THYROID GLAND

Dr. Silva
Surgical 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
Surgical Pathology

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
Page 1 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 nodule
o Solitary colloid nodule
o Prominent nodule in MNG
o 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 Hrthle cells
2. Cellular microfollicular lesion
o Microfollicular adenoma
o Low-grade follicular carcinoma
o Hyperplastic microfollicular
lesions in HT or MNG
*Notes: 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
Surgical Pathology

25% with diagnosis of suggestive of

follicular neoplasm have malignancy at
excision
3. Hurthle cell lesion
o Hurthle cell adenoma
o Hurthle cell carcinoma
o Hyperplastic Hurthle cell nodule
in HT or MNG
*Notes: 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 Hrthle
(oncocytic) cells and abundant naked tumor
cell nuclei are suggestive of Hrthle cell
carcinoma
4. Primary malignant tumor
o Papillary carcinoma
o High-grade microfollicular
carcinoma
o Insular carcinoma
o Medullary carcinoma
o Anaplastic carcinoma
o Lymphoma
5. Cystic lesions
o Benign colloid nodule
o Papillary carcinoma
o 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. Thyroiditis
o Acute thyroiditis
o Hashimoto thyroiditis
o Subacute thyroiditis
7. Other lesions
- Graves disease
- Metastatic cancer
8. Non-diagnostic category
* HT, Hashimoto thyroiditis; MNG,
Page 2 of 24

multinodular colloid goiter

Other classification groupings for
cytology of thyroid gland
Probably benign: colloid, histiocytes,
normal looking follicular cells; nondiagnostic cases with no Hrthle 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

Surgical Pathology

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
Page 3 of 24

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
Surgical Pathology

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 viruses
DD: 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,
Hashimotos thyroiditis, and most
forms of thyroiditis in this section
except infectious
Rosai differentiates based on
follicular epithelium: lymphocytic
thyroiditis if relatively normal
follicles, Hashimotos thyroiditis if
oncocytic change, Graves disease if
diffusely hyperplastic follicles
Children often present with
asymptomatic goiter of short
duration
Page 4 of 24

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

Hashimotos 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, Sjgrens 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 antiTSH; antithyroglobulin;
antithyroid peroxidase
Treatment: often no tx needed,
thyroid hormone for hypothyroidism;
Surgical Pathology

subtotal thyroidectomy to relieve

mass effect
Notes: Laboratory: autoantibodies include
anti-TSH (specific for Hashimotos and
Graves disease); anti-thyroglobulin (less
sensitive but similar specificity as antithyroid 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 Hashimotos 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 Hrthle
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,
Page 5 of 24

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 cells
EM: oncocytic cells have many large
mitochondria, reduced numbers of other
organelles
Subacute thyroiditis
inflammation of thyroid gland that
includes granulomas
Also called de Quervains thyroiditis
or granulomatous thyroiditis
Rare, much less common than
Hashimotos 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
Surgical Pathology

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.

Page 6 of 24

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 light
Negative 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,
Basedows disease (in Europe)
Surgical Pathology

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. longacting); 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 Hashimotos 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 doesnt fill the
Page 7 of 24

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

#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

Histopathological image of diffuse

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

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

Toxic multinodular goiter

multinodular goiter plus
hyperthyroidism (toxic)
Also called Plummers disease
(particularly if single nodule)
Surgical Pathology

Page 8 of 24

Here is another follicular neoplasm (a

follicular adenoma histologically) that is
surrounded by a thin white capsule. It is
sometimes difficult to tell a welldifferentiated 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

Normal thyroid follicles appear at the lower

right. The follicular adenoma is at the
center to upper left. This adenoma is a welldifferentiated 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
Thin and uniform fibrous capsule

Groups that were consistently classified as

microfollicular. Cases usually consisted of
Surgical Pathology

Page 9 of 24

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 Hashimotos thyroiditis
o Familial adenomatous
polyposis
o Is familial in 4.5%, similar
prognosis as sporadic disease

Surgical Pathology

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, 1015% 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 extension
o history of previous irradiation
o tumor size
o capsule and margins
o multicentricity
o poorly differentiated,
squamous or anaplastic foci
o grading
o EMA and Leu-M1 positivity
o DNA ploidy
o Rb protein and circulating
tumor cells
Treatment: lobectomy, total
thyroidectomy for high risk tumors
Gross: solid, white, firm, often
multifocal (20%), encapsulated
Page 10 of 24

(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%)

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, ckit (weak), alpha-1-antitrypsin (90%),
p63 (82%,), thyroid peroxidase
(50%), galectin-3; Bax and Pcadherin 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

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
Surgical Pathology

A loose sheet of tumor cells showing

minimal nuclear crowding and two cells with
intranuclear cytoplasmic inclusions in FNA
of a conventional papillary carcinoma (DiffQuik stain, 400).

Page 11 of 24

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 1020% 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

Surgical Pathology

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
Page 12 of 24

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
Surgical Pathology

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 Hrthle 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

Page 13 of 24

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
Surgical Pathology

Microcarcinoma variant of papillary

carcinoma of thyroid gland
1 cm or less (WHO); some authors use 1.5
cm or less
Formerly called occult sclerosing carcinoma
Mean diameter 6 mm, so fix specimen and
cut thin
Incidental finding in 21-36% of carefully
sectioned thyroids at surgery or autopsy
Oncocytic variant of papillary
carcinoma of thyroid gland
Definition: oncocytic (oxyphilic,
Hrthle 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 Hrthle 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
Page 14 of 24

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
Surgical Pathology

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 Hrthle
cell and poorly differentiated
carcinomas
Historically 5-15% of thyroid
carcinoma and 25-40% in iodidedeficient 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
Page 15 of 24

- 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 dont 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, Hrthle 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

Surgical Pathology

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 Hrthle 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
Page 16 of 24

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)

Hrthle 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
Hrthle cells / oncocytes by
themselves are nonspecific, and are
seen in Hashimotos thyroiditis and
other neoplasms
Usually adult women
Tend to infarct after fine needle
aspiration
Surgical Pathology

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;
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 Hrthle cells (abundant
granular cytoplasm, round nuclei,
often prominent nucleoli), often
Page 17 of 24

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
Hrthle 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,

Surgical Pathology

(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 (folliclerelated) 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, TTF1; 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,
Cushings 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
Page 18 of 24

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-tanyellow, 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

Surgical Pathology

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
Page 19 of 24

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 Warthins
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
Hashimotos 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
Surgical Pathology

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 Hrthle 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
Page 20 of 24

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 (welldifferentiated 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)
Surgical Pathology

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 Hassalls 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 Hassalls
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,
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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
Hashimotos 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,
Surgical Pathology

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 (Musshoffs 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 fishflesh 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
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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 Lymphoma

Tumor cells grow between non-neoplastic
follicles, some of w/c show packing of
lumina by tumor cells
Hodgkins 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 fibrosis
Teratoma 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
Surgical Pathology

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
surgeons 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 assessed
T0: No evidence of primary tumor
T1: Limited to thyroid, 2 cm or less in
greatest dimension
T1a: Limited to thyroid, 1 cm or less
T1b: Limited to thyroid, more than 1 cm
but not more than 2 cm
T2: Limited to thyroid, greater than 2 cm,
but not more than 4 cm
T3: 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 disease
Tumor of any size extending beyond the
thyroid capsule to invade subcutaneous soft
tissues, larynx, trachea, esophagus or
recurrent laryngeal nerve
T4b: Very advanced disease
Tumor invades prevertebral fascia or
encases carotid artery or mediastinal
vessels
Anaplastic carcinoma - all are considered
T4 tumors
T4a: Intrathyroidal anaplastic carcinoma
T4b: Anaplastic carcinoma with gross
extrathyroid extension
Regional lymph nodes (N) of thyroid
gland
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NX: Regional lymph nodes cannot be

assessed
N0: No regional lymph node metastasis
N1: Regional lymph node metastasis
N1a: 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)

Anaplastic carcinoma - all cases are

Stage IV
Stage IVA
T4a any N M0
Stage IVB
T4b any N M0
Stage IVC
Any T any N M1
__END__

Notes:
Selective neck dissection usually includes
6+ lymph nodes
Radical or modified radical neck dissection
includes 10+ lymph nodes
Regional lymph nodes are the central
compartment, lateral cervical and upper
mediastinal lymph nodes
Distant metastasis (M) of thyroid gland
M0: No distant metastasis
M1: Distant metastasis
Stage grouping of thyroid gland
Stage groups are based on histologic type
and age:
Papillary or follicular:

Stage I
Stage II

Under 45
years
Any T any N
M0
Any T any N
M1

Stage III
Stage IVA
Stage IVB
Stage IVC

45 years or
older
T1 N0 M0
T2 N0 M0
T3 N0 M0 or
T1-3 N1a M0
T4a N0-1a M0
or T1-4a N1b
M0
T4b any N M0
Any T any N
M1

Medullary carcinoma
Stage I
T1 N0 M0
Stage II
T2-3 N0 M0
Stage III
T1-3 N1a M0
Stage IVA
T4a N0-1a M0 or T1-4a N1b
M0
Stage IVB
T4b any N M0
Stage IVC
Any T any N M1
Surgical Pathology

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