surgical pathology thyroid gland

THYROID GLANDDr. SilvaSurgical Pathology

EMBRYOLOGY OF THE 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

Normal anatomy of thyroid gland• 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%, is

vestige of thyroglossal duct; is a narrow projection of thyroid tissue extending upward from isthmus and lying on surface of thyroid cartilage

• 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

Normal histology of thyroid gland• 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

Normal thyroid seen microscopically consists of follicles lined by a an epithelium and filled with colloid. The follicles vary

Surgical Pathology of 24

somewhat in size. The interstitium, which may contain "C" cells, is not prominent.

This immunoperoxidase stain with antibody to calcitonin identifies the "C" cells (parafollicular cells) of the thyroid interstitium between the follicles or adjacent to the epithelium of follicles. These cells secrete calcitonin.

Nodular hyperplasia showing so-called ‘Sanderson's polster’.

Cytodiagnostic Groups with Commonly Encountered Thyroid Nodular Lesions

1. Benign colloid noduleo Solitary colloid noduleo Prominent nodule in MNGo Macrofollicular adenoma

*Notes: 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 lesiono Microfollicular adenomao Low-grade follicular carcinomao Hyperplastic microfollicular

lesions in HT or MNG*Notes: Very challenging, often reported as indeterminate or suspicious for malignancyAbundant 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

3. Hurthle cell lesiono Hurthle cell adenomao Hurthle cell carcinomao Hyperplastic Hurthle cell nodule

in HT or MNG*Notes: Challenging diagnosisNumerous 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

4. Primary malignant tumoro Papillary carcinomao High-grade microfollicular

carcinomao Insular carcinomao Medullary carcinomao Anaplastic carcinomao Lymphoma

5. Cystic lesionso Benign colloid noduleo Papillary carcinomao Other thyroid neoplasms

*Notes: 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. Thyroiditiso Acute thyroiditiso Hashimoto thyroiditiso Subacute thyroiditis

7. Other lesions- Graves disease- Metastatic cancer

8. Non-diagnostic category* HT, Hashimoto thyroiditis; MNG,


multinodular colloid goiter

Other classification groupings for cytology of thyroid gland

Probably benign: colloid, histiocytes, normal looking follicular cells; non-diagnostic cases with no Hürthle cell change and no atypia

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

A monolayered sheet of benign follicular epithelial cells with honeycomb pattern in FNA of a benign colloid nodule (Diff-Quik stain, × 400)

Sheets of Benign thyroid follicles

Monotonous population of follicular cells arranged in cohesive follicular groups with nuclear overlapping and crowding, case diagnosed as follicular neoplasm (1A). Histologic follow-up showing follicular adenoma (thickly encapsulated follicular patterned lesion with no capsular or vascular invasion), the inset shows the same nuclear features as seen in cytology (1B).

A fine-needle aspiration biopsy specimen suspicious for papillary thyroid cancer (original magnification x510) demonstrating marked cellularity (A), papillary formation (B), and nuclear inclusions and grooves (arrows) (C) from a patient with a final pathologic diagnosis of papillary carcinoma.

Congenital Anomalies

Aplasia / hypoplasia of thyroid gland• total or partial absence of thyroid

gland• Most common cause of congenital

hypothyroidism• Occurs in 1 per 3-4K live births;

rarely is familial• Hemiagenesis (aplasia of one lobe) is

not associated with functional defects; has incidence of 1 per 2000 schoolchildren in iodine sufficient area

Heterotopic thyroid tissue• Also called ectopic thyroid tissue;

very common• Most common site is base of tongue

also larynx, trachea, rarely pericardium

• Also found within thyroglossal duct cysts (25-65%) and along path of migration of thyroglossal duct from foramen cecum to lower neck

• Thyroid tissue in ovary (struma ovarii) usually represents teratoma


http://www.pathologyoutlines.com/ovarytumor.html

http://www.pathologyoutlines.com/ovarytumor.html

• Heterotopic thyroid has same diseases as thyroid gland

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

Thyroglossal duct / cyst and thyroid gland• 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

• Usually detected in childhood, occasionally in adults

• May be familial• Rarely associated with papillary

thyroid carcinoma• Excellent prognosis after excision,

even if carcinoma present• After radiation therapy for unrelated

head and neck cancer, may enlarge and undergo cystic transformation

Parasitic nodule and thyroid gland• thyroid nodule in neck anatomically

separate from thyroid gland• Also called sequestered or accessory

nodule• 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

*Notes: 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

ACUTE / INFECTIOUS THYROIDITIS• 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

• Is rarely suppurative ; may be associated with pyriform sinus fistula

• Diagnosis: usually based on serologic tests

• Treatment: drainage, antibiotics, fistulectomy

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

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

*Notes: Stains: Gram stain or GMS/PAS may help identify bacteria or fungi; use ISH or IHC for virusesDD: subacute thyroiditis, ischemic necrosis

Autoimmune thyroiditis• 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


Focal lymphocytic thyroiditis• focal lymphocytes in thyroid gland• Usually an incidental finding• 5-20% of adult autopsies, more

common in elderly women• Associated with low levels of

antithyroid antibodies, lack of clinical symptoms

• May be early or mild form of autoimmune thyroiditis

• 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

Hashimoto’s thyroiditis• focal lymphocytes in thyroid gland• Usually an incidental finding• 5-20% of adult autopsies, more

common in elderly women• Associated with low levels of

antithyroid antibodies, lack of clinical symptoms

• May be early or mild form of autoimmune thyroiditis

• 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

• 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

• LAB: autoantibodies includes anti-TSH; antithyroglobulin; antithyroid peroxidase

• Treatment: often no tx needed, thyroid hormone for hypothyroidism;

subtotal thyroidectomy to relieve mass effect

Notes: Laboratory: autoantibodies include anti-TSH (specific for Hashimoto’s and Graves’ disease); anti-thyroglobulin (less sensitive but similar specificity as anti-thyroid peroxidase, 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’

• 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

• 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; 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+

Hashimoto thyroiditis showing in FNA numerous lymphoid cells admixed with a sheet of follicular epithelial cells (Papanicolaou stain, × 100).

Positive stains: high molecular weight keratin, p63; may have elevated kappa/lambda ratio; mixture of T and B cellsEM: oncocytic cells have many large mitochondria, reduced numbers of other organelles

Subacute thyroiditis• 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

• 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

• 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

This is subacute granulomatous thyroiditis (DeQuervain's disease), which probably follows a viral infection and leads to a painful enlarged thyroid. This disease is usually self-limited over weeks to months and the patients return to a euthyroid state. Note the foreign body giant cells with destruction of thyroid follicles.


Fine-needle aspiration thyroid: Unique epithelioid cells (bottom right), giant cell of Langhans type, and lymphocytes.

Hyperplasia/goiter of thyroid gland• Amyloid goiter of thyroid gland• 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

This is a greatly enlarged thyroid gland from a case of amyloidosis. The external and cut surfaces can be seen. The photo on the right reveals the birefringent apple green staining of amyloid viewed under polarized light.Positive stains: Congo red shows salmon color and birefringence of apple green staining under polarized lightNegative stains: calcitonin, thyroglobulin (in amyloid area)

Graves’ disease• 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

• 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

• 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

• Treatment: beta blockers, propylthiouracil or other drugs, radioiodine ablation, rituximab, surgery (subtotal thyroidectomy,); surgery may improve exophthalmos

• Gross: diffusely enlarged thyroid gland up to 150g, red and succulent


cut surface resembles pancreas; prominent vascularity

• 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

Histopathological image of diffuse hyperplasia of the thyroid gland clinically presenting as hyperthyroidism. H & E stain.

Toxic multinodular goiter• 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

• Usually older patients than those with nontoxic multinodular goiter, with long evolution time

• 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

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

• Treatment: radioactive iodine, total thyroidectomy if obstructive symptoms or large

• 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

Benign neoplasms of thyroid gland

Follicular adenoma of thyroid gland• benign encapsulated tumor with

follicular differentiation• Most common thyroid neoplasm• Almost all are “cold” on

radionucleotide scan


• Usually non-functional; functional tumors may shrink after TSH administration

• May have very low malignant potential even without carcinoma present

• Almost always solitary; if multiple, diagnose as multinodular goiter with adenomatous change

Here is another follicular neoplasm (a follicular adenoma histologically) that is surrounded by a thin white capsule. It is sometimes difficult to tell a well-differentiated follicular carcinoma from a follicular adenoma. Thus, patients with follicular neoplasms are treated with subtotal thyroidectomy just to be on the safe side.

Follicular Adenoma• Gross: solitary, spherical, usually

encapsulated; bulges when fresh, compresses adjacent thyroid; resembles multinodular goiter due to hemorrhage, necrosis, fibrosis and calcification

• Micro: completely encapsulated, follicular differentiation throughout, architecturally & cytologically different from surrounding gland, surrounding thyroid tissue is compressed; may have spindle cell metaplasia

• Cytology: high cellularity, syncytial 3 dimensional arrangement, prom nuclear crowding but no papillary nuclear features, minimal colloid

Thin and uniform fibrous capsule

Normal thyroid follicles appear at the lower right. The follicular adenoma is at the center to upper left. This adenoma is a well- differentiated neoplasm because it closely resemble normal tissue. The follicles of the adenoma contain colloid, but there is greater variability in size than normal.

Microfollicles have regular nuclei and interfollicular edema

• Atypical adenoma: pleomorphism, cellularity, mitotic figures or necrosis, but without capsular or vascular invasion; typically considered to have benign behavior

notes: Markedly cellular tumor with irregular growth pattern, mild to moderate


pleomorphism; no capsular or vascular invasion

Groups that were consistently classified as microfollicular. Cases usually consisted of fewer than 15 cells arranged in a flat circle with a lumen that was at least two-thirds complete (Papanicolaou, original magnification ×1000 [A through D])

Monotonous population of follicular cells arranged in cohesive follicular groups with nuclear overlapping and crowding, case diagnosed as follicular neoplasm (1A). Histologic follow-up showing follicular adenoma (thickly encapsulated follicular patterned lesion with no capsular or vascular invasion), the inset shows the same nuclear features as seen in cytology (1B).

Notes: Positive stains: low molecular weight keratin, thyroglobulin Negative stains: CK19

Thyroid Carcinomas

Papillary thyroid carcinoma• 75-80% of thyroid carcinomas• Usually women (70%) of

reproductive age• Occult tumors in 6% at autopsy (1 to

10 mm), 46% multicentric, 14% with nodal metastases

• Occult tumors in up to 24% with other thyroid disease, but with male predominance

• Risk factors: o Ionizing radiation before age

20 (for acne, tonsillitis, tinea capitis, enlarged thymus)

o Post-Chernobyl (particularly children, or after exposure to nuclear explosions at Marshall Islands

o Hashimoto’s thyroiditis o Familial adenomatous

polyposiso Is familial in 4.5%, similar

prognosis as sporadic disease• Usu presents as painless nodule or

mass in neck or cervical node; usually cold on scan

• Usually diagnosed by FNA• At presentation, 67% in thyroid only,

13% in thyroid and cervical nodes, 20% in nodes only

• Nodal involvement is often not clinically apparent due to small size and similar consistency; nodal metastases may undergo cystic change and resemble branchial cleft cysts

• Proteomic analysis of serum may be useful in future for screening or followup

• Prognosis: 10 year survival is 98%, similar to general population (versus 92% for follicular carcinoma); 100% if under age 20, even with nodal metastases; cervical nodal involvement does NOT affect prognosis

• 5-20% have local recurrences, 10-15% have distant metastases (lung, bones, CNS)

• Poorer prognosis: age 40+ or elderly, male (possibly), local invasion (associated with higher incidence of nodal metastases, distant metastases (other sites worse than lung, large tumor size, multicentricity, tall cell, columnar or diffuse sclerosing variants; poorly differentiated, anaplastic or squamous foci; lymphatic invasion

• Other prognostic factors:o extrathyroidal extensiono history of previous irradiationo tumor sizeo capsule and marginso multicentricityo poorly differentiated,

squamous or anaplastic focio grading


o EMA and Leu-M1 positivityo DNA ploidyo Rb protein and circulating

tumor cells• Treatment: lobectomy, total

thyroidectomy for high risk tumors• Gross: solid, white, firm, often

multifocal (20%), encapsulated (10%) or infiltrative; variable cysts, fibrosis, calcification

• Micro: complex, branching, randomly oriented papillae with fibrovascular cores asso. w/ follicles; usu. dense fibrosis; papillae lined by cuboidal cells, nuclei are overlapping w/ finely dispersed optically clear chromatin; micronucleoli, eosinophilic intranuclear inclusions & nuclear longitudinal grooves; stromal elastosis in 66%; often lymphatic invasion

• Psammoma bodies: in 50% of tumors in papillary stalk in fibrous stroma between tumor cells (usually not in neoplastic follicles); due to tumor cell necrosis; fairly specific but may also be seen in metastases; resembles inspissated colloid

• Note: presence of psammoma body in neck or within cervical lymph node means papillary thyroid carcinoma must be ruled out; 75% are microscopically multifocal, often associated with tall cell variant (30%)

Bisected thyroid lobe shows papillary CA at one pole; tumor is well-circumscribed but non-encapsulated, solid, granular and bulging

This is the microscopic appearance of a papillary carcinoma of the thyroid. The fronds of tissue have thin fibrovascular cores. The fronds have an overal papillary pattern. There is no such thing as a papillary adenoma, and all papillary neoplasms of the thyroid should be considered malignant.

• Positive stains: CK19 (strong and diffuse staining) and HBME-1 recommended to differentiate from benign mimics; also CK7, high molecular weight keratin, RET, thyroglobulin (less intense than follicular neoplasms), TTF-1, S100, EMA, vimentin, estrogen receptors, c-kit (weak), alpha-1-antitrypsin (90%), p63 (82%,), thyroid peroxidase (50%), galectin-3; Bax and P-cadherin are less sensitive but more specific compared to normal thyroid; occasional CEA

• Negative stains: CK20• EM: highly indented nuclear

membrane with pseudoinclusions and multilobation; clusters of large interchromatin granules, nucleoli have microfibrillar cortex with segregation of their components; also dense RNA containing microspherules in nucleoli


A loose sheet of tumor cells showing minimal nuclear crowding and two cells with intranuclear cytoplasmic inclusions in FNA of a conventional papillary carcinoma (Diff-Quik stain, × 400).

Immunohistochemistry for CK19. A, Diffuse immunoreactivity is strong in a classical papillary carcinoma. B, Follicular variant papillary carcinoma also exhibits diffuse cytoplasmic immunoreactivity. C, A hyperplastic lesion is entirely negative for CK19.

a, HBME-1 demonstrates strong membranous and cytoplasmic staining in papillary thyroid carcinoma (original magnification ×200). b, The cytokeratin 19 stains papillary thyroid carcinoma with diffuse cytoplasmic staining. Note the adjacent compressed benign follicles also stain with cytokeratin 19, a feature that can be a pitfall

Papillary thyroid carcinoma in children• Children present with more

advanced disease than adults, but have better prognosis

• Regional nodal metastases occur in 60-80%, distant metastases in 10-20% at diagnosis, often lung

• Overall survival 100% and progression free survival is 77%, after median followup of 16 years

• Risk factors: family history, prior radiation exposure

• Tall cell morphology has no prognostic significance, in comparison with adults

• Molecular: RET rearrangements more common than adults, BRAF activation less common (20% versus 77% in adults

Variants of papillary thyroid carcinoma

Columnar cell variant of papillary carcinoma of thyroid gland

• tall cells with clear to eosinophilic cytoplasm, nuclear stratification and no/minimal papillary nuclear features

• Rare, aggressive tumor with widespread dissemination (lung, brain, bone) and fatal outcome

• Gross: usually > 6 cm• Micro: often parallel cords of

markedly elongated follicles forming tram tracks or train tracks; tall cells (at least twice as tall as wide) with clear or vacuolated cytoplasm, squamoid morules, enlarged and elongated nuclei with nuclear stratification, coarse chromatin and small nucleoli; nuclei lack polarity and are unevenly spaced within cells; prominent mitotic figures; usually no characteristic nuclear findings of papillary carcinoma; usually sparse colloid

• Cytology: moderately cellular; sheets, papillary clusters and microfollicles of columnar cells with palisading oval nuclei containing uniformly finely granular chromatin, but no classic nuclear changes of papillary thyroid carcinoma; usually no colloid

• Positive stains: cytokeratin, thyroglobulin, Ki-67

• Negative stains: calcitonin, chromogranin

Cribriform-morular variant of papillary carcinoma of thyroid gland


• cribriform growth pattern and morular formations

• Rare, 0.2% of papillary thyroid carcinoma ; associated with sporadic or germline mutations of APC gene

• Presence of tumor may suggest colon cancer screening for the patient

• Usually young women aged 16-30 years

• Similar prognosis as classic papillary carcinoma

• Micro: tumors are encapsulated or circumscribed with cribriform, solid, papillary, tall columnar and morular patterns; contains follicles without colloid, papillary formations of tall cells with abundant eosinophilic cytoplasm and pseudostratification, hyperchromatic nuclei with grooves and pseudoinclusions; morular (squamoid) metaplasia with nuclear clearing resembling viral inclusions; also spindle cells; vascular and capsular invasion common

• Cytology: papillary fragments and acini composed of columnar cells with fine to granular chromatin and nuclear grooves; also occasional groups of epithelial cells forming morules

• Positive stains: thyroglobulin, keratin, EMA; also beta catenin (nuclear and cytoplasmic staining)

• EM: numerous microfilaments approximately 100 nm long at the nuclear clearing area of the morular regions

Cribriform areas with back to back follicles and no fibrovascular stroma

Diffuse sclerosing variant of papillary carcinoma of thyroid gland

• diffuse involvement of papillary carcinoma with dense sclerosis, abundant psammoma bodies, solid

foci, squamous metaplasia, marked lymphocytes and extensive lymphatic invasion

• Rare; 1-2% of papillary thyroid carcinoma

• Often younger female patients or children who present with diffuse goiter

• Cervical nodal and lung metastases common

• Historically had poorer prognosis than usual papillary carcinoma, but similar prognosis today due to radical surgery (including nodal dissection) and radiotherapy

• Laboratory: anti-thyroglobulin and anti-thyroid peroxidase antigens common, perhaps due to destruction of normal thyroid follicles by tumor and exposure of cryptic antigens

• Micro: diffuse involvement of one or both lobes, dense sclerosis, numerous micropapillary formations within lymphatic like spaces, frequent psammoma bodies, extensive solid foci and squamous metaplasia, prominent lymphocytic infiltration

• Cytology: abundant squamous cells, lymphocytes and follicular epithelial cells with nuclear features of papillary carcinoma, occasional psammoma bodies

• Positive stains: CK 19, thyroglobulin, TTF1, S100+ dendritic cells, p53 (often)

Encapsulated variant of papillary carcinoma of thyroid gland

• papillary carcinoma totally surrounded by a capsule

• 8-13% of papillary carcinomas• Excellent prognosis; may have nodal

metastases, but only rarely angiolymphatic invasion or distant metastases

• Gross: thick capsule, resembles follicular adenoma

• Micro: nuclear changes of papillary carcinoma and psammoma bodies

• Cytology: scattered clusters of follicular cells with focal Hürthle cell changes and prominent nuclear pleomorphism, mixed with colloid


and normal appearing follicular cells; may not show classic papillary nuclear features

Encapsulated Follicular Lesion with nuclear features of Papillary Carcinoma

Follicular variant of papillary carcinoma of thyroid gland

• papillary carcinoma composed almost completely of follicles, with classic papillary nuclear features

• same prognosis as typical papillary carcinoma

• Metastases are usually nodal, not distant, with classic papillary features

• Suggested to classify encapsulated tumors separately due to their superior prognosis

• Micro: wide fibrous bands incompletely divide tumor into lobules; follicular architecture but papillary cytology; usually infiltrative with fibrous trabeculation, psammoma bodies, strongly eosinophilic colloid with scalloping

• Important diagnostic criteria include pseudoinclusions (cytoplasmic invaginations into nucleus), abundant nuclear grooves, ground glass nuclei; also nuclear clearing, nuclear overlapping and crowding, nuclear enlargement

• Cytology: increased cellularity, moderate thin watery colloid with variable eosinophilic colloid; cells are in sheets, small acini or syncytial fragments; nuclear enlargement, but may lack prominent nuclear features of papillary carcinoma; highly suggestive if syncytial clusters, microfollicular architecture, chromatin clearing and nuclear grooves

• Positive stains: Low and high molecular weight keratin

• Macrofollicular variant of papillary carcinoma of thyroid gland

• macrofollicles (large dilated follicles) >50% of cross sectional area, with papillary nuclear features

• Very rare; similar clinical features as classic papillary carcinoma (female predominant, occasional nodal metastases, few deaths)

• May have minor (<5%) insular component that does not appear to affect prognosis

Microcarcinoma variant of papillary carcinoma of thyroid gland1 cm or less (WHO); some authors use 1.5 cm or lessFormerly called occult sclerosing carcinomaMean diameter 6 mm, so fix specimen and cut thinIncidental finding in 21-36% of carefully sectioned thyroids at surgery or autopsy

Oncocytic variant of papillary carcinoma of thyroid gland

• Definition: oncocytic (oxyphilic, Hürthle cell like) cytoplasm but nuclear features of papillary carcinoma

• Up to 10% of papillary thyroid carcinomas; 80% women, ages 34-86 years

• Frequently associated with autoimmune thyroiditis

• May have similar behavior as classic papillary carcinoma

• Gross: mean 2 cm, mahogany brown

• Micro: papillary structures at least focally, may be mixed with follicular growth pattern; predominantly oncocytic cytoplasm but papillary nuclear features; may be encapsulated or invasive


Oncocytic papillary carcinoma is an accepted diagnosis when the tumour has complex papillary architecture with thin papillae that have true fibrovascular cores, and the papillae are lined predominantly or entirely by Hürthle cells.

Solid variant of papillary carcinoma of thyroid gland

• Definition: 50-70% or more solid growth pattern with papillary cytologic features, without necrosis

• Rare in adults (3% of all papillary carcinomas)

• In children, solid/trabecular variant is very common, has higher risk of relapse; also seen in post-Chernobyl cases

• Associated with slightly poorer prognosis and slightly more distant metastases than classic papillary carcinoma, but better prognosis than poorly differentiated carcinoma

• Micro: unencapsulated with invasive borders; composed of round solid nests resembling filled up follicles, surrounded by fibrous / hyaline stroma; may have vague papillary or follicular formations; nuclear features of papillary carcinoma are present

Histological sample of papillary carcinoma solid variant. Note the solid architecture of this carcinoma traversed by delicate fibrous septa that delimitates islands and sheets of neoplastic cells (H&E staining 10×)

Tall cell variant of papillary carcinoma of thyroid gland

• Definition: cells twice as tall as wide comprise 50% of tumor, have abundant eosinophilic cytoplasm and papillary nuclear features

• 4-10% of papillary thyroid carcinomas

• Usually older age• Often underdiagnosed

• Aggressive with poor prognosis due to high stage

• Distant metastases common• May have better prognosis if

coexisting lymphocytic thyroiditis• Rare breast cancer cases have

similar histology• Gross: usually large (> 6 cm) with

extrathyroidal extension• Micro: intricate, well formed, long

papillae lined by single layer of tall columnar cells (height is twice width) with sharply delineated cell borders, intensely eosinophilic, finely granular cytoplasm; nuclei are enlarged with grooves, chromatin clearing and pseudoinclusions but no nuclear stratification; often with lymphocytic thyroiditis, prominent vascular invasion, mitotic activity; no squamoid morules

• Note: tall cells should comprise >50% of tumor cells for diagnosis

• Cytology: tall cells (30% of aspirated cells) with well-defined granular eosinophilic cytoplasm, nuclei with nuclear grooves or intracytoplasmic inclusions which resemble “soap bubbles” due to multiple inclusions in same nucleus also lymphocytes

• Positive stains: thyroglobulin, vimentin, keratin, Leu-7; also CD15

Follicular carcinoma of thyroid gland• thyroid carcinoma with follicular

differentiation but no papillary nuclear features; excludes Hürthle cell and poorly differentiated carcinomas

• Historically 5-15% of thyroid carcinoma and 25-40% in iodide-deficient areas, but these data may include follicular variant of papillary carcinoma

• Usually solitary, but not occult; usually “cold” on radionuclide scan


• 75% women, older age than papillary carcinoma

• Risk factors: radiation exposure, iodine deficiency, older age; does not arise from preexisting adenomas

• Metastases: does not invade lymphatics but does spread to lungs, liver, bone, brain via veins

• Distant metastases common in grossly invasive disease: 50% if vascular and capsular invasion; 75% if local invasion and vascular or capsular invasion; metastases may pulsate because of their vascularity

• Rosai recommends classifying definitive follicular carcinomas as follows:

• Encapsulated• - with capsular invasion only• - with limited (<4 vessels) vascular

invasion• - with extensive (≥4 vessels)

vascular invasion• Widely invasive• Poor prognostic factors: distant

metastases, age > 45 years, large size, extensive vascular invasion, extrathyroidal extension, poorly differentiated or widely invasive tumors

• Treatment: T3/T4 to suppress endogenous TSH, then thyroidectomy & radioactive iodine; no need for nodal dissection since tumors don’t metastasize to LNs

• Gross: gray-tan-pink; usually single encapsulated nodule, focally hemorrhagic; variable fibrosis and calcification; large lesions may often be infiltrative

• Micro: need convincing evidence of invasion of adjacent thyroid parenchyma, capsule (complete penetration) or blood vessels (medium sized veins or larger vessels in or beyond the capsule); capsule is typically thick with calcification; common architectural patterns are follicular or solid; may have nuclear atypia, Hürthle cells, focal spindled areas, mitotic figures; usually no squamous metaplasia, no nuclear features of papillary

carcinoma, no psammoma bodies, no/rare lymphatic invasion

• Cytology: nuclear enlargement, overlapping and crowding; cannot distinguish between follicular adenoma and carcinoma by fine needle aspiration since need evidence of capsular or vascular invasion or invasion of adjacent parenchyma

Mushroom-shaped capsular invasion of Follicular Carcinoma

Microscopic features of overtly invasive follicular carcinoma. A, Broad-based invasion through the tumor capsule. B, Multifocal vascular invasion with tumor thrombi identifiable in four consecutive blood vessels within the tumor capsule (arrows). Note that despite the readily identifiable features of invasive growth, these tumors preserve overall encapsulation.

Massive vascular invasion obliterating the vascular lumen


Minimally invasive follicular carcinoma of thyroid gland

• invasion of small to medium vessels (i.e. those without a continuous muscular layer), capsular invasion of up to full thickness, no parenchymal tumor extension, no tumor necrosis, excludes Hürthle cell tumors

• Overall very good prognosis • Metastases occur in 1% with

capsular invasion only compared to 5% with blood vessel invasion

• Gross: well encapsulated solid and fleshy tumor; capsule is usually thicker and more irregular than adenoma

• Micro: encapsulated with thicker and more irregular capsule than adenoma, invasion of adjacent tissue or CD31+ vessels of venous caliber in or immediately outside the capsule (not within the tumor), with tumor clusters attached to the wall or protruding into the lumen;

• capsular invasion must be full thickness, tumor then expands in a mushroom-like fashion into adjacent area; may have additional “capsules” in the advancing tumor edge; growth pattern resembles embryonal, fetal or atypical adenoma; often hemorrhage, necrosis, infarction or significant mitotic activity

Histologic mimics of vascular invasion include (A) artifactual tumor within an ectatic vessel, (B) papillary endothelial hyperplasia, and (C) retraction artifacts mimicking an endothelial-lined space (hematoxylin-eosin, original magnifications ×400)

Hürthle cell (oncocytic) tumors of thyroid gland

• follicular neoplasm in which 75% or more of follicular cells have oncocytic features and no chronic thyroiditis is present

• Hürthle cells / oncocytes by themselves are nonspecific, and are seen in Hashimoto’s thyroiditis and other neoplasms

• Usually adult women• Tend to infarct after fine needle

aspiration• Size is predictive; 2 cm or less -

almost always adenoma; 6 cm or more - almost always carcinoma (World J Surg 2008;32:702 )

• Carcinomas have 5 year survival of 60-80%, with metastases to lung, bone and regional lymph nodes

• Malignant if capsular or vascular invasion

• Poorer prognosis if higher N/C ratio, small cell pattern, p53+/bcl2-; also metastatic lymph nodes or other metastases, high stage

• Treatment: adenomas are cured with excision

• Gross: solid, tan, encapsulated, lobulated, well vascularized; invasion into adjacent tissue not apparent

• Micro: at least 75% of follicular cells are oncocytic with large size, distinct cell borders, deeply eosinophilic and granular cytoplasm, large nucleus with prominent nucleolus; follicular, trabecular, solid or papillary growth patterns; large follicles have adjacent fibrovascular septa that resemble papillae when cut tangentially; may have inspissated intraluminal colloid with concentric laminations that resemble psammoma bodies, usually in lumina; nuclear atypia common but not anaplasia

• Rarely has Kaposi-like endothelial proliferation with spindle cells containing plump nuclei and focal nesting pattern, focal red blood cell extravasation, but no mitotic figures;


http://www.ncbi.nlm.nih.gov/pubmed/18224463



spindle cells positive for CD31 and factor VIII, negative for keratin and thyroglobulin

• Cytology: highly cellular, 75% or more Hurthle cells, often discohesive cells, some enlarged & pleomorphic w/ intracytoplasmic lumina, no/rare colloid, lymphos, histiocytes,plasma cells or ordinary follicular cells; cannot definitively diagnosed malignancy based on cytologic material

• Cytology: highly cellular, 75% or more Hürthle cells (abundant granular cytoplasm, round nuclei, often prominent nucleoli), often discohesive cells, some enlarged and pleomorphic with intracytoplasmic lumina (empty vacuoles with magenta [Diff-Quik] or green [Pap] or no material; also transgressing vessels (capillaries in clusters of Hürthle cells, Arch Pathol Lab Med 2001;125:1031); no/rare colloid, lymphocytes, histiocytes, plasma cells or ordinary follicular cells; cannot definitively diagnose malignancy based on cytologic material (Am J Clin Pathol 1993;100:231, Acta Cytol 2008;52:659) but malignant cases tend to have small or large cell dysplasia, nuclear crowding and discohesive cells (Diagn Cytopathol 2008;36:149 ); metastatic tumors may have bland cytologic features

Focal papillary formations lined by columnar oncocytic epithelium with apical nuclei

Insular carcinoma of thyroid gland• diffuse insular (island like) growth

pattern; some authors include solid or trabecular growth patterns

• Also called poorly differentiated carcinoma

• Older patients, more common in Europe and South America than US

• May be a poorly differentiated form of papillary or follicular carcinoma

• Intermediate behavior between well differentiated and anaplastic carcinoma; has nodal and hematogenous metastases and 3 year survival of 38%

• Tumors with >50% poorly differentiated component have poorer prognosis than <50%

• Gross: large, gray-white, extensive necrosis, invasive

• Micro: Turin consensus diagnostic criteria: (1) solid / trabecular / insular growth pattern, (2) no nuclear features of papillary carcinoma, (3) presence of at least one of following: convoluted nuclei, 3+ mitotic figures/10 HPF, tumor necrosis

• other: pleomorphic tumor cells without any organoid (follicle-related) arrangement; may have small globoid cells with uniform nuclei and intracytoplasmic thyroglobulin deposits resembling primordial fetal thyroid cells; may have peritheliomatous pattern (tumor cells around blood vessels with necrosis of tumor cells further away from vessels), vascular and capsular invasion; better differentiated tumor may also be present; often artifactual clefts between nests of cells

• Cytology: highly cellular with cell clusters or trabeculae that may merge with follicular areas, often associated with microfollicles; necrotic background, scant colloid; cells have poorly defined cytoplasm and cytoplasmic vacuoles, mild atypia with hyperchromatic nuclei

• Positive stains: thyroglobulin, TTF-1; also bcl2 and p53 (in areas of active infiltrating growth

• Negative stains: calcitonin

Medullary carcinoma of thyroid gland• neuroendocrine tumor derived from

C cells (formerly called parafollicular


















cells) of ultimobranchial body of neural crest, which secrete calcitonin

• 5-10% of thyroid carcinomas• Either sporadic (nonhereditary) or

hereditary (familial)• Sporadic: 75-80%, age 40-60 years,

solitary, usually have paraneoplastic syndromes (diarrhea from VIP, Cushing’s syndrome), dysphagia and hoarseness from tumor bulk

• Familial: 20-25%, younger patients (mean age 35 years); due to MEN 2A or 2B syndromes, familial medullary thyroid carcinoma syndrome, von Hippel-Lindau disease or neurofibromatosis; usually bilateral, multicentric with C cell hyperplasia; usually discovered by screening test for serum calcitonin or peripheral blood RET oncogene mutational analysis

• MEN 2: due to germ line mutations in RET proto-oncogene

• Clinical: invades locally, metastases to cervical and mediastinal nodes, lung, liver and bone; metastases may be initial presentation of disease and usually contain amyloid

• 5 year survival: 86%• Poor prognostic factors: high

stage; also older age, cervical nodal metastases, male, sporadic forms, high mitotic activity, small cell type; somatic RET mutation, possibly frequency of allelic loss in tumor suppressor genes

• Favorable prognostic factors: young age, female, familial forms, microcarcinoma

• Laboratory: high serum calcitonin and chromogranin A levels; can monitor for recurrence with calcitonin levels; only rarely negative for serum calcitonin

• Treatment: total thyroidectomy (particularly for familial forms) with cervical lymphadenectomy for node positive patients

• Treatment: total thyroidectomy (particularly for familial forms) with cervical lymphadenectomy for node positive patients

• Gross: single or multiple; typically nonencapsulated; solid, gray-tan-

yellow, firm, may be infiltrative; larger lesions have hemorrhage and necrosis, tumor usually in mid or upper portion of gland (with higher concentration of C cells)

• Micro: round, polygonal or spindle cells in nests, cords or follicles, defined by sharply outlined fibrous bands; tumor cells have granular cytoplasm and uniform round/oval nuclei with punctate chromatin; stroma has amyloid deposits from calcitonin, prominent vascularity with glomeruloid configuration or long cords of vessels, coarse calcifications; mucin in 42% ;often angiolymphatic invasion; occasionally marked neutrophilic infiltrate, oncocytic tumor cells, papillary patterns; may entrap follicles; C cell hyperplasia present in familial but not sporadic cases

• Cytology: highly cellular, syncytial arrangement of plasmacytoid (eccentric nuclei, uni- or binucleated), spindle and polygonal cells, cells have abundant cytoplasm, occasionally pink azurophilic granules and intranuclear inclusions, amyloid present occasionally

Medullary Carcinoma – Infiltrative solid tumor nodules forming cysts

• Positive stains: calcitonin (include percentage of cells staining in pathology report), Congo-Red for amyloid; also calcitonin gene related peptide, CEA, low molecular weight keratin, chromogranin A and B, synaptophysin, neuron specific enolase, TTF1, progesterone receptors

• Note: immunocytochemistry for calcitonin; CEA and thyroglobulin is useful with thin layer cytology

• , estrogen receptors


• EM: single membrane-bound electron dense granules in cytoplasm

Mucoepidermoid carcinoma of thyroid gland

• low grade neoplasm with squamous change and mucin production, usually negative staining for thyroglobulin

• Rare, affects all ages, female predominance

• May represent papillary carcinoma with extreme squamous and mucinous metaplasia

• May arise from thyroid follicular epithelium based on molecular studies or from solid cell nests based on ciliated epithelium

• Good prognosis; may metastasize to regional lymph nodes, but only rare distant metastases or death

• Gross: partially circumscribed, soft• Micro: low grade tumor with

squamoid change and mucin production; resembles salivary gland tumors with mucin containing cysts and solid squamoid epithelial nests; also intracytoplasmic mucin; may have associated foci of papillary carcinoma, eosinophils, ciliated epithelium, lymphocytic thyroiditis

• Positive stains: cytokeratin, CAM5.2, CEA (polyclonal), intracytoplasmic mucin stains with Alcian blue and mucicarmine

• Negative stains: calcitonin, chromogranin, thyroglobulin (usually)

• Molecular: may have t(11;19) and CRTC1/MAML2 fusion transcript and have common origin with Warthin’s tumor

Squamous cell carcinoma of thyroid gland

• Very rare, <100 cases reported• Affects older patients with chronic

goiter, usually rapidly enlarging neck mass

• Usually part of an anaplastic carcinoma

• Must rule out the more common secondary involvement from laryngeal or tracheal primary or lung

metastasis; metastases usually present as multiple nodules

• May derive from squamous cells of thyroglossal duct or branchial pouch remnants or squamous metaplasia in Hashimoto’s thyroiditis or papillary carcinoma

• Associated with classic and tall cell variants of papillary carcinoma (

• Extrathyroidal extension and cervical nodal metastases are common, distant metastases are rare

• Poor prognosis with median survival < 6 months; death in almost all cases, usually due to local progression or airway compression

• Treatment: aggressive surgery and radiation

• Gross: firm, large areas of necrosis • Micro: islands of squamous cells in

various states of differentiation with intercellular bridges; multinucleated tumor cells common

• Positive stains: keratin (100%), particularly CK7 & CK19, thyroglobulin (63%), TTF1 (38%); increased p53, M1B1

• Negative stains: CK20, calcitonin

Anaplastic carcinoma of thyroid gland• undifferentiated (high grade)

carcinoma of thyroid gland• Also called undifferentiated

carcinoma, carcinosarcoma, sarcomatoid carcinoma

• 2% of thyroid cancers but 40% of thyroid cancer deaths

• Mean age 65 years, 75% in women• 50% have prior multinodular goiter,

20% have prior differentiated carcinoma, 20% have concurrent differentiated carcinoma

• Probably arises as anaplastic transformation of papillary, follicular or Hürthle cell carcinoma; most cases have a core of conserved mutations in well differentiated and anaplastic areas, plus increases in mutation rates in anaplastic areas

• Rapidly enlarging, bulky neck mass invades adjacent structures causing hoarseness, dysphagia, dyspnea

• Most thyroid sarcoma-like tumors are probably anaplastic carcinomas;


small cell types reported in past were probably lymphoma or variants of medullary or insular carcinoma

• Treatment: resistant to all treatments, death usually within 1 year (mean survival 6 months); <10% survive at least 2 years

• Gross: large solid tumor with necrosis and hemorrhage that invades adjacent structures

• Micro: three patterns:• 1) large, pleomorphic giant cells

resembling osteoclasts with cellular connective tissue septae, may have cavernous blood filled sinuses resembling aneurysmal bone cyst

• 2) spindle cells resembling sarcoma• 3) squamoid cells that are relatively

undifferentiated but also appear epithelial with occasional focal keratinization

• These patterns are often mixed with better differentiated cells palisading at necrotic edges and with precursor well differentiated carcinoma; necrosis, vascular invasion and mitotic figures are common; rarely has rhabdoid inclusions

Microscopic appearance of anaplastic thyroid carcinoma is highly variable. Frequently encountered patterns include squamoid (a), giant cell (b), and spindle cell (c).

• Cytology: giant cell subtype, large bizarre cells w/ prom nucleoli; spindle cell type has spindled cells w/ necrotic debris

• Positive stains: keratin (not in sarcomatoid variants), vimentin (spindle cell component); p53 (well-differentiated tumor usually p53 negative); CD68 (osteoclast-like cells), increased Ki-67 and PCNA; also Pax8 (79%,; variable EMA and CEA

• Negative stains: usually thyroglobulin, TTF-1, bcl2, calcitonin, desmin, muscle specific actin

• EM: no junctional complexes or obvious epithelial elements in osteoclast-like giant cells

CASTLE of thyroid gland• CArcinoma Showing Thymus-Like

differentiation• Also called intrathyroidal epithelial

lymphoma, intrathyroidal thymoma, lymphoepithelial-like carcinoma

• Terminology first used in 1991• Rare; resembles ectopic thymic

carcinoma• Mean age 51 years• May originate from ectopic thymic

tissue or branchial pouch remnants (solid cell nests)

• Good prognosis, with 5-year survival of 82%; poorer prognosis if nodal metastases or tumor extension

• Treatment: total thyroidectomy with neck dissection and radiation

• Micro: lobular architecture with fibrous bands separating solid islands of squamoid or spindled epithelial cells with whorls resembling Hassall’s corpuscles, variable lymphocytes (usually T cells); tumor cells have ill defined cytoplasm with eosinophilic or amphophilic cytoplasm, round/oval vesicular nuclei and prominent nucleoli

• Cytology: resembles nasopharyngeal carcinoma

• Positive stains (similar to thymic carcinoma): keratin (high molecular weight), CD5, bcl2, p63, CEA

• Negative stains: EBV, thyroglobulin, TTF1, calcitonin, amyloid

SETTLE of thyroid gland• Spindle Epithelial Tumor with

Thymus-Like Differentiation• Rare (<25 cases reported), initially

indolent tumor of neck in young patients (median age 15 years), with thymic or branchial pouch differentiation and delayed (after 5


years) metastases to lymph nodes or lungs

• Gross: circumscribed, whorled appearance

• Micro: invasive, highly cellular tumor with sclerotic bands (thick and thin); biphasic with bland spindle cells in fascicles and tubulopapillary epithelial structures or mucinous glands; may have foci of squamous differentiation resembling Hassall’s corpuscles; rare mitotic activity or focal necrosis

• Cytology: tumor with minimal epithelial component was moderately cellular with single and loosely grouped spindle cells in homogeneous metachromatic material resembling amyloid

• Positive stains: keratin (strongest for high molecular weight keratin, stains spindled and epithelioid cells), vimentin (focal), alpha smooth muscle actin, muscle specific actin

• Negative stains: CD3, CD5, CD20, TdT, EMA, calcitonin, desmin, thyroglobulin, S100

Well differentiated carcinoma, NOS of thyroid gland

• follicular growth, definite capsular or vascular invasion, focal or poorly developed papillary nuclear features

• Terminology proposed by Chernobyl pathologists

• Malignant, but cannot distinguish between papillary and follicular carcinoma

• well differentiated tumor with incomplete or equivocal features of papillary thyroid carcinoma, and no or equivocal capsular or vascular invasion

• Borderline lesions whose behavior cannot be predicted, but will likely be benign

• Recommended to rely on morphologic criteria, not on immunostains

• Terminology proposed by Chernobyl pathologists

• Micro: well differentiated tumor with incomplete or equivocal features of papillary thyroid carcinoma, and no

or equivocal capsular or vascular invasion

Other malignancies of thyroid gland

Lymphoma of thyroid gland• 1-5% of thyroid tumors• 75% women, usually adults or elderly• Rapidly enlarging mass that may

compress trachea or larynx• Usually cold nodule on scan• Primary tumors often arise in

background of lymphocytic or Hashimoto’s thyroiditis after 20-30 years (particularly MALT lymphomas), sequence similarity in clonal IgH bands suggests lymphoma may arise from thyroiditis

• Secondary involvement seen in 20% dying of generalized lymphoma, although usually does not produce clinical hypothyroidism

• Usually B cell origin; most common subtype is diffuse large B cell lymphoma; also marginal zone B cell/MALT lymphoma and mixtures of these two; rarely follicular cell lymphoma, although many marginal zone lymphomas colonize reactive follicles

• May be misdiagnosed as undifferentiated carcinoma

• Hong Kong / Chinese cases are only rarely EBV+

• Staging (Musshoff’s modification of Ann Arbor system):

• IE-negative nodes• 2E-nodal involvement on same side

of diaphragm• 3E-nodal involvement on opposite

sides of diaphragm or spleen• IV-dissemination to extranodal sites• Overall 5 year survival is 80%• Poor prognostic factors: diffuse B

cell lymphoma subtype, perithyroidal soft tissue invasion, stage 2E or higher

• Good prognostic factors: marginal zone lymphoma subtype or stage IE

• Treatment: often curable by radiation or chemotherapy, in contrast to anaplastic carcinoma; surgery is now rare


• Gross: white cut surface with fish-flesh appearance

• Micro: specific features of lymphoma subtype; infiltration of thyroid epithelium creates lymphoepithelial lesions (lymphocytes “stuff” glandular lumina, most patients have background lymphocytic thyroiditis

• Cytology: may be misdiagnosed as lymphocytic thyroiditis; monotonous population of large atypical lymphoid cells (scant cytoplasm, finely granular chromatin, prominent nucleoli), lymphoglandular bodies present (cytoplasmic fragmentation), karyorrhexis

• Positive stains: CD20 and keratin highlight lymphoepithelial lesions; thyroglobulin stains entrapped follicular epithelium; also CD45

• Cytogenetics: t(11;18) is not present in thyroid MALT lymphomas

Cut surface of a Diffuse large cell lymphoma of the thyroid

Diffuse Large Cell LymphomaTumor cells grow between non-neoplastic follicles, some of w/c show packing of lumina by tumor cells

Hodgkin’s lymphoma of thyroid gland• Rare; usually females, usually

nodular sclerosing subtype• May present as solitary thyroid

nodule• Favorable outcome• Cytology: some atypical cells, may

have marked fibrosisTeratoma of thyroid gland

• Usually congenital, associated with polyhydramnios

• May be painful due to enlarging cysts; may become huge and obstruct airway

• Benign in children, malignant in adults

• Gross: median 7 cm, often cystic• Micro: primarily neuroglial tissue,

also mixture of thyroid and other tissues with pseudocapsule; in adults, may have primitive neuroepithelial component with rosettes, well differentiated cartilage

TNM Staging of carcinomas of thyroid gland

• Clinical staging: based on inspection / palpation of thyroid gland and regional lymph nodes; indirect laryngoscopy is performed to evaluate vocal cord motion; other imaging procedures without iodine contrast may be useful (iodine contrast delays use of I-131 for treatment)

• Preoperative ultrasound recommended for papillary thyroid carcinoma

• Pathologic staging: based on all information used for clinical staging plus histologic examination plus surgeon’s description of gross unresected residual tumor

• AJCC 6th edition for staging has better predictive value than AJCC 5th edition

Primary tumor (T) of thyroid gland Categories may be subdivided as solitary tumor (s) or multifocal tumor (m); the largest determines the classification TX: Primary tumor cannot be assessedT0: No evidence of primary tumorT1: Limited to thyroid, 2 cm or less in greatest dimensionT1a: Limited to thyroid, 1 cm or lessT1b: Limited to thyroid, more than 1 cm but not more than 2 cmT2: Limited to thyroid, greater than 2 cm, but not more than 4 cmT3: Limited to thyroid and > 4 cm OR any tumor with minimal extrathyroid extension


(e.g. extension to sternothyroid muscle or perithyroid soft tissues)T4a: Moderately advanced diseaseTumor of any size extending beyond the thyroid capsule to invade subcutaneous soft tissues, larynx, trachea, esophagus or recurrent laryngeal nerveT4b: Very advanced diseaseTumor invades prevertebral fascia or encases carotid artery or mediastinal vessels Anaplastic carcinoma - all are considered T4 tumorsT4a: Intrathyroidal anaplastic carcinomaT4b: Anaplastic carcinoma with gross extrathyroid extension

Regional lymph nodes (N) of thyroid gland NX: Regional lymph nodes cannot be assessedN0: No regional lymph node metastasisN1: Regional lymph node metastasisN1a: Metastasis to Level VI (pretracheal, paratracheal and prelaryngeal/Delphian lymph nodes)N1b: Metastasis to unilateral, bilateral or contralateral cervical (Levels I, II, III, IV or V) or retropharyngeal or superior mediastinal lymph nodes (Level VII) Notes:Selective neck dissection usually includes 6+ lymph nodesRadical or modified radical neck dissection includes 10+ lymph nodesRegional lymph nodes are the central compartment, lateral cervical and upper mediastinal lymph nodes Distant metastasis (M) of thyroid glandM0: No distant metastasisM1: Distant metastasis

Stage grouping of thyroid glandStage groups are based on histologic type and age:Papillary or follicular:

Under 45 years

45 years or older

Stage I Any T any N M0

T1 N0 M0

Stage II Any T any N M1

T2 N0 M0

Stage III T3 N0 M0 or T1-3 N1a M0

Stage IVA T4a N0-1a M0 or T1-4a N1b M0

Stage IVB T4b any N M0Stage IVC Any T any N

M1

Medullary carcinomaStage I T1 N0 M0Stage II T2-3 N0 M0Stage III T1-3 N1a M0Stage IVA T4a N0-1a M0 or T1-4a N1b M0Stage IVB T4b any N M0Stage IVC Any T any N M1 Anaplastic carcinoma - all cases are Stage IVStage IVA T4a any N M0Stage IVB T4b any N M0Stage IVC Any T any N M1

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