008;103:291)

Graves’ disease - thyroid gland (continued)

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Gross: diffusely enlarged thyroid gland up to 150g, red and succulent cut surface resembles pancreas; prominent vascularity

Gross images: markedly enlarged gland; diffusely swollen and hyperemic gland #1; #2

Micro: diffuse hyperplasia and hypertrophy of follicular cells with retention of lobular architecture and prominent vascular congestion; tall follicular cells with papillae usually lacking fibrovascular cores; nuclei are round, often polarized, rarely overlap, colloid is pale with scalloped margins (colloid doesn’t fill the lumen, and scalloping is a fixation artifact), lymphoid follicles represent autoimmune phenomena, mostly T cells; also oncocytes, fibrosis; nuclear clearing (15%), florid papillary hyperplasia (13%, may resemble papillary thyroid carcinoma), nuclear grooves or pseudonuclear inclusions (8%), nuclear enlargement, multinucleation, pleomorphism or prominent nucleoli (7%), mitotic figures (6%), psammoma bodies (1%), hyperplastic follicles may extend into adjacent skeletal muscle (1%); rarely small clusters of normal thyroid follicles in adjacent lymph node sinuses (Hum Pathol 2008;39:1080)

Note: preoperative potassium iodide to suppress vascularity causes epithelial involution and colloid accumulation; gland may look normal after 3 weeks of treatment; preoperative PTU exaggerates the hyperplasia and hypertrophy; radioactive iodine initially causes dissolution of some follicles, vascular changes and nuclear changes; late changes are follicular atrophy, fibrosis, nodularity and oncocytic changes

Periorbital tissue: lymphoplasmacytic infiltrate present in periorbital soft tissue and extraorbital skeletal muscles

Skin: hyperkeratosis, deposition of acid mucopolysaccharides in dermis

Cytology: follicular cells in clusters and sheets; cells are tall with finely granular cytoplasm, marginal vacuoles and basal nuclei; malignant cells in cases with papillary thyroid carcinoma have prominent nuclear elongation, pale powdery chromatin, intranuclear grooves and small eccentric nucleoli (Diagn Cytopathol 2004;31:64)

Micro images: prominent infoldings of hyperplastic epithelium #1; #2; #3; #4; #5; epithelium is tall columnar, colloid shows scalloping; no nuclear changes of papillary thyroid carcinoma; various images; numerous plasma cells; follicles with pale colloid; colloid has scalloped margins #1; #2; lobulated parenchyma with irregular follicles #1; #2; irregular follicles with pseudopapillary epithelium and sparse colloid; follicles with tall epithelium and sparse colloid; lymphoid follicles; figure 2B-mild atypia; Graves’ versus papillary thyroid carcinoma: H&E and p27

AFIP images: diffuse hyperplasia with well developed papillae; follicular cells lining papillae are tall and columnar with basal nuclei that are small and hyperchromatic; hyperplastic small follicles are closely mixed with skeletal muscle-do not interpret as malignancy

Graves’ disease - thyroid gland (continued)

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skin - pretibial myxedema #1; #2

Virtual slides: #1; #2; #3; IgM stain

Videos: Graves’ disease #1; #2

Positive stains: p27 (Mod Pathol 2000;13:1014) may distinguish it from papillary thyroid carcinoma; HLA-DR in cytoplasm of thyrocytes and lymphocytes

Negative stains: p63 (Hum Pathol 2003;34:764)

EM: prominent rough endoplasmic reticulum and Golgi, well developed nucleoli in enlarged nuclei

DD: papillary thyroid carcinoma (enlarged overlapping nuclei, nuclear grooves, nuclear inclusions)

DD of thyrotoxicosis: Graves’ disease, Hashitoxicosis, toxic follicular adenoma, toxic sporadic goiter, trophoblastic tumor, struma ovarii, amiodarone induced

References: Wikipedia, eMedicine #1, #2

Simple goiter and nontoxic multinodular goiter - thyroid gland

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Goiter: enlargement of thyroid gland for any reason; usually euthyroid, but may be hypo- or hyperthyroid

Also called nodular hyperplasia

Goiter is visible in 10% of thyroid glands at autopsy, but microscopic nodularity is present in 40%

Most common disease of thyroid gland

May put pressure on trachea (Asian Cardiovasc Thorac Ann 2006;14:416) or esophagus, or grow behind sternum or clavicle (“plunging goiter”)

90% of those affected are women, develops more frequently during adolescence and pregnancy

Cancer present in 11-14% (J Postgrad Med 2007;53:157, Acta Biomed 2004;75:114)

Nontoxic: no hyperthyroidism present

Physiology: low T3/T4 (various mechanisms) means negative feedback loop is inactive, causes increased TSH, which causes follicular hypertrophy and hyperplasia (goiter) with minimal colloid, later follicular atrophy with massive storage of colloid

Simple goiter: also called diffuse nontoxic goiter or colloid goiter; thyroid gland usually 40g or more; eventually converts into multinodular goiter

Multinodular goiter: irregular enlargement of thyroid gland due to repeated episodes of hyperplasia and involution (degeneration) of simple goiter; thyroid gland often 100g or more, and may resemble a neoplasm, particularly if a single firm dominant nodule is present; nodules are clonal or polyclonal, and are due to heterogeneous responses of follicular epithelium to TSH; exophthalmos of Graves’ disease is not present

Colloid goiter: descriptive but not a diagnostic term; means massive storage of colloid within follicles often with flattened epithelium

Causes of simple goiter or nontoxic multinodular goiter:

Endemic goiter: see above

Sporadic goiter: usually teen/young women; caused by goitrogens, hereditary or unknown; usually euthyroid

Drug induced goiter: sulfonamides and phenylbutazone inhibit organification of iodine; iodine containing drugs such as amiodarone interfere with thyroglobulin proteolysis; iodine or lithium interfere with thyroglobulin breakdown and release of T3/T4

Goitrogens: cassava, cabbage, cauliflower, brussels sprouts and turnips interfere with T3/T4 synthesis; cassava contains a thiocyanate which inhibits iodide transport within the thyroid

Hereditary: see above

Plummer syndrome: hyperfunctioning thyroid nodule within a goiter, without ophthalmopathy or dermopathy of Graves’ disease

Plummer-Vinson (Paterson-Kelly) syndrome is different: iron deficiency anemia, glossitis, esophageal dysphasia related to webs, may have thyroid enlargement (World J Surg Oncol 2006;4:65)

Simple and nontoxic multinodular goiter (continued)

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Laboratory: usually normal T3/T4, normal radioactive iodine uptake, thyroglobulin may be elevated

Case reports: with cystic parathyroid adenoma (J Clin Ultrasound 2008;36:243)

Treatment: thyroxine (reduces TSH and size of diffuse simple goiters, less effective for multinodular goiter), radioactive iodine (safe and effective but may cause hypothyroidism), total thyroidectomy eliminates recurrences except for rare cases due to growth in embryonic remnants outside thyroid gland (World J Surg 2007;31:593), near total thyroidectomy reduces hypoparathyroidism (Langenbecks Arch Surg 2006;391:567)

Gross: simple goiters are usually firm with amber cut surface; multinodular goiters are asymmetric, large, up to 2 kg, cystic and hemorrhagic with brown gelatinous colloid nodules with focal calcification and variable size, capsule usually intact and surface is bumpy

Gross images: colloid goiter #1; #2; #3; #4; nodular goiter #1; #2; retrosternal goiter

AFIP images: with various sized nodules, some incompletely encapsulated, with secondary hemorrhage, necrosis and cystic degeneration; nodular hyperplasia with intrathoracic extension, bilateral nodularity and characteristic asymmetric enlargement; cut surface shows numerous poorly circumscribed nodules of variable size; with clear cell change microscopically (clear cell nodules are well circumscribed, white-gray with variable size)

Micro description:

Simple goiter: only one nodule grossly; diffuse enlargement of follicles but with varying size, lined by flattened epithelium with involutional changes; smaller follicles have more columnar epithelium; also asymmetric papillary projections of crowded columnar cells

Multinodular goiter: multiple nodules grossly; dilated follicles of varying sizes with flattened to hyperplastic epithelium; degenerative changes of scarring, hemorrhage and hemosiderin laden macrophages, calcifications, cysts, cholesterol clefts; may have papillary projections and Sanderson’s polsters; may have granulomatous reaction to colloid, oncocytic cells, osseous metaplasia, chronic thyroiditis, highly atypical nuclei if exposed to radioactive substances; rarely vascular invasion at periphery of nodule

Cytology: abundant cracked to watery colloid, flat sheets of uniform follicular cells, macrophages, oncocytic cells

Micro images: irregularly enlarged follicles with flattened epithelium; colloid goiter #1; #2 with cholesterol clefts; squamous metaplasia (CK 5/6+) in capsule #1; #2

AFIP images: no capsule is identified; with Sanderson’s polster (cluster of small follicles projecting into large dilated follicle) covered by columnar epithelium and numerous reabsorption vacuoles; with hypercellular focus exhibiting clear cell changes, some with signet-ring configuration (inset); with adipose metaplasia of stroma; papillary area, with papillae facing center of cystically dilated cavity, no papillary carcinoma nuclear features are present; clear cell change; with focal squamous metaplasia, probably due to degenerative and necrotic changes

Simple and nontoxic multinodular goiter (continued)

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Cytology images: watery colloid and focal dense colloid; large amounts of background colloid

Virtual slides: nodular goiter #1; #2

Videos: nodular goiter; colloid goiter

DD: dyshormonogenetic goiter (increased cellularity is usually diffuse), follicular carcinoma (has vascular or capsular invasion, although multinodular goiter may have vascular invasion at periphery of nodule), toxic goiter (clinical hyperthyroidism)

DD of dominant nodule in nodular goiter vs. adenoma: adenoma is usually single, totally surrounded by capsule, dissimilar from remaining parenchyma, compresses adjacent tissue, composed of follicles smaller than normal gland, monoclonal

Solitary papillary hyperplastic nodule of thyroid gland

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Frequently occurs in children and teenagers

Gross: encapsulated, tan-brown nodules replace entire thyroid lobe, often central cystic change with brown hemorrhagic fluid

Micro: well circumscribed and encapsulated nodules with central cystic and degenerative changes, prominent papillae with edematous stalks and occasional prominent vessels, lining cells have abundant cytoplasm and round nuclei, occasional prominent nucleoli, nuclear grooves or psammoma bodies, calcification; no intranuclear inclusions or well defined nuclear changes of papillary carcinoma

Cytology: pediatric solitary papillary hyperplastic nodules have broad flat sheets and 3D clusters, short nonbranching papillae with transgressing vessels, mild to moderate nuclear pleomorphism and nuclear atypia, occasional nuclear grooves; unlike papillary thyroid carcinoma has fire flares, short nonbranching papillae, watery and inspissated colloid; no intranuclear inclusions; negative for CK19 (Arch Pathol Lab Med 2001;125:1575)

Cytology images: pediatric solitary papillary hyperplastic nodules- various images #1; #2

Toxic multinodular goiter - thyroid gland

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Definition: multinodular goiter plus hyperthyroidism (“toxic”)

Also called Plummer’s disease (particularly if single nodule)

#2 cause of hyperthyroidism after Graves’ disease, #1 in elderly, particularly in iodine deficient areas (J Endocrinol Invest 2002;25:16)

Usually older patients than those with nontoxic multinodular goiter, with long evolution time (Surg Today 2005;35:901)

Associated with atrial fibrillation, tachycardia, weakness and muscle wasting, only rarely with eye disease

Toxic nodular goiter: also called toxic adenoma, may arise in background of multinodular goiter

Laboratory: slight increase in T3/T4 (less than Graves’ disease), reduced TSH

Treatment: radioactive iodine, total thyroidectomy if obstructive symptoms or large (World J Surg 2008;32:1278)

Gross: enlarged thyroid gland with multiple nodules exhibiting fibrosis, old and new hemorrhage and dystrophic calcification

Micro: hyperplastic nodules with discrete fibrous capsule, composed of follicles with papillary hyperplasia and tall columnar cells; nonfunctioning nodules may appear inactive and have degenerative changes of fibrosis, calcification and hemorrhage (old and new)

Molecular: monoclonal or polyclonal

DD: nontoxic multinodular goiter (difficult to distinguish histologically, need imaging studies and clinical correlation), dyshormonogenetic goiter (diffuse changes compared to focal changes in toxic multinodular goiter), Graves’ disease (uniformly enlarged gland with uniformly diffuse hyperplasia and no nodules), follicular carcinoma (vascular invasion or invasion beyond thyroid gland)

References: eMedicine

Miscellaneous non-neoplastic thyroid disorders

Black/pigmented thyroid

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Definition: pigment deposition in thyroid gland in patients on minocycline or related tetracyclines

Pigment also deposited in bone and oral mucosa (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2004;97:718)

Pigment has characteristics of lipofuscin (Am J Clin Pathol 1983;79:738, Hum Pathol 1985;16:72); may be an oxidative product of minocycline, due to its competitive inhibition with thyroid peroxidase

Pigment may also be due to doxepin, lithium carbonate or tricyclic antidepressants; tissue may be dark red (Arch Pathol Lab Med 1994;118:79)

May also be age related (Am J Clin Pathol 1986;85:411)

Not associated with alterations in thyroid function

Hypopigmented foci in gross specimens that are otherwise pigmented should be thoroughly examined to rule out papillary carcinoma (Mod Pathol 1999;12:1181, Arch Pathol Lab Med 2004;128:355)

Case reports: 18 year old man with cystic fibrosis (Case of the Week #98), similar effect from doxycycline (Head Neck 2006;28:373), with hyalinizing trabecular tumor (Endocr J 2008;55:1109), with thyroiditis and papillary microcarcinoma (Thyroid 2008;18:795)

Treatment: none

Gross: normal size, dark-brown to black, minimal fibrosis

Gross images: thyroid gland with dark brown/black pigment #1; #2 at autopsy

Micro: dark brown, dustlike cytoplasmic pigment within thyroid epithelium, colloid or macrophages

Micro images: #1; #2; #3; #4; #5; fig 1: nodule uninvolved by pigmentation represents carcinoma; fig 2: tumor (no pigment) and pigmented non-tumorous follicles (arrow); fig 3: pigmented follicular epithelial cells and macrophages; fig 4: pigment is negative for iron stain

Cytology: may have degenerative changes in follicular epithelial cells with nuclear hyperchromasia and chromatin clumping, suggestive of neoplasia; also pigment in follicular epithelial cells and macrophages (Diagn Cytopathol 1991;7:640); often no specific findings (Diagn Cytopathol 2006;34:106)

Positive stains: Fontana-Masson

EM: lipofuscin pigment in lysosomes

DD: hemochromatosis, ochronosis or cystic fibrosis may also cause pigment

Calcification of thyroid gland

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Nonspecific change; may be associated with benign findings, papillary carcinoma (psammoma bodies) or other malignancy (J Ultrasound Med 2007;26:1349, Head Neck 2002;24:651)

Case reports: associated with intrathyroidal hemorrhage into normal gland (Cases J 2008 May 25;1:11)

Gross images: hemorrhagic gland with peripheral calcification

Micro images: calcification induced artifacts

Killian-Jamieson diverticulum and thyroid gland

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Definition: outpouches of anterolateral wall of cervical esophagus adjacent to cricoid cartilage, near thyroid gland

Also called proximal lateralcervical esophageal diverticula or lateral diverticula fromthe pharyngoesophageal junction area

Less common and smaller than Zenker’s diverticulum (AJR Am J Roentgenol 2001;177:85)

Usually asymptomatic

Case reports: 62 year old woman with incidental thyroid nodule (Arch Pathol Lab Med 2005;129:1497)

Cytology: abundant, bland, mature squamous cells, single and in clusters, with background of inflammatory cells; may contain vegetable material and fungi, consistent with oropharyngeal contents

Micro images: fig 1: ultrasound shows apparent nodule in posterior left lobe (arrows), fig 2: bland, mature squamous cells, fig 3: filamentous bacterial forms and amorphous debris, fig 4: suggestive of vegetable matter

DD of oropharyngeal contents in thyroid gland: fistulas of thyroglossal duct or pyriform sinus

Malakopla